Higher Fibroblast Growth Factor 23 Research Articles

Tumor-induced Osteomalacia Secondary to Phosphaturic Mesenchymal Tumor.

HomeRadiology: Imaging CancerVol. 5, No. 2 PreviousNext Images in CancerFree AccessTumor-induced Osteomalacia Secondary to Phosphaturic Mesenchymal TumorAmit Agarwal , Girish Bathla, Vivek GuptaAmit Agarwal , Girish Bathla, Vivek GuptaAuthor AffiliationsFrom the Departments of Radiology (A.A.) and Neuroradiology (V.G.), Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224; and Department of Radiology, Mayo Clinic, Rochester, Minn (G.B.).Address correspondence to A.A. (email: [email protected]).Amit Agarwal Girish BathlaVivek GuptaPublished Online:Mar 10 2023https://doi.org/10.1148/rycan.220170MoreSectionsPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked In Tumor-induced osteomalacia (TIO), or oncogenic osteomalacia, is an uncommon paraneoplastic syndrome characterized by urinary phosphate wasting due to an increased production of fibroblast growth factor 23 (FGF23), secondary to an underlying phosphaturic mesenchymal tumor (PMT). Patients usually present with bone pain and pathologic fractures caused by hypophosphatemic hyperphosphaturic osteomalacia (Fig 1), characterized by high serum FGF23 levels (Fig 2) and low serum calcitriol levels. Given the rarity of this entity and nonspecific clinical and imaging features, these tumors are challenging to diagnose and can go undetected for many years (1). Tumors can be found in any osseous or soft-tissue location, however, and are typically observed in the extremities, most commonly the femur, of middle-aged adults. TIO is also associated with other mesenchymal tumors, including solitary fibrous tumors and giant cell tumors, primarily due to FGF23 secretion. A combination of nuclear scans using somatostatin analogs, such as gallium-68 tetraazacyclododecane tetraacetic acid octreotate (68Ga-DOTATATE) and indium-111 (111In)-pentetreotide (OctreoScan), provides the highest sensitivity for detecting tumors, which are usually small in size and not evident at clinical examination. These lesions appear to be moderately fluorodeoxyglucose avid, potentially aiding in diagnosis, but have wide variability in uptake and limited specificity. CT and MRI are noncontributory for initial location but are usually needed later to evaluate anatomic extent. Surgical resection of PMTs is typically curative, resulting in complete resolution of the syndrome (2,3). While few cases of PMT have been reported, it is important to consider this diagnosis in all patients with hypophosphatemic osteomalacia.Figure 1: (A) Methylene diphosphonate bone scan in a 65-year-old female patient with bone pain reveals multiple foci of increased uptake (arrowheads) over bilateral femur and sternum, along with prominent costochondral beadings (rosary), suggesting metabolic bone disease (osteomalacia). Serologic workup revealed a high serum fibroblast growth factor 23 (FGF23) level of 1155 reference unit (RU)/mL (reference range, ≤180 RU/mL) with low serum phosphate level and elevated alkaline phosphatase level. (B) Coronal noncontrast CT image of the lumbar spine reveals a lytic lesion in the right transverse process of L3 (arrow) with (C) increased fluorodeoxyglucose uptake (standardized uptake value, 9.8) (arrow) on the axial PET/CT image.Figure 1:Download as PowerPointOpen in Image Viewer Figure 2: Histopathologic features of phosphaturic mesenchymal tumors, with predominantly spindled cells on hematoxylin-eosin (H&E) stains and strong expression of fibroblast growth factor 23 (FGF-23) mRNA on in situ hybridization (ISH).Figure 2:Download as PowerPointOpen in Image Viewer Disclosures of conflicts of interest: A.A. Consulted for and expert testimony for Authnetic4D in 2020; institutional CME fund (attending meetings/travel); stocks in Gilead Pharma. G.B. Grant from Foundation of Sarcoidosis Research, unrelated to current work. V.G. No relevant relationships.Keywords: Osteomalacia, Phosphaturic, Spine, Tumor MicroenvironmentAuthors declared no funding for this work.

High Plasma Levels of Fibroblast Growth Factor 23 Are Associated with Increased Risk of COVID-19 in End-Stage Renal Disease Patients on Hemodialysis: Results of a Prospective Cohort.

We performed a prospective cohort of ESRD patients in hemodialysis who had measurements of plasma intact FGF23 in 2019. We determined COVID-19 infections, hospitalizations, and mortality between January 2020 and December 2021. We evaluated 243 patients. Age: 60.4 ± 10.8 years. Female: 120 (49.3%), diabetes: 110 (45.2%). During follow-up, 45 patients developed COVID-19 (18.5%), 35 patients were hospitalized, and 12 patients died (mortality rate: 26.6%). We found that patients with higher FGF23 levels (defined as equal or above median) had a higher rate of SARS-CoV-2 infection versus those with lower levels (18.8% versus 9.9%; Hazard ratio: 1.92 [1.03-3.56], p = 0.039). Multivariate analysis showed that increased plasma FGF23 was independently associated with SARS-CoV-2 infection and severe COVID-19. Our results suggest that high plasma FGF23 levels are a risk factor for developing COVID-19 in ESRD patients. These data support the potential immunosuppressive effects of high circulating FGF23 as a factor implicated in the association with worse clinical outcomes. Further data are needed to confirm this hypothesis.

Correlation of FGF-23 With Biochemical Markers and Bone Density in Chronic Kidney Disease-Bone Mineral Density Disorder.

Aim The purpose of this study was to determine the relationship between biochemical markers such as serum calcium (Ca), phosphorus (P), intact parathyroid hormone (iPTH), 25(OH) vitamin D, and fibroblast growth factor 23 (FGF23) in our study group, as well as to correlate dual-energy X-ray absorptiometry (DEXA) findings with these biochemical markers. Methodology An eligible group of 50 chronic hemodialysis (HD) patients, age 18 and older, who have undergone HD two times a week for at least six months participated inthis retrospective cross-sectional study. We compared serum FGF23, intact parathyroid hormone (iPTH), 25(OH) vitamin D, calcium, phosphorus, and dual-energy X-ray absorptiometry scan showing bone mineral density disorder (BMD) around the femoral neck, distal radius, and lumbar spine. Human FGF23 Enzyme Linked Immuno Sorbent Assay (ELISA) Kit PicoKine®(Catalog # EK0759; Boster Biological Technology, Pleasanton, CA) was used in the optimum moisture content (OMC) lab to measure FGF23 levels. For the analysis of associations with various studied variables, the levels of FGF23 were split into two groups, which were high (group 1, FGF23 50 to 500 pg/ml), that is, up to 10 times the normal levels and extremely high (group 2, FGF23 > 500 pg/ml) FGF23 levels. All the tests were conducted for routine examination where the data obtained was analyzed in this research project. Results The mean age of patients was 39.18 ±12.84 years, of whom 35 (70%) were males and 15 (30%) were females. For the entire cohort, serum PTH levels were consistently high, and vitamin D levels were low. FGF23 levels were high in the whole cohort. The average iPTH concentration was 304.20 ± 113.18 pg/ml, while the average 25(OH) vitamin D concentration was 19.68±7.49 ng/ml. The mean FGF23 levels were 1877.36±1378.67 pg./ml. The mean calcium value was 8.23±1.05 mg /dl and the mean phosphate of 6.56±2.28 mg /dl. In the whole cohort, FGF23 showed a negative correlation with vitamin D and a positive correlation with PTH, but not statistically significant. Extremely high FGF23 levels were associated with lower bone densitycompared to high FGF23 values. Considering that in the whole cohort of patients, only nine had high FGF-23 and the rest of 41 patients had extremely high FGF23, we could not ascertain differences in PTH, calcium, phosphorus, and 25(OH) vitamin Dlevels between the two groups. The average length of time on dialysis was eight months, and there was no link between FGF-23 levels and the length of time on dialysis. Conclusion Bone demineralization and biochemical abnormalities are a hallmark in chronic kidney disease (CKD) patients. Abnormalities in serum phosphate, parathyroid hormone, calcium, and 25(OH) vitamin Dplay critical roles in the development of BMD in CKD patients. With the discovery of FGF-23 as a biomarker that is increased early in CKD patients, new questions arise about the effects and actions of FGF-23 in controlling bone demineralization and other biochemical markers. Our study found no statistically significant correlation to suggest an effect of FGF-23 on these parameters. But the findings need to be looked at more in prospective, controlled research, especially to find out if therapies that successfully target FGF-23 can make a big difference in how people with CKD feel about their health.

Impact of X-Linked Hypophosphatemia on Muscle Symptoms

X-linked hypophosphatemia (XLH) is the most common hereditary form of rickets and deficiency of renal tubular phosphate transport in humans. XLH is caused by the inactivation of mutations within the phosphate-regulating endopeptidase homolog X-linked (PHEX) gene and follows an X-dominant transmission. It has an estimated frequency of 1 case per 20,000, and over 300 distinct pathogenic variations have been reported that result in an excess of fibroblast growth factor 23 (FGF23) in the serum. Increased levels of FGF23 lead to renal phosphate loss, decreased serum 1,25-dihydroxyvitamin D, and increased metabolism of 1,25-dihydoxyvitamin D, resulting in hypophosphatemia. Major clinical manifestations include rickets, bone deformities, and growth retardation that develop during childhood, and osteomalacia-related fractures or pseudo-fractures, degenerative osteoarthritis, enthesopathy, dental anomalies, and hearing loss during adulthood, which can affect quality of life. In addition, fatigue is also a common symptom in patients with XLH, who experience decreased motion, muscle weakness, and pain, contributing to altered quality of life. The clinical and biomedical characteristics of XLH are extensively defined in bone tissue since skeletal deformations and mineralization defects are the most evident effects of high FGF23 and low serum phosphate levels. However, despite the muscular symptoms that XLH causes, very few reports are available on the effects of FGF23 and phosphate in muscle tissue. Given the close relationship between bones and skeletal muscles, studying the effects of FGF23 and phosphate on muscle could provide additional opportunities to understand the interactions between these two important compartments of the body. By describing the current literature on XLH and skeletal muscle dysfunctions, the purpose of this review is to highlight future areas of research that could contribute to a better understanding of XLH muscular disability and its management.

SIRT7 Deficiency Protects against Aging-Associated Glucose Intolerance and Extends Lifespan in Male Mice.

Sirtuins (SIRT1-7 in mammals) are evolutionarily conserved nicotinamide adenine dinucleotide-dependent lysine deacetylases/deacylases that regulate fundamental biological processes including aging. In this study, we reveal that male Sirt7 knockout (KO) mice exhibited an extension of mean and maximum lifespan and a delay in the age-associated mortality rate. In addition, aged male Sirt7 KO mice displayed better glucose tolerance with improved insulin sensitivity compared with wild-type (WT) mice. Fibroblast growth factor 21 (FGF21) enhances insulin sensitivity and extends lifespan when it is overexpressed. Serum levels of FGF21 were markedly decreased with aging in WT mice. In contrast, this decrease was suppressed in Sirt7 KO mice, and the serum FGF21 levels of aged male Sirt7 KO mice were higher than those of WT mice. Activating transcription factor 4 (ATF4) stimulates Fgf21 transcription, and the hepatic levels of Atf4 mRNA were increased in aged male Sirt7 KO mice compared with WT mice. Our findings indicate that the loss of SIRT7 extends lifespan and improves glucose metabolism in male mice. High serum FGF21 levels might be involved in the beneficial effect of SIRT7 deficiency.

Circulating Adipokines and Associations With Incident Cardiovascular Disease in Rheumatoid Arthritis.

To assess whether circulating levels of adiponectin, leptin, and fibroblast growth factor 21 (FGF-21) are associated with incident cardiovascular disease (CVD) in rheumatoid arthritis (RA). Adipokines were measured using banked enrollment serum from patients with RA and dichotomized above/below the median value. Incident CVD events (coronary artery disease [CAD], stroke, heart failure [HF] hospitalization, venous thromboembolism, CVD-related deaths) were identified using administrative data and the National Death Index. Covariates were derived from medical record, biorepository, and registry databases. Multivariable Cox models were generated to quantify associations between adipokine concentrations and CVD incidence. Five-year incidence rates were predicted. Among 2,598 participants, 639 (25%) had at least 1 CVD event over 19,585 patient-years of follow-up. High adiponectin levels were independently associated with HF hospitalization (hazard ratio [HR] 1.39 [95% confidence interval (95% CI) 1.07-1.79], P=0.01) and CVD-related death (HR 1.49 [95% CI 1.16-1.92], P=0.002) but not with other CVD events. High leptin was independently associated with CVD-related death (HR 1.44 [95% CI 1.05-1.97], P=0.02). High FGF-21 levels were independently associated with lower rates of CAD (HR 0.75 [95% CI 0.58-0.97], P=0.03). In subgroup analyses, associations between high adiponectin and leptin levels with CVD-related death were driven by strong associations in nonobese patients. Adipokines are associated with HF hospitalization and CVD-related death in patients with RA, with stronger associations in nonobese participants. These findings suggest that adipokines effectively predict clinically important outcomes in RA perhaps through an association with body composition and metabolic health. Further study is needed to determine whether adipokine measures might augment existing tools to identify RA patients at increased risk of CVD.

High serum fibroblast growth factor 21 levels were related to the prognosis and ventricular remodeling of heart failure patients with mildly reduced and reduced ejection fraction.

Previous studies have shown that fibroblast growth factor 21 (FGF21) is involved in the ventricular remodeling process in heart failure with preserved ejection fraction (HFpEF). We hypothesized that high levels of FGF21 correlated with the ventricular remodeling of heart failure patients with mildly reduced (HFmrEF) and reduced ejection fraction (HFrEF). A total of 203 participants with HFmrEF or HFrEF were enrolled and followed up from June 2018 to June 2021. 68 subjects without heart failure (HF) underwent physical examinations during the same time were selected as the control group. The primary endpoint was the occurrence of major adverse cardiovascular events (MACEs), which were defined as all-cause or cardiac mortality and rehospitalization for decompensation. Serum FGF21 levels were measured early the next morning after admission using enzyme-linked immunosorbent assay (ELISA). The FGF21 levels were significantly higher in patients with HFmrEF or HFrEF than that in the control group (213.57 ± 42.65pg/mL, 222.93 ± 34.36pg/mL vs 171.00 ± 12.86pg/mL, p < .001). The serum levels of FGF21 and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were both higher in the endpoint event group than those of non-endpoint event group regardless of the HFmrEF or HFrEF group (p < .001). Spearman's correlation revealed that FGF21 was positively correlated with left ventricular end-systolic diameter left ventricular end-diastolic diameter left ventricular mass index (p < .01). Moreover, there was a negative correlation between FGF21 and left ventricular ejection fraction in addition to relative wall thickness (p < .001). The area under the receiver operating characteristic (ROC) curve (AUC) of FGF21 was 0.874. The optimal cut-off value of FGF21 determined by ROC curve was 210.11pg/mL. The Kaplan-Meier analysis demonstrated that the low FGF21 levels group had an increased MACE-free survival rate compared with the high FGF21 levels group. On univariate and multivariate Cox analysis, it was seen that both serum FGF21 and NT-proBNP were independent predictors of a poor prognosis in HF patients. Baseline levels of FGF21 and NT-proBNP were related to the ventricular remodeling of patients with a mildly reduced or reduced ejection fraction. FGF21 and NT-proBNP both had good prognostic value for MACEs in heart failure patients with a mildly reduced and reduced ejection fraction.

Association of Genetically Predicted Fibroblast Growth Factor-23 with Heart Failure: A Mendelian Randomization Study.

Elevated fibroblast growth factor-23 (FGF23) has been consistently associated with heart failure, particularly heart failure with preserved ejection fraction, among patients with CKD and in the general population. FGF23 may directly induce cardiac remodeling and heart failure. However, biases affecting observational studies impede robust causal inferences. Mendelian randomization leverages genetic determinants of a risk factor to examine causality. We performed a two-sample Mendelian randomization to assess causal associations between FGF23 and heart failure. Genetic instruments were genome-wide significant genetic variants associated with FGF23, including variants near PIP5K1B, RGS14, LINC01229, and CYP24A1. We analyzed data from the Heart Failure Molecular Epidemiology for Therapeutic Targets and BioVU biobanks to examine associations of the four variants with overall heart failure, heart failure with preserved ejection fraction, and heart failure with reduced and mid-range ejection fraction. We developed an eGFR polygenic risk score using summary statistics from the Chronic Kidney Disease Genetics Consortium (CKDGen) genome-wide association study of eGFR in >1 million individuals and performed stratified analyses across eGFR polygenic risk score strata. Genetically determined FGF23 was not associated with overall heart failure in the Heart Failure Molecular Epidemiology for Therapeutic Targets consortium (odds ratio, 1.13; 95% confidence interval, 0.89 to 1.42 per unit higher genetically predicted log FGF23) and the full BioVU sample (odds ratio, 1.32; 95% confidence interval, 0.95 to 1.84). In stratified analyses in BioVU, higher FGF23 was associated with overall heart failure (odds ratio, 3.09; 95% confidence interval, 1.38 to 6.91) among individuals with low eGFR-polygenic risk score (<1 SD below the mean), but not those with high eGFR-polygenic risk score (P interaction = 0.02). Higher FGF23 was also associated with heart failure with preserved ejection fraction among all BioVU participants (odds ratio, 1.47; 95% confidence interval, 1.01 to 2.14) and individuals with low eGFR-polygenic risk score (odds ratio, 7.20; 95% confidence interval, 2.80 to 18.49), but not those high eGFR-polygenic risk score (P interaction = 2.25 × 10-4). No significant associations were observed with heart failure with reduced and midrange ejection fraction. We found no association between genetically predicted FGF23 and heart failure in the Heart Failure Molecular Epidemiology for Therapeutic Targets consortium. In BioVU, genetically elevated FGF23 was associated with higher heart failure risk, specifically heart failure with preserved ejection fraction, particularly among individuals with low genetically predicted eGFR. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_07_28_CJN00960122.mp3.

Association between amorphous calcium-phosphate ratios in circulating calciprotein particles and prognostic biomarkers in hemodialysis patients

Calciprotein particles (CPPs) are circulating colloidal mineral-protein complexes containing crystalline and/or non-crystalline (amorphous) calcium-phosphate (CaPi). Serum CPP levels correlate with vascular stiffness and calcification in patients with chronic kidney disease (CKD). In vitro studies showed that CPPs containing crystalline CaPi were more arteriosclerogenic and inflammogenic than CPPs without containing crystalline CaPi. Thus, we hypothesized that not only the quantity but also the quality of CPPs (the phase of CaPi) might affect clinical outcomes. To test this hypothesis, we quantified amorphous CaPi ratio defined as the ratio of the amorphous CaPi amount to the total CaPi amount in serum CPPs from 183 hemodialysis patients and explored its possible correlation with serum parameters associated with prognosis of hemodialysis patients. Multivariate analysis revealed that the amorphous CaPi ratio correlated positively with hemoglobin and negatively with fibroblast growth factor-21 (FGF21), which remained significant after adjusting for the total CaPi amount. Because low hemoglobin and high FGF21 are associated with increased mortality, the present study warrants further studies to determine whether low amorphous CaPi ratio in circulating CPPs may be associated with poor prognosis in hemodialysis patients.

The direct effect of fibroblast growth factor 23 on vascular smooth muscle cell phenotype and function.

In chronic kidney disease (CKD) patients, increased levels of fibroblast growth factor 23 (FGF23) are associated with cardiovascular mortality. The relationship between FGF23 and heart hypertrophy has been documented, however, it is not known whether FGF23 has an effect on vasculature. Vascular smooth muscle cells VSMCs may exhibit different phenotypes; our hypothesis is that FGF23 favours a switch from a contractile to synthetic phenotype that may cause vascular dysfunction. Our objective was to determine whether FGF23 may directly control a change in VSMC phenotype. This study includes in vitro, in vivo and ex vivo experiments and evaluation of patients with CKD stages 2-3 studying a relationship between FGF23 and vascular dysfunction. In vitro studies show that high levels of FGF23, by acting on its specific receptor FGFR1 and Erk1/2, causes a change in the phenotype of VSMCs from contractile to synthetic. This change is mediated by a downregulation of miR-221/222, which augments the expression of MAP3K2 and PAK1. miR-221/222 transfections recovered the contractile phenotype of VSMCs. Infusion of recombinant FGF23 to rats increased vascular wall thickness, with VSMCs showing a synthetic phenotype with a reduction of miR-221 expression. Ex-vivo studies on aortic rings demonstrate also that high FGF23 increases arterial stiffening. In CKD 2-3 patients, elevation of FGF23 was associated with increased pulse wave velocity and reduced plasma levels of miR-221/222. In VSMCs, high levels of FGF23, through the downregulation of miR-221/222, causes a change to a synthetic phenotype. This change in VSMCs increases arterial stiffening and impairs vascular function, which might ultimately worsen cardiovascular disease.

Associations between endogenous sex hormones and FGF-23 among women and men in the Multi-Ethnic Study of Atherosclerosis.

Elevated levels of testosterone and fibroblast growth factor 23 (FGF-23) are both independently associated with a higher risk of cardiovascular disease (CVD). However, the relationship between sex hormones and FGF-23 is not well established. We explored the association between sex hormones and FGF-23 among middle-aged to older men and women in MESA. We studied 3,052 men and 2,868 postmenopausal women free of CVD at the time of enrollment with baseline serum sex hormones [total testosterone (T), free T, estradiol (E2) and sex hormone binding globulin (SHBG)] and intact FGF-23. In sex-stratified analyses, we examined the cross-sectional associations between log-transformed sex hormones (per 1 SD) and log-transformed FGF-23 using multiple linear regression adjusted for socio-demographics, CVD risk factors, estimated glomerular filtration rate and mineral metabolites (25-hydroxyvitamin D, calcium, phosphorus and parathyroid hormone). The mean (SD) age of study participants was 64 (10) years. The median (IQR) of FGF-23 was similar in women and men [38 (30–46) vs 38 (31–47) pg/mL]. In adjusted analyses, among women, 1 SD increment in free T was associated with 3% higher FGF-23 while SHBG was associated with 2% lower FGF-23. In men, 1 SD increment in E2 was associated with 6% higher FGF-23 whereas total T/E2 ratio was associated with 7% lower FGF-23. In conclusion, this exploratory analysis found that a more androgenic sex hormone profile was directly associated with FGF-23 in women and inversely associated with FGF-23 in men. Longitudinal studies are required to determine whether FGF-23 mediates the relationship between sex hormones and CVD risk.

FC026: Chronic High Phosphate Level Impairs Cardiac Health

Abstract BACKGROUND AND AIMS Patients with chronic kidney disease (CKD) suffer from disturbed mineral metabolism in which the chronic phosphate load leads to the elevation of the phosphaturic hormones parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23). Persistent hyperphosphatemia predisposes to cardiovascular events and increased morbidity and mortality rates. It is discussed that even in the general population, consumption of highly processed food increases phosphate level, which in turn may increase cardiovascular risk. Here, we aim to elucidate the pathological mechanisms of how chronic high phosphate intake mediates cardiac remodeling and dysfunction, respectively. METHOD Male C57BL/6 wild type mice received a high phosphate diet containing 2% inorganic phosphate (HPD) or a 0.8% normal phosphate diet (NPD) for 6 months. Echocardiographic analysis and ex-vivo measurements in cardiomyocytes using IonOptix system were assessed to evaluated cardiac function and contractility. Bulk RNA sequencing of whole heart tissue followed by pathway analysis was done to identify affected relevant signaling pathways, which were verified by in vitro studies using neonatal rat ventricular myocytes (NRVM). RESULTS Chronic phosphate overload resulted in increased level of serum and urinary phosphate and high plasma PTH and FGF23 concentrations. HPD caused impaired heart function as shown by reduced ejection fraction, increased end-systolic volumes and enlarged systolic left ventricular internal diameter accompanied by impaired left ventricular relaxation as seen in Doppler echocardiography. Histological analysis showed increased cardiomyocyte area and length in HPD-fed mice compared with NPD demonstrating cellular hypertrophy. RNA sequencing revealed differentially expressed genes of calcium signaling pathways in the HPD group. Besides, immunoblot analysis of whole heart tissue showed altered Phospholamban activity after 6 months of HPD compared with NPD, indicating altered calcium pump in cardiomyocytes. Preliminary analysis of sarcomere movements and changes of intracellular calcium levels in single cardiomyocytes isolated from NPD and HPD mice after 6 months suggested impaired contractility. Detailed results will be presented here. In vitro stimulation of isolated NRVM with high phosphate induced a hypertrophic growth response, verifying a direct effect of high phosphate on the heart. CONCLUSION HPD in mice causes a dilated cardiac phenotype including cellular hypertrophy, altered contractility and differentially expressed genes involved in calcium signaling pathways, indicating that a chronic high phosphate load is harmful for the heart also in the general population.

Nutritional Predictors of Cardiovascular Risk in Patients after Kidney Transplantation-Pilot Study

Asymmetric dimethylarginine (ADMA) is a marker of endothelial damage. Research confirms the association of ADMA with an increased cardiovascular risk (CVR) among kidney transplant recipients (KTRs). Additionally, increased circulating levels of fibroblast growth factor 23 (FGF-23) are associated with pathological cardiac remodeling and vascular alterations. The aim of the study is the analysis of the relationship between ADMA, FGF-23, nutritional, biochemical parameters in healthy subjects and KTRs. 46 KTRs and 23 healthy volunteers at mean age of 50.8 ± 15.4 and 62.5 ± 10.7 years were enrolled. The anthropometric and biochemical parameters such as ADMA, FGF-23, albumin, prealbumin were assessed. Fat tissue mass among KTRs was 30.28 ± 9.73%, lean body mass 64.5 ± 14.8%. Overweight and obesity was presented by 65.2% of recipients. Albumin level was 38.54 ± 3.80 g/L, prealbumin 27.83 ± 7.30 mg/dL and were significantly lower than in the control (p &lt; 0.05). Patients with ADMA &gt; 0.66 µmol/L had a lower concentration of prealbumin, albumin and increased concentration of oxidized low density lipoprotein (oxLDL), high sensitive C-reactive protein (hsCRP) and FGF-23. FGF-23 was significantly higher in patients with higher hsCRP (p &lt; 0.05). KTRs with elevated ADMA had a longer transplantation vintage, lower eGFR and higher albuminuria. Diabetes mellitus (DM) was associated with higher levels of ADMA and FGF-23. Even in stable KTRs a relationship between inflammatory state, nutritional status, graft function and endothelial dysfunction biomarkers was observed.

Effect of different phosphate binders on fibroblast growth factor 23 levels in patients with chronic kidney disease: a systematic review and meta-analysis of randomized controlled trials.

Serum intact fibroblast growth factor 23 (FGF23) levels are progressively increased in relation to the severity of kidney dysfunction. High serum intact FGF23 concentration is associated with the increased cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). Clinically, phosphate binders are commonly used to reduce serum intact FGF23 levels in CKD patients by lowering serum phosphate levels. It is not clear whether all kinds of phosphate binders can reduce serum intact FGF23 levels, or which kind of phosphate binders is more effective in reducing serum intact FGF23 levels in patients with CKD. The aim of this systematic review and meta-analysis was to compare the efficiency of different kinds of commonly used phosphate binders on serum intact FGF23 levels in patients with CKD. Systematic searches were performed through PubMed, Cochrane Central Register of Controlled Trials and Embase from 1999 to 2020. We included the studies performed only in human subjects. All randomized clinical trials (RCTs) were included. Reviews, case reports, letters, commentaries, abstracts and unpublished articles were excluded. Risk of bias was assessed by the Cochrane Collaboration's tool. Random effect was performed in meta-analysis. Meta-regression was used to investigate heterogeneity. Of 1,895 articles, 15 RCTs (comprising 1,098 participants) were included. Common sources of bias were selection bias. Phosphate binders could reduce serum intact FGF23 levels in patients with CKD [standard mean difference (SMD) of total change in serum intact FGF23 levels was 0.91 PG/mL (95% confidence interval: 0.38 to 1.44 PG/mL]. Meta-regression explained 89.02% of heterogeneous sources, indicating that dietary phosphate intake could weaken the effect of phosphate binders on reducing serum intact FGF23 levels, and the effect of phosphate binders on reducing serum intact FGF23 levels in dialysis patients was better than that in early-to-middle CKD patients. Phosphate binders can effectively reduce serum intact FGF23 levels in CKD patients, and iron-based phosphate binders have better effect on reducing serum intact FGF23 levels than other phosphate binders.

High C-Terminal Fibroblast Growth Factor-23, Intact Parathyroid Hormone, and Interleukin-6 as Determinants of Valvular Calcification in Regular Hemodialysis Patients.

PurposeBiggest cause of death in chronic kidney disease-hemodialysis (CKD-HD) patients is cardiovascular disease (CVD). Cardiovascular disease is often associated with mineral bone disorders (MBD), especially vascular and valvular calcification. Biomarkers such as C-terminal-fibroblast growth factor-23 (FGF-23), intact parathyroid hormone (iPTH), and interleukin-6 (IL-6) were investigated. Only few studies have focused on valvular calcification in CKD-HD patients, with controversial results. The present study aimed to investigate whether high C-terminal-FGF-23, iPTH, and IL-6 can be used as determinants of valvular calcification in CKD-MBD patients undergoing regular HD.Patients and MethodsThis was an analytical cross-sectional study which involved CKD-HD patients aged 18–60 years with no history of CVD, malignancy, and diabetes mellitus. C-terminal FGF-23 was measured using enzyme-linked immunosorbent assay (ELISA) kit, iPTH using chemiluminescent immunometric method, and IL-6 using sandwich enzyme immunoassay technique. Valvular calcification on aortic and mitral valves was examined with echocardiography. Data analysis was done using Chi-squared test or Fisher’s exact test as appropriate and multivariate logistic regression analysis.ResultsBivariate analysis with Fisher’s exact test showed significant association of prevalence ratio (PR) of C-terminal FGF-23 (PR = 1.33; p = 0.003; CI (1.017–1.748)), iPTH (PR = 1.361; p = 0.002; CI (1.02–1.816)), and IL-6 (PR = 1.2; p = 0.019; CI (1.000–1.446)) with valvular calcification. Multivariate analysis with logistic regression showed high C-terminal FGF-23 (exp (B) value of 16.44; p = 0.045; CI (1.07–252.75)), iPTH (exp (B) value of 33.312; p = 0.016; CI (1.94–571.71)), and IL-6 (exp (B) value of 21.58; p = 0.0381; CI (1.18–394.87)) were determinants of valvular calcification in CKD-MBD patients undergoing regular HD.ConclusionThis study demonstrated that high C-terminal FGF-23, iPTH, and IL-6 were determinants of valvular calcification in CKD-MBD patients undergoing regular HD.

Fibroblast Growth Factor 21 Predicts Short-Term Prognosis in Patients With Acute Heart Failure: A Prospective Cohort Study.

BackgroundRecent studies of fibroblast growth factor 21 (FGF21), first recognized as a regulator of glucose and lipid metabolism, have found that the level of in serum FGF21 is associated with the prognosis of many cardiovascular diseases, but its relationship to acute heart failure (AHF) patients remains unknown. Our study aimed to investigate whether circulating FGF21 could predict the short-term prognosis of AHF patients.MethodsFour hundred and two AHF patients and 19 healthy controls were recruited into the prospective cohort study, and blood samples of participants were collected, in tubes without anticoagulant, within the first 24 h after hospital admission. Serum FGF21 levels were detected by enzyme-linked immunosorbent assay (ELISA). All patients were followed-up at least 6 months after discharge. The primary endpoint was all-cause death, and secondary endpoint was a composite endpoint of death and heart failure readmission. Mortality and composite end point events were analyzed using Kaplan-Meier curves. ROC curves compared the difference between the FGF21 and NT-proBNP in predicting 3- and 6-months mortality. Time-to-event data were evaluated using Kaplan-Meier estimation and Cox proportional hazards models.ResultsIn the present study, the serum FGF21 concentrations were significantly higher in the 402 AHF patients enrolled, compared with the 19 healthy controls (p < 0.001). The average age was 70 (±12) years, and 58% were males. Participants were divided into two groups according to the median FGF21 level (262 pg/ml): a high FGF21 group (n = 201, FGF21 ≥ 262 pg/ml) and low FGF21 group (n = 201, FGF21 <262 pg/ml). FGF21 was positively correlated with NT-proBNP, BUN, AST, creatinine and cholesterol, and negatively correlated with ALB and HDL. After a median follow-up of 193 days, the high FGF21 group had higher mortality and composite endpoint events compared with the low FGF21 group (HR: 3.91, 95% CI 2.21–6.92, p <0.001), even after adjusting for NT-proBNP (HR: 3.17, 95% CI 1.72–5.81, p < 0.001). ROC analysis shows that FGF21 was better than NT-proBNP in predicting death at both 3 (AUC, 0.77 vs. 0.63, p < 0.001) and 6 months (AUC, 0.78 vs. 0.66).ConclusionHigh baseline FGF21 levels are associated with adverse clinical outcomes in AHF patients. Serum FGF21 might be a potential predictive biomarker of AHF patients.

Serum Fibroblast Growth Factor 21 Level Is Associated with Aortic Stiffness in Patients on Maintenance Hemodialysis.

Background Fibroblast growth factor 21 (FGF-21) is a hormone that regulates glucose and lipid metabolism. High serum FGF-21 levels are associated with carotid atherosclerosis and coronary artery disease. This cross-sectional study aimed to assess the relationship between serum FGF-21 levels and carotid-femoral pulse wave velocity (cfPWV) in patients on maintenance hemodialysis (HD). Methods Blood samples and baseline characteristics were collected from 130 HD patients. Serum FGF-21 concentrations were measured with an enzyme-linked immunosorbent assay kit. Aortic stiffness was defined as a carotid-femoral pulse wave velocity (cfPWV) of more than 10 m/s. Results Of the 130 HD patients, aortic stiffness was diagnosed in 54 (41.5%). Serum FGF-21 levels were significantly higher in those with aortic stiffness than those without (P < 0.001). The FGF-21 level was independently associated with aortic stiffness (odds ratio (OR): 1.008; 95% CI: 1.003–1.012; P=0.001) after adjusting for diabetes mellitus, age, hypertension, C-reactive protein, and body weight in multivariable logistic regression analysis. Multivariable forward stepwise linear regression analysis also confirmed that the logarithmically transformed FGF-21 level (β = 3.245, 95% CI: 1.593–4.987, P < 0.001) was an independent predictor of cfPWV values. The area under the receiver operating characteristic (ROC) curve predicting aortic stiffness by the serum FGF-21 level was 0.693 (95% CI: 0.606–0.771, P < 0.001). Conclusions Serum FGF-21 level positively correlates with cfPWV and is also an independent predictor of aortic stiffness in maintenance HD patients.

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.

Tumor-Induced Osteomalacia With Normal Fibroblast Growth Factor-23 (FGF23) and Idiopathic Hypercalciuria

Tumor-induced osteomalacia (TIO) is a rare acquired paraneoplastic syndrome characterized by low serum phosphate, phosphaturia, inappropriately low/normal levels of serum calcitriol, and normal or elevated levels of fibroblast growth factor-23 (FGF23). Finding this mesenchymal tumor is challenging since it is usually benign, small, slow-growing, and is localized in the appendicular skeleton. We report a 58-year-old male patient who arrived at the endocrinology outpatient clinic due to slowly progressive low back pain and generalized weakness since the age of 48. On physical examination, only a reduced range of motion was noted. Laboratory tests revealed hypophosphatemia with normal parathyroid hormone (PTH) levels, normal serum calcium, high 24-hour urine calcium, normal 1,25-dihydroxyvitaminD levels, low renal threshold phosphate concentration (TmPO4/GFR), and high FGF23. The 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) reported a hypermetabolic extramedullary lesion in the C1-C2 vertebral bodies measuring 1.5 x 1.1 cm. Two months after the 18F-FDG PET/CT, complete excision of the cervical tumor was performed. The pathology ward reported a histiocytic mesenchymal neoplasm with accumulations of multinucleated giant cells compatible with phosphaturic mesenchymal tumor. After surgery, the patient’s hypophosphatemia was completely resolved. With this, the diagnosis of TIO was confirmed. The patient remains asymptomatic, with normal phosphate levels at one year of follow-up. Hypophosphatemia due to renal losses in an adult patient is a challenging diagnosis and one must consider TIO, autosomal dominant hypophosphatemic rickets, fibrous dysplasia, and even Fanconi syndrome. FGF23 can be extremely useful during the diagnostic approach since acquired dependent hypophosphatemia (FGF23 ≥ 30 RU/mL) highly suggests TIO. In this case report, we want to highlight the paramount importance of adequate tumor screening in adult patients with acquired FGF23-dependent hypophosphatemia. TIO is a reversible cause of hypophosphatemia with potentially disabling consequences if left untreated. These manifestations are non-specific (bone pain and muscle weakness), while others are progressive and severely disabling (bone deformities and multiple fractures). In this case report, we want to highlight the paramount importance of adequate tumor screening in adult patients with acquired hypophosphatemia, and the crucial lead that phosphate and vitamin D regulating hormones (FGF23) have for suspecting TIO.

Hypophosphatemia after intravenous iron therapy: Comprehensive review of clinical findings and recommendations for management.

Contemporary intravenous iron formulations allow administration of high doses of elemental iron and enable correction of total iron deficit in one or two infusions. An important but underappreciated complication of certain formulations is hypophosphatemia caused by increased secretion of the phosphaturic hormone, fibroblast growth factor 23 (FGF23). The pathophysiology of FGF23-induced hypophosphatemia due to certain intravenous iron formulations has been recently investigated in prospective clinical trials. To reach the correct diagnosis, clinicians must recognize the typical clinical manifestations of intravenous iron-induced hypophosphatemia and identify a specific pattern of biochemical changes (hyperphosphaturic hypophosphatemia triggered by high FGF23 that causes low 1,25 (OH)2 vitamin D, hypocalcemia and secondary hyperparathyroidism). Physicians and patients should be aware of hypophosphatemia as a common complication of intravenous iron therapy and monitor serum phosphate concentrations in patients receiving repeated doses of specific intravenous iron formulations. Symptoms of hypophosphatemia are associated with severity and duration. Persistent hypophosphatemia can occur with iron therapy and can cause debilitating diseases including myopathy, osteomalacia and fractures. This review summarizes the current understanding of the iron-phosphate axis as well as complications of intravenous iron-induced hypophosphatemia.