Diagnostic utility of FGF-23 in mineral bone disorder during chronic kidney disease

Our data confirm that intact fibroblast growth factor 23 (iFGF-23) concentration is increased in patients with chronic kidney disease (CKD) and that it increases with disease progression (stages I-V). Therefore, iFGF-23 could be considered an early biomarker in the course of chronic kidney disease-mineral bone disorder (CKD-MBD), which has several aspects that make it potentially useful in clinical practice. The availability of an automated method for iFGF-23 assay may represent an added value in the management of the patient with CKD-MBD already from the early stages of the disease, before the increase of the routinely used laboratory parameters, 1-84 parathyroid hormone (PTH) and 25-OH-vitamin D (25-OH-vitD), which occur in more advanced stages of the disease.

Oncogenic osteomalacia secondary to hemangiopericytoma: a case report

<p>We are going to present a case of hypo-phosphatemic rickets secondary to phosphaturic mesenchymal tumour who came with complaints of proximal muscle weakness which limited his effort tolerance and activities of daily life like standing from squatting position and rib pain. His FGF-23 levels were very high above normal levels and PET CT revealed a well-defined enhancing lesion abutting femoral neurovascular bundle. After consultation with endocrinologist, we have d done complete excision of the mass. Post-surgery all symptoms were relieved, proximal muscle strength improved gradually and serum levels of phosphorus, ALP and FGF-23 came back to normal.</p>

Fibroblast Growth Factor 23 Stimulates Cardiac Fibroblast Activity through Phospholipase C-Mediated Calcium Signaling

Fibroblast growth factor (FGF)-23 induces hypertrophy and calcium (Ca2+) dysregulation in cardiomyocytes, leading to cardiac arrhythmia and heart failure. However, knowledge regarding the effects of FGF-23 on cardiac fibrogenesis remains limited. This study investigated whether FGF-23 modulates cardiac fibroblast activity and explored its underlying mechanisms. We performed MTS analysis, 5-ethynyl-2’-deoxyuridine assay, and wound-healing assay in cultured human atrial fibroblasts without and with FGF-23 (1, 5 and 25 ng/mL for 48 h) to analyze cell proliferation and migration. We found that FGF-23 (25 ng/mL, but not 1 or 5 ng/mL) increased proliferative and migratory abilities of human atrial fibroblasts. Compared to control cells, FGF-23 (25 ng/mL)-treated fibroblasts had a significantly higher Ca2+ entry and intracellular inositol 1,4,5-trisphosphate (IP3) level (assessed by fura-2 ratiometric Ca2+ imaging and enzyme-linked immunosorbent assay). Western blot analysis showed that FGF-23 (25 ng/mL)-treated cardiac fibroblasts had higher expression levels of calcium release-activated calcium channel protein 1 (Orai1) and transient receptor potential canonical (TRPC) 1 channel, but similar expression levels of α-smooth muscle actin, collagen type IA1, collagen type Ⅲ, stromal interaction molecule 1, TRPC 3, TRPC6 and phosphorylated-calcium/calmodulin-dependent protein kinase II when compared with control fibroblasts. In the presence of ethylene glycol tetra-acetic acid (a free Ca2+ chelator, 1 mM) or U73122 (an inhibitor of phospholipase C, 1 μM), control and FGF-23-treated fibroblasts exhibited similar proliferative and migratory abilities. Moreover, polymerase chain reaction analysis revealed that atrial fibroblasts abundantly expressed FGF receptor 1 but lacked expressions of FGF receptors 2-4. FGF-23 significantly increased the phosphorylation of FGF receptor 1. Treatment with PD166866 (an antagonist of FGF receptor 1, 1 μM) attenuated the effects of FGF-23 on cardiac fibroblast activity. In conclusion, FGF-23 may activate FGF receptor 1 and subsequently phospholipase C/IP3 signaling pathway, leading to an upregulation of Orai1 and/or TRPC1-mediated Ca2+ entry and thus enhancing human atrial fibroblast activity.

Different Effects of Empagliflozin on Markers of Mineral-Bone Metabolism in Diabetic and Non-Diabetic Patients with Stage 3 Chronic Kidney Disease

Background and objectives: Treatment with sodium–glucose co-transporter 2 (SGLT2) inhibitors decrease tubular reabsorption of phosphate, which may explain the reduction of bone mineral density and an excess of bone fractures observed in some studies with this class of drugs. Since an increased risk of bone fractures may also be a result of diabetes itself, our study aimed to compare the effect of empagliflozin on the markers of mineral-bone metabolism between diabetic (DKD) and non-diabetic (ND-CKD) patients with stage 3 chronic kidney disease (CKD). Materials and Methods: Forty-two patients with stage 3 CKD and A2 albuminuria, including 18 with DKD and 24 ND-CKD, were investigated. All subjects received 10 mg empagliflozin for 7 days. Serum calcium, phosphate, parathormone (PTH), calcitriol, bone alkaline phosphatase (BAP), FGF-23 and urine calcium, phosphate, albumin and the renal tubular maximum reabsorption rate of phosphate to the glomerular filtration rate (TmP-GFR) were measured before and after empagliflozin administration. Differences in biomarkers response to empagliflozin between DKD and ND-CKD were the main measures of outcome. Results: There was a significant increase of PTH, FGF-23 and phosphate in DKD but not in ND-CKD whereas BAP and TmP/GFR did not change in either group. The reduction of albuminuria was only significant in ND-CKD. Conclusions: The effect of SGLT2 inhibitor on serum mineral and bone markers and on albuminuria in patients with CKD may be differently modified by the presence of diabetes mellitus.

Serum Cystatin C, Kidney Injury Molecule-1, Neutrophil Gelatinase-Associated Lipocalin, Klotho and Fibroblast Growth Factor-23 in The Early Prediction of Acute Kidney Injury Associated With Sepsis in a Chinese Emergency Cohort Study

Background: Acute kidney injury (AKI) was a common and critical complication of sepsis, and is associated with unacceptable morbidity and mortality. Current diagnostic criteria for AKI was insensitive for early detection. Novel biomarkers included cystatin C, KIM-1, NGAL, klotho and FGF-23 which can predict AKI earlier may allow immediate interventions. We aimed to determine the diagnostic performance of these biomarkers for detecting AKI in sepsis patients.Methods: This prospective observational study was conducted from May 2018 and November 2020, enrolling sequential 162 sepsis patients. AKI’s definition was according to 2012 KDIGO criteria and we divided patients into non-AKI (n=102) and AKI (n=60) groups. Serum levels of several AKI biomarkers were detected by ELISA. The relationship between biomarker levels on admission of AKI were analyzed and discrimination performances comparison were performed.Results: AKI incidence was up to 37.0% (60/162) during hospitalization. Compared with non-AKI group, both serum cystatin C, KIM-1, NGAL and FGF-23 were significantly elevated at admission in septic AKI patients. The areas under the receiver operating curves demonstrated that serum cystatin C had modest discriminative powers for predicting AKI after sepsis, and cystatin C combined with serum creatinine in the prediction of septic AKI increased the diagnostic sensitivity prominently.Conclusion: Serum cystatin C, KIM-1, NGAL and FGF-23 levels are both increased in septic AKI patients. Our study provides reliable evidence that cystatin C solely and combined with serum creatinine may accurately and sensitively predict septic AKI when patients on admission.

Fibroblast Growth Factor-23-Klotho Axis in Cardiorenal Syndrome: Mediators and Potential Therapeutic Targets

Cardiorenal syndrome (CRS) is a complex disorder that refers to the category of acute or chronic kidney diseases that induce cardiovascular disease, and inversely, acute or chronic heart diseases that provoke kidney dysfunction. There is a close relationship between renal and cardiovascular disease, possibly due to the presence of common risk factors for both diseases. Thus, it is well known that renal diseases are associated with increased risk of developing cardiovascular disease, suffering cardiac events and even mortality, which is aggravated in those patients with end-stage renal disease or who are undergoing dialysis. Recent works have proposed mineral bone disorders (MBD) as the possible link between kidney dysfunction and the development of cardiovascular outcomes. Traditionally, increased serum phosphate levels have been proposed as one of the main factors responsible for cardiovascular damage in kidney patients. However, recent studies have focused on other MBD components such as the elevation of fibroblast growth factor (FGF)-23, a phosphaturic bone-derived hormone, and the decreased expression of the anti-aging factor Klotho in renal patients. It has been shown that increased FGF-23 levels induce cardiac hypertrophy and dysfunction and are associated with increased cardiovascular mortality in renal patients. Decreased Klotho expression occurs as renal function declines. Despite its expression being absent in myocardial tissue, several studies have demonstrated that this antiaging factor plays a cardioprotective role, especially under elevated FGF-23 levels. The present review aims to collect the recent knowledge about the FGF-23-Klotho axis in the connection between kidney and heart, focusing on their specific role as new therapeutic targets in CRS.

La proteína de unión a los ácidos grasos cardíaca (HFABP) está relacionada con la gravedad de la insuficiencia cardíaca y sus biomarcadores cardíacos conocidos

Resumen Objetivos Determinar las concentraciones de proteína de unión a los ácidos grasos cardíaca (HFABP) en pacientes con insuficiencia cardíaca con fracción de eyección reducida (ICFEr) y su potencial valor pronóstico. Métodos Se determinaron las concentraciones circulantes de HFABP mediante un inmunoensayo quimioluminiscente automático en 25 voluntarios sanos y 60 pacientes con ICFEr. Resultados Los pacientes con insuficiencia cardíaca (IC) presentaron concentraciones de HFABP significativamente mayores que los voluntarios sanos. Se observó una correlación significativa entre los niveles de HFABP, la clasificación de la New York Heart Association (NYHA), y las concentraciones de los biomarcadores de disfunción y remodelado cardíaco (NT-proBNP, FGF-23 y galectina-3). Las concentraciones de HFABP también mostraron valor predictivo de muerte cardiovascular, y su combinación con NT-proBNP podría ser sinérgica a la hora de evaluar el riesgo. Conclusiónes Las concentraciones de HFABP están aumentadas en los pacientes con ICFEr, se relacionan con el riesgo cardiovascular y podrían ayudar a los especialistas en el manejo de los pacientes.

Inhibition of Fibroblast Growth Factor-23 (FGF-23) Rescues Bone and Hematopoietic Stem Cell Niche Defects in Beta-Thalassemia, Uncovering the Missing Link between Hematopoiesis and Bone

The bone marrow (BM) niche regulation and interactions with hematopoietic stem cells (HSC) have been extensively studied in steady state conditions and malignancies, but are still underexplored in hematological inherited disorders. We provided the first demonstration of impaired HSC function caused by an altered BM niche in a non-malignant disease, beta-thalassemia (BT) (Aprile et al., Blood 2020). BT is a globally widespread congenital hemoglobin disorder, resulting in severe anemia, ineffective erythropoiesis and multi-organ secondary complications, including bone alterations. Correction of the genetic defect is achieved by transplantation of HSC from healthy donors or autologous HSC from patients upon gene therapy. Since the quality and the engraftment of HSC depend on the BM microenvironment, niche-HSC crosstalk plays a crucial role for transplantation outcome. During the analysis of different components of the niche, we found reduced bone density in BT th3 mice, along with a defective HSC supporting activity by the BM stromal niche. Interestingly, osteoporosis is a constant hallmark in BT patients. We investigated the mechanisms underlying bone and HSC niche defects focusing on the role of fibroblast growth factor-23 (FGF-23), a hormone mainly secreted by osteocytes, but also by erythroid cells, which negatively modulates bone metabolism. Since FGF-23 is stimulated by the anemia-related factor erythropoietin (EPO), we hypothesized that the high EPO levels in BT might contribute to increase FGF-23, potentially affecting bone and BM niche homeostasis. We found high levels of circulating FGF-23 in th3 mice (wt vs. th3: 290.5±27.3 vs. 1823±136.1 pg/ml, p&lt;0.0001) and in BT patients (HD vs. THAL: 94.7±1.8 vs. 117.2±5.3 RU/ml, p&lt;0.01), associated to its increased expression by bone and BM erythroid cells. In vivo neutralization of EPO axis was sufficient to normalize FGF-23 levels (th3 vs. th3+anti-EPO: 1591±162.2 vs. 496.1±33.3 pg/ml, p&lt;0.001), thus demonstrating the causative role of EPO. EPO stimulation and signaling inhibition strategies highlighted the involvement of Erk1/2 and Stat5 pathways in activating Fgf-23 transcription in bone and BM erythroid cells, respectively. To provide proof of concept data on the contribution of FGF-23 to BT bone and stromal niche alterations, we inhibited FGF-23 signaling. In vivo administration of FGF-23 blocking peptide rescued the trabecular bone density in th3 mice (th3 vs. th3+FGF23inh: 138.2±4.9 vs. 166.9±5.2 mg/cm 3, p&lt;0.01). Short-term inhibition treatment (38 hours) was sufficient to enhance bone mineralization by acting on Alkaline Phosphatase and on the expression of the main regulators of mineralization Dmp1 and Mepe by osteocyte, whereas long-term administration (12 days) restored also osteoblast number and bone deposition. Importantly, FGF-23 inhibition normalized the expression of key niche molecules, such as Jagged-1 and osteopontin, involved in the functional crosstalk between HSC and the stromal niche. Consistently, the treatment restored the frequency of th3 HSC by expanding the pool of quiescent cells (th3 vs. th3+FGF23inh: 0.026 vs. 0.045% on Lin neg BM cells, p&lt;0.01). FGF-23 inhibition had also a positive anti-apoptotic effect on the expanded BM erythroid compartment (th3 vs. th3+FGF23inh: 61.6±1.3 vs. 51.1±2.1% of BM Ter119 + cells, p&lt;0.001), promoting the maturation of early erythroid precursors (th3 vs. th3+FGF23inh: 8.5±1 vs. 16.4±1.1% of BM Pro-Erythroblasts, p&lt;0.0001), as already shown in models of secondary anemias. Evidence in BT patients showed negative correlations between FGF-23 levels and markers of bone homeostasis (e.g. osteocalcin R 2=0.88, p&lt;0.05) and positive correlations with makers of ineffective erythropoiesis (e.g. circulating reticulocytes R 2=0.83, p&lt;0.05), thus positioning FGF-23 as the molecule at the crossroads of erythropoiesis and bone metabolism in BT. Our findings uncover an underexplored role of FGF-23 in bone and BM niche defects in a primary anemia, as a condition of chronic EPO stimulation, and propose FGF-23 as the missing link between hematopoiesis and bone regulation. The inhibition of FGF-23 signaling might provide a novel strategy to ameliorate bone compartment and restore HSC-BM niche interactions in BT by a 'two birds with one stone' approach, with a potential translational relevance in improving HSC transplantation and gene therapy. Disclosures Cappellini: Celgene: Consultancy, Research Funding; Vifor: Consultancy; La Jolla: Research Funding; Protagonist Therapeutics: Research Funding; IONIS Pharmaceuticals: Consultancy; CRISPR Therapeutics: Research Funding; Novartis: Consultancy, Honoraria, Research Funding.

Effect of Fibroblast Growth Factor-23 (FGF-23) on Two-Year Mortality Rate in Chronic Kidney Disease Patients With Hemodialysis

Introduction Chronic kidney disease (CKD) is a global problem with increasing prevalence, poor prognosis, and high costs. Most deaths of CKD patients with hemodialysis (HD) is cardiovascular disorders. One of risk factors related to cardiovascular disorder is Fibroblast Growth Factor-23 (FGF-23). FGF-23 level is associated with increased mortality in CKD patients with HD. Aim & Objectives The aim of this study is to show the effect of Fibroblast Growth Factor-23 (FGF-23 on two year mortality rate in chronic kidney disease patients with hemodialysis. Materials and Method This retro-prospective mixcohort study with survival analysis obtained data from medical records of CKD patients undergoing HD at the Rasyidah Renal Hospital in the first week of January 2018. Patients were followed up next two years until 31st of December 2019. Kaplan Meier analysis was used to determine the effect of independent variables on dependent variable that was two years mortality, multivariate cox regression analysis to determine the dominant factor and magnitude of the association between independent variable and dependent variable. P-value <0.05 indicates a significant association. Result Kaplan Meier curve showed significant effect of FGF-23 level and Diabetes Mellitus on a two-year survival rate of patients (p = 0.01 and p = 0.04). Based on cox regression multivariate analysis, it was found patients with FGF-23 levels> 365ng/ml had a risk of 3.53 (CI95% 1,104-11,337) times more than group of patients with FGF-23 ≤ 365ng/ml while the presence of diabetes mellitus was risk factor on mortality with HR 3.71 (CI 1,279-10,796). Conclusion Statistically, FGF-23 level> 365 ng/ml is dominant factor that significantly influences 2-year mortality rate of CKD patients with HD other than Diabetes Mellitus. Key Words: Fibroblast Growth Factor, Chronic kidney disease on Hemodialysis, Mortality