Elevated Fibroblast Growth Factor 23 Levels Research Articles

Acquired hypophosphatemic osteomalacia: case series from a Peruvian referral center (1999-2023).

Acquired hypophosphatemic osteomalacia (AHO) is a rare metabolic bone disorder characterized by hypophosphatemia and impaired bone mineralization. Tumor-induced osteomalacia (TIO) is the most common cause of AHO, caused by phosphaturic tumors that overproduce fibroblast growth factor 23 (FGF-23). To present the clinical characteristics, diagnostic challenges, and outcomes of seven cases of AHO in Peruvian patients between 1999 and 2023. A retrospective review of seven patients diagnosed with AHO was conducted. Clinical data, including diagnostic procedures, treatments, and outcomes, were collected. Seven cases of AHO were reviewed. In case one, osteomalacia did not improve despite supraphysiological doses of vitamin D (ergocalciferol/cholecalciferol), and no tumor was detected with available tests, resulting in the patient's death. Cases two and three involved tumors located in the right leg and right hemithorax, respectively, with symptom resolution following total resection. In cases four, five, and seven, exhaustive exams failed to locate tumors. Cases four, six, and seven showed elevated FGF-23 levels, while case five had inappropriately normal FGF-23 levels. Case seven was the first patient in Peru to receive burosumab treatment. In case six, a tumor in the head of the femur was identified, but the patient opted for nonsurgical management. The diagnosis of AHO is challenging, requiring a high index of clinical suspicion and biochemical confirmation. TIO is the most common cause of AHO, emphasizing the importance of locating the phosphaturic tumor. However, in some cases, the tumor remains elusive despite exhaustive diagnostic workups. This is particularly challenging in developing countries like Peru, where resources are limited.

Causal association of serum calcium, phosphate, vitamin D, parathyroid hormone, and FGF23 with the risk of aortic stenosis

Abstract Aim Disorders of mineral metabolism, including elevated levels of serum calcium, phosphate, 25-hydroxyvitamin D (25OH-VitD), parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23), have been reported in patients with calcific aortic valve stenosis (CAVS). However, evidence of the causal role of mineral metabolism in CAVS is still lacking. We aimed to investigate the causality between mineral metabolism and CAVS. Methods A systematic pipeline combining Mendelian randomization (MR), Steiger directionality test, colocalization analysis, protein-protein network, and enrichment analysis was applied to investigate the causal effect. Genome-wide association study (GWAS) and protein quantitative trait loci data for mineral metabolism markers were extracted from large-scale meta-analyses. Summary statistics for CAVS were obtained from two independent GWAS datasets as discovery and replication cohorts (n=374,277 and 653,867). Results In MR analysis, genetic mimicry of serum FGF23 elevation was associated with increased CAVS risk [ORdiscovery=3.081 (1.649-5.760), Pdiscovery=4.21×10-4; ORreplication=2.280 (1.461-3.558), Preplication=2.82×10-4] without evidence of reverse causation (Psteiger=7.21×10-98). Strong colocalisation association with CAVS was observed for FGF23 expression in the blood (PP.H4 = 0.96). Additionally, we identified some protein-protein interactions between FGF23 and known CAVS causative genes. Serum calcium, phosphate, 25OH-VitD, and PTH failed to show causal effects on CAVS at Bonferroni-corrected significance (all P>0.05/5=0.01). Conclusions Elevated serum FGF23 level is a causal risk factor for CAVS, and its mechanism of action in CAVS development may be independent of its function in regulating mineral metabolism. Hence, FGF23 may serve as a circulating marker and a promising preventive target for CAVS, warranting further investigation.

Assessment of experimental circulating biomarkers in volume and pressure overload: insights from a cohort study

Abstract Introduction Experimental biomarkers including Angiopoietin-2 (ANG2), bone morphogenetic protein 10 (BMP10), fibroblast growth factor 23 (FGF23), and insulin-like growth factor-binding protein 7 (IGFBP7) are hypothesized to reflect cardiac pathophysiological processes that are potentially present in adverse cardiac remodeling in volume or pressure overload. This study aims to elucidate the relationship between these circulating biomarkers and the presence of hemodynamically significant pressure or volume overload and adverse outcomes and compare it to N-terminal pro B-type natriuretic peptide (NT-proBNP). Methods We studied the association between the four experimental circulating biomarkers in patients with pressure or volume overload with reference to none/mild valvular disease in N=1302 of an observational outpatient cardiology cohort. The median age was 63.0 (25th/75th quartile 51.5, 71.4) years, 445 (34.2%) were women. Circulating biomarkers were quantified using a novel antibody-based method. Logistic regression models with cox regression plots were employed to assess the association of each biomarker with the severity of valve disease concerning volume or pressure overload, adjusted for age and sex. Results In the overall population, elevated levels of ANG2, BMP10, FGF23 and IGFB7 were positively associated with the presence of significant volume overload (ANG2: Odds ratio (OR) 1.26 (95% confidence interval (CI) 1.17-1.35), p<0.001; BMP10: OR 2.57 (CI 1.89-3.48), p<0.001; FGF23: OR 1.51 (CI 1.14-1.20), p=0.004; IGFBP7: OR 1.39 (CI 1.14-1.69), p=0.001, NT-proBNP: OR 1.69 (CI 1.47-1.95), p<0.001). No statistically significant association between circulating biomarkers and pressure overload was observed. Over a median follow-up of 4 years, 31 (20.1%) participants died in the group of volume overload and 9 (40.9%) individuals in the group of pressure overload. After multivariable-adjustment, elevated levels of BMP 10 showed a borderline association with an increased risk of all-cause mortality in individuals with volume overload compared to none/mild valvular disease: hazard ratio (HR) 1.51 (CI 0.96- 2.38), p=0.075. Higher concentrations of all biomarkers were predictive of all-cause mortality for both individuals with volume overload and those with none/mild valvular disease (ANG2: HR 3.72 (CI 1.67-8.33), p=0.001; BMP10: HR 1.65 (CI 1.20-2.26), p=0.002; FGF23: HR 2.08 (CI 1.65-2.62), p<0.001; IGFBP7: HR 1.55 (CI 1.25-1.91), p<0.001; NT-proBNP: HR 1.72 (CI 1.47-2.00), p<0.001). Conclusions This study demonstrates that circulating biomarkers involved in distinct pathophysiological pathways of inflammation, fibrosis and calcification are elevated in patients with hemodynamically significant volume overload. Since they are also related to mortality, their clinical role needs to be explored further, also in context with the routine biomarker NT-proBNP.

Vitamin D-Parathyroid Hormone-Fibroblast Growth Factor 23 Axis and Cardiac Remodeling.

Cardiac remodeling is a compensatory adaptive response to chronic heart failure (HF) altering the structure, function, and metabolism of the heart. Many nutritional and metabolic diseases can aggravate the pathophysiological development of cardiac remodeling. Vitamin D deficiency leads to cardiac remodeling by activating the renin-angiotensin-aldosterone system (RAAS), resulting in enhanced inflammation and directly promoting cardiac fibrosis and extracellular matrix deposition. Hyperparathyroidism upregulates protein kinase A or protein kinase C, enhances intracellular calcium influx, promotes oxidative stress, activates RAAS, and increases aldosterone levels, thereby aggravating cardiac remodeling. Besides, fibroblast growth factor 23 (FGF23) plays a direct role in the heart, resulting in ventricular hypertrophy and myocardial fibrosis. Vitamin D deficiency leads to hyperparathyroidism, which in turn increases the level of FGF23. Elevated levels of FGF23 further inhibit vitamin D synthesis. Evidence exists that vitamin D deficiency, hyperparathyroidism, and marked elevations in FGF23 concentration form a vicious cycle and are believed to contribute directly to cardiac remodeling. Therefore, the purpose of this article is to introduce the specific effects of the above substances on the heart and to explain the significance of understanding the vitamin D-parathyroid hormone-FGF23 axis in improving or even reversing cardiac remodeling, thus contributing to the treatment of patients with HF.

Increased Cadmium Load, Vitamin D Deficiency, and Elevated FGF23 Levels as Pathophysiological Factors Potentially Linked to the Onset of Acute Lymphoblastic Leukemia: A Review.

The preventability of acute lymphocytic leukemia during childhood is currently receiving great attention, as it is one of the most common cancers in children. Among the known risk factors so far are those affecting the development of gut microbiota, such as a short duration or absence of breastfeeding, cesarean section, a diet lacking in short-chain fatty acids (SCFAs), the use of antibiotics, absence of infection during infancy, and lack of pets, among other factors. Namely, it has been shown that iron deficiency anemia (IDA) and lack of vitamin D may cause intestinal dysbiosis, while at the same time, both increase the risk of hematological malignancies. The presence of IDA and vitamin D deficiency have been shown to lead to a decreased proportion of Firmicutes in stool, which could, as a consequence, lead to a deficit of butyrate. Moreover, children with IDA have increased blood concentrations of cadmium, which induces systemic inflammation and is linked to the onset of an inflammatory microenvironment in the bone marrow. Finally, IDA and Cd exposure increase fibroblast growth factor 23 (FGF23) blood levels, which in turn suppresses vitamin D synthesis. A lack of vitamin D has been associated with a higher risk of ALL onset. In brief, as presented in this review, there are three independent ways in which IDA increases the risk of acute lymphocytic leukemia (ALL) appearance. These are: intestinal dysbiosis, disruption of vitamin D synthesis, and an increased Cd load, which has been linked to systemic inflammation. All of the aforementioned factors could generate the appearance of a second mutation, such as ETV6/RUNX1 (TEL-AML), leading to mutation homozygosity and the onset of disease. ALL has been observed in both IDA and thalassemia. However, as IDA is the most common type of anemia and the majority of published data pertains to it, we will focus on IDA in this review.

Genetic association of serum calcium, phosphate, vitamin D, parathyroid hormone, and FGF23 with the risk of aortic stenosis

Disorders of mineral metabolism, including elevated levels of serum calcium, phosphate, 25-hydroxyvitamin D (25OH-VitD), parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23), have been reported in patients with calcific aortic valve stenosis (CAVS). However, evidence of the causal role of mineral metabolism in CAVS is still lacking. In this study, we employed a systematic pipeline combining Mendelian randomization (MR), Steiger directionality test, colocalization analysis, protein-protein network, and enrichment analysis to investigate the causal effect of mineral metabolism on CAVS. Genome-wide association study (GWAS) and protein quantitative trait loci data for mineral metabolism markers were extracted from large-scale meta-analyses. Summary statistics for CAVS were obtained from two independent GWAS datasets as discovery and replication cohorts (n = 374,277 and 653,867). In MR analysis, genetic mimicry of serum FGF23 elevation was associated with increased CAVS risk [ORdiscovery = 3.081 (1.649–5.760), Pdiscovery = 4.21 × 10−4; ORreplication = 2.280 (1.461 – 3.558), Preplication = 2.82 × 10−4] without evidence of reverse causation (Psteiger= 7.21 × 10−98). Strong colocalisation association with CAVS was observed for FGF23 expression in the blood (PP.H4 = 0.96). Additionally, we identified some protein-protein interactions between FGF23 and known CAVS-associated genes. Serum calcium, phosphate, 25OH-VitD, and PTH failed to show causal effects on CAVS at Bonferroni-corrected significance (all P > 0.05/5 = 0.01). In conclusion, elevated serum FGF23 level may act as a causal risk factor for CAVS, and its mechanism of action in CAVS development may be independent of its function in regulating mineral metabolism. Hence, FGF23 may serve as a circulating marker and a promising preventive target for CAVS, warranting further investigation.

Estimated Proximal Tubule Fluid Phosphate Concentration and Renal Tubular Damage Biomarkers in Early Stages of Chronic Kidney Disease

IntroductionAn increase in proximal tubule fluid phosphate concentration is caused by increased serum fibroblast growth factor 23 (FGF23) levels, which resulted in renal tubular damage in a mouse model of chronic kidney disease (CKD). However, few human studies have supported this concept. This study aimed to explore the association among estimated proximal tubule fluid phosphate concentration (ePTFp), serum FGF23 levels, and renal tubular damage biomarkers in middle-aged and older populations with mild decline in renal function. MethodsThis cross-sectional study included 218 participants aged ≥45 with CKD stages G2–G4. Anthropometric measurements, blood tests, spot urine biomarkers, renal ultrasonography, cardiovascular assessment, smoking status, and medication usage were obtained in the morning in fasted states. The ePTFp was calculated using serum creatinine, urine phosphate, and creatinine concentrations. Urinary β2-microglobulin and liver-type fatty acid-binding protein (L-FABP) levels were evaluated to assess renal tubular damage.Results: ePTFp, serum FGF23, urinary β2-microglobulin, and urinary L-FABP levels increased with CKD stage progression (stages G2, G3, and G4). However, serum and urine phosphate concentrations were comparable across the CKD stages. Univariate analysis revealed a stronger correlation of ePTFp with serum FGF23, urinary β2-microglobulin, and urinary L-FABP levels than with the corresponding serum and urine phosphate concentrations. Multivariate analyses demonstrated that increased ePTFp was independently associated with elevated serum FGF23 and urinary β2-microglobulin levels, even after adjusting for potential covariates, including the estimated glomerular filtration rate and urinary albumin-to-creatinine ratio. ConclusionsOur results are consistent with the concept in mouse model and suggest that increased ePTFp are associated with increased serum FGF23 levels and renal tubular damage during the early stages of CKD.

Roles of Parathyroid Hormone and Fibroblast Growth Factor 23 in Advanced Chronic Kidney Disease.

Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) each play a central role in the pathogenesis of chronic kidney disease (CKD)-mineral and bone disorder. Levels of both hormones increase progressively in advanced CKD and can lead to damage in multiple organs. Secondary hyperparathyroidism (SHPT), characterized by parathyroid hyperplasia with increased PTH secretion, is associated with fractures and mortality. Emerging evidence suggests that these associations may be partially explained by PTH-induced browning of adipose tissue and increased energy expenditure. Observational studies suggest a survival benefit of PTHlowering therapy, and a recent study comparing parathyroidectomy and calcimimetics further suggests the importance of intensive PTH control. The mechanisms underlying the regulation of FGF23 secretion by osteocytes in response to phosphate load have been unclear, but recent experimental studies have identified glycerol-3-phosphate, a byproduct of glycolysis released by the kidney, as a key regulator of FGF23 production. Elevated FGF23 levels have been shown to be associated with mortality, and experimental data suggest off-target adverse effects of FGF23. However, the causal role of FGF23 in adverse outcomes in CKD patients remains to be established. Further studies are needed to determine whether intensive SHPT control improves clinical outcomes and whether treatment targeting FGF23 can improve patient outcomes.

Hypericin Alleviates Chronic Kidney Disease-induced Left Ventricular Hypertrophy by Regulation of FGF23-FGFR4 Signaling Pathway.

Chronic kidney disease (CKD) is a significant global health threat that imposes a substantial burden on both individuals and societies. CKD frequently correlates with cardiovascular events, particularly left ventricular hypertrophy (LVH), which contributes to the high mortality rate associated with CKD. Fibroblast growth factor 23 (FGF23), a hormone primarily involved in regulating calcium and phosphorus metabolism, has been identified as a major risk factor for LVH in CKD patients. Elevated serum FGF23 levels are known to induce LVH and myocardial fibrosis by activating the fibroblast growth factor receptor 4 (FGFR4) signal pathway. Therefore, targeting FGFR4 and its downstream signaling pathways holds potential as a treatment strategy for cardiac dysfunction in CKD. In our current study, we have discovered that Hypericin, a key component derived from Hypericum perforatum , has the ability to alleviate CKD-related LVH by targeting the FGFR4/phospholipase C gamma 1 (PLCγ1) signaling pathway. Through in vitro experiments using rat cardiac myocyte H9c2 cells, we observed that Hypericin effectively inhibits FGF23-induced hypertrophy and fibrosis by suppressing the FGFR4/PLCγ1/calcineurin/nuclear factor of activated T-cell (NFAT3) signaling pathway. In addition, our in vivo studies using mice on a high-phosphate diet and rat models of 5/6 nephrectomy demonstrated that Hypericin has therapeutic effects against CKD-induced LVH by modulating the FGFR4/PLCγ1/calcineurin/NFAT3 signaling pathway. In conclusion, our research highlights the potential of Hypericin as a candidate for the treatment of CKD-induced cardiomyopathy. By suppressing the FGFR4/PLCγ1 signaling pathway, Hypericin shows promise in attenuating LVH and myocardial fibrosis associated with CKD.

FgF23 and soluble klotho effects on the myocardium: an ex vivo study

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): German Center for Cardiovascular research Background Fibroblast Growth Factor 23 (FGF23) and soluble Klotho (sKL) play a critical role in mineral homeostasis in the body by acting on the kidney to regulate phosphate levels. Circulating FGF23 levels rise in patients with kidney disease and dysregulation of the FGF23 –sKL- axis is a common phenomenon in uremic cardiomyopathy. Studies have shown that elevated FGF23 levels induce cardiac hypertrophy by targeting cardiac myocytes via FGF receptor isoform 4 (FGFR4), while sKL mitigates these effects and may also exert an independent protective effect on the heart(1,2). Purpose We aimed to study the effects of FGF23 and sKL on myocardial contractility, calcium handling and molecular signaling pathways in the human heart using an ex vivo model of cultured contracting myocardial slices. Methods We obtained human heart slices from explanted hearts from patients undergoing cardiac transplantation at the LMU Klinikum Munich, Germany. The 300 µm thick slices were cultured under continuous stimulation (1 Hz, 3 ms pulse width) with 1 mN preload, and contractile function were recorded continuously. Slices with vehicle, recombinant FGF23 protein (100ug/ml), recombinant sKL protein (200ug/ml) and both FGF23((100ug/ml)+sKL (200ug/ml) were continuously monitored over 10 days. We checked for mRNA expression using RT PCR. Results Treatment of human left ventricular tissue with recombinant FGF23 protein resulted in enhanced mRNA expression of the FGFR4. sKL treatment alone induced downregulation of the FGFR4 gene and mitigated upregulation of FGFR4 in FGF23+ sKL treated slices. Post pause potentiation (PPP), assessed by pausing the stimulation of the slices for 120s and then measuring the relative height of the first beat after resumption of pacing, is an indirect measure of sarcoplasmic reticulum Ca2+ handling capacity. PPP was reduced in FGF23 treated slices and heightened in the slices with sKL compared to vehicle treated ones, indicating that FGF23 and sKL play a role in intracellular Ca2+ handling. Conclusions sKL and FGF23 have opposite effects on human cardiac muscle with sKL mitigating FGF23-induced upregulation of FGFR4. Furthermore, sKL improves, while FGF23 impairs myocardial calcium handling . As altered calcium handling may also be involved in hypertrophic signaling altered calcium handling may provide a means by which FGF23 promotes and sKL inhibits myocardial hypertrophy. sKL is advocated as a promising candidate in exploring it therapeutic role in FGF23 mediated cardiomyopathy. We intend to advance our understanding of sKL-FGF23signaling mechanisms by combining transcriptomic analysis with functional data in this model of myocardial slice culture.

Cardiovascular health in pediatric patients with X-linked hypophosphatemia under two years of burosumab therapy.

X-linked hypophosphatemia (XLH) is caused by an inactivating mutation in the phosphate-regulating endopeptidase X-linked (PHEX) gene whose defective product fails to control phosphatonin fibroblast growth factor 23 (FGF23) serum levels. Although elevated FGF23 levels have been linked with detrimental cardiac effects, the cardiologic outcomes in XLH patients have been subject to debate. Our study aimed to evaluate the prevalence and severity of cardiovascular morbidity in pediatric XLH patients before, during, and after a 2-year treatment period with burosumab, a recombinant anti-FGF23 antibody. This prospective observational study was conducted in a tertiary medical center, and included 13 individuals with XLH (age range 0.6-16.2 years) who received burosumab every 2 weeks. Clinical assessment at treatment initiation and after .5, 1, and 2 years of uninterrupted treatment included anthropometric measurements and cardiologic evaluations (blood pressure [BP], electrocardiogram, conventional echocardiography, and myocardial strain imaging). The linear growth of all patients improved significantly (mean height z-score: from -1.70 ± 0.80 to -0.96 ± 1.08, P=0.03). Other favorable effects were decline in overweight/obesity rates (from 46.2% to 23.1%) and decreased rates of elevated BP (systolic BP from 38.5% to 15.4%; diastolic BP from 38.5% to 23.1%). Electrocardiograms revealed no significant abnormality throughout the study period. Cardiac dimensions and myocardial strain parameters were within the normative range for age at baseline and remained unchanged during the study period. Cardiologic evaluations provided reassurance that 2 years of burosumab therapy did not cause cardiac morbidity. The beneficial effect of this treatment was a reduction in cardiovascular risk factors, as evidenced by the lower prevalence of both overweight/obesity and elevated BP.

Relationships of serum FGF23 and α-klotho with atherosclerosis in patients with type 2 diabetes mellitus

BackgroundCompelling evidence suggests that calcium/phosphorus homeostasis-related parameters may be linked to diabetes mellitus and cardiovascular events. However, few studies have investigated the association of fibroblast growth factor 23 (FGF23), α-klotho and FGF23/α-klotho ratio with atherosclerosis in patients with type 2 diabetes mellitus (T2DM).ObjectiveThis study was designed to evaluate whether FGF23, α-klotho and FGF23/α-klotho ratio are associated with T2DM and further to explore the relationships between these three factors and atherosclerosis in Chinese patients with T2DM.MethodsSerum FGF23 and α-klotho levels were measured via an enzyme-linked immunosorbent assay (ELISA) kit, and the carotid intima-media thickness (CIMT) was assessed via high-resolution color Doppler ultrasonography. The associations of serum FGF23, α-klotho and FGF23/α-klotho ratio with atherosclerosis in T2DM patients were evaluated using multivariable logistic regression models.ResultsThis cross-sectional study involved 403 subjects (207 with T2DM and 196 without T2DM), 41.7% of the patients had atherosclerosis, and 67.2% of the carotid intima were thickened to a thickness greater than 0.9 mm. Compared with those in the lowest tertile, higher tertiles of FGF23 levels and FGF23/α-klotho ratio were positively associated with T2DM after adjusting for covariates, and serum α-klotho concentration was inversely correlated with T2DM (all P values < 0.01). Moreover, elevated serum FGF23 levels and FGF23/α-klotho ratio were positively associated with CIMT and carotid atherosclerosis in T2DM patients (all P values < 0.01). Further spline analysis similarly revealed linear dose‒response relationship (all P values < 0.01). And there was still significant differences in CIMT and carotid atherosclerosis between the highest group of α-klotho and the reference group in T2DM patients (P values = 0.05).ConclusionsT2DM was positively linearly related to serum FGF23 concentration and FGF23/α-klotho ratio, and negatively correlated with serum α-klotho concentration. Furthermore, both FGF23 and FGF23/α-klotho ratio were positively correlated with CIMT and atherosclerosis in T2DM patients, while α-klotho was inversely correlated with both CIMT and atherosclerosis, although the associations were not completely significant. Prospective exploration and potential mechanisms underlying these associations remain to be further elucidated.

Gα11 deficiency increases fibroblast growth factor 23 levels in a mouse model of familial hypocalciuric hypercalcemia.

Fibroblast growth factor 23 (FGF23) production has recently been shown to increase downstream of Gαq/11-PKC signaling in osteocytes. Inactivating mutations in the gene encoding Gα11 (GNA11) cause familial hypocalciuric hypercalcemia (FHH) due to impaired calcium-sensing receptor signaling. We explored the effect of Gα11 deficiency on FGF23 production in mice with heterozygous (Gna11+/-) or homozygous (Gna11-/-) ablation of Gna11. Both Gna11+/- and Gna11-/- mice demonstrated hypercalcemia and mildly raised parathyroid hormone levels, consistent with FHH. Strikingly, these mice also displayed increased serum levels of total and intact FGF23 and hypophosphatemia. Gna11-/- mice showed augmented Fgf23 mRNA levels in the liver and heart, but not in bone or bone marrow, and also showed evidence of systemic inflammation with elevated serum IL-1β levels. Furin gene expression was significantly increased in the Gna11-/- liver, suggesting enhanced FGF23 cleavage despite the observed rise in circulating intact FGF23 levels. Gna11-/- mice had normal renal function and reduced serum levels of glycerol-3-phosphate, excluding kidney injury as the primary cause of elevated intact FGF23 levels. Thus, Gα11 ablation caused systemic inflammation and excess serum FGF23 in mice, suggesting that patients with FHH - at least those with GNA11 mutations - may be at risk for these complications.

Phosphate Restriction Prevents Metabolic Acidosis and Curbs Rise in FGF23 and Mortality in Murine Folic Acid-Induced AKI.

Patients with AKI suffer a staggering mortality rate of approximately 30%. Fibroblast growth factor 23 (FGF23) and phosphate (P i ) rise rapidly after the onset of AKI and have both been independently associated with ensuing morbidity and mortality. This study demonstrates that dietary P i restriction markedly diminished the early rise in plasma FGF23 and prevented the rise in plasma P i , parathyroid hormone, and calcitriol in mice with folic acid-induced AKI (FA-AKI). Furthermore, the study provides evidence for P i -sensitive osseous Fgf23 mRNA expression and reveals that P i restriction mitigated calciprotein particles (CPPs) formation, inflammation, acidosis, cardiac electrical disturbances, and mortality in mice with FA-AKI. These findings suggest that P i restriction may have a prophylactic potential in patients at risk for AKI. In AKI, plasma FGF23 and P i rise rapidly and are independently associated with disease severity and outcome. The effects of normal (NP) and low (LP) dietary P i were investigated in mice with FA-AKI after 3, 24, and 48 hours and 14 days. After 24 hours of AKI, the LP diet curbed the rise in plasma FGF23 and prevented that of parathyroid hormone and calcitriol as well as of osseous but not splenic or thymic Fgf23 mRNA expression. The absence of Pth prevented the rise in calcitriol and reduced the elevation of FGF23 in FA-AKI with the NP diet. Furthermore, the LP diet attenuated the rise in renal and plasma IL-6 and mitigated the decline in renal α -Klotho. After 48 hours, the LP diet further dampened renal IL-6 expression and resulted in lower urinary neutrophil gelatinase-associated lipocalin. In addition, the LP diet prevented the increased formation of CPPs. Fourteen days after AKI induction, the LP diet group maintained less elevated plasma FGF23 levels and had greater survival than the NP diet group. This was associated with prevention of metabolic acidosis, hypocalcemia, hyperkalemia, and cardiac electrical disturbances. This study reveals P i -sensitive FGF23 expression in the bone but not in the thymus or spleen in FA-AKI and demonstrates that P i restriction mitigates CPP formation, inflammation, acidosis, and mortality in this model. These results suggest that dietary P i restriction could have prophylactic potential in patients at risk for AKI.

High pretransplant FGF23 level is associated with persistent vitamin D insufficiency and poor graft survival in kidney transplant patients

Vitamin D3 (25[OH]D3) insufficiency and fibroblast growth factor 23 (FGF23) elevation are usually attenuated after kidney transplantation (KT). However, elevated FGF23 may be associated with poor graft outcomes and vitamin D insufficiency after KT. This study investigated the effect of pretransplant FGF23 levels on post-KT 25(OH)D3 status and graft outcomes. Serum FGF23 levels from 400 participants of the KoreaN Cohort Study for Outcome in Patients With Kidney Transplantation were measured. Annual serum 25(OH)D3 levels, all-cause mortality, cardiovascular event, and graft survival were assessed according to baseline FGF23 levels. Serum 25(OH)D3 levels were initially increased 1 year after KT (12.6 ± 7.4 vs. 22.6 ± 6.4 ng/mL). However, the prevalence of post-KT vitamin D deficiency increased again after post-KT 3 years (79.1% at baseline, 30.8% and 37.8% at 3 and 6 years, respectively). Serum FGF23 level was decreased 3 years post-KT. When participants were categorized into tertiles according to baseline FGF23 level (low, middle, high), 25(OH)D3 level in the low FGF23 group was persistently low at a median follow-up of 8.3 years. Furthermore, high baseline FGF23 level was a risk factor for poor graft survival (HR 5.882, 95% C.I.; 1.443–23.976, P = 0.013). Elevated FGF23 levels are associated with persistently low post-transplant vitamin D levels and poor graft survival.

Bone Marrow Sinusoidal Endothelial Cells Are a Site of Fgf23 Upregulation in Murine ß-Thalassemia

Fibroblast growth factor-23 (FGF23) is a bone-derived hormonal regulator of mineral metabolism with emerging functions in the bone marrow. FGF23 has been reported to negatively regulate erythropoiesis [PMID:24509850] and promote hematopoietic progenitor mobilization from the bone marrow [PMID:33512467]. Elevated FGF23 levels in the circulation have been described in iron-deficient subjects and also in subjects with the iron-loading anemia β-thalassemia. Recently, we reported bone marrow sinusoidal endothelial cells (BM-SEC) as a novel site of Fgf23 upregulation in mice with chronic iron-deficiency anemia and acute, phlebotomy-induced anemia [PMID:37417950]. We and others have detected Fgf23 mRNA elevation in total bone marrow of Hbb th3/+ mice, a model of non-transfusion dependent β-thalassemia that exhibits systemic iron loading. In the present study, we sought to clarify sites of Fgf23 promoter activity in Hbb th3/+ bone marrow using a reporter allele in which the enhanced green fluorescent protein (eGFP) coding sequence is knocked into the endogenous Fgf23 locus ( Fgf23 eGFP). We generated Hbb +/+ and Hbb th3/+ female littermates that carried either one ( Fgf23 +/eGFP) or zero ( Fgf23 +/+) copies of the Fgf23 reporter allele, which were raised on a standard rodent diet (200 mg/kg iron, 1.0% calcium, 0.7% phosphorus). Fgf23 eGFP/eGFP homozygotes were not generated due to known early growth retardation and mortality in Fgf23 null mice. After blood and tissue collection at 8 weeks of age, phenotypes of the 4 Hbb-Fgf23 genotype combinations were compared by two-way ANOVA. Compared to mice with intact Hbb and Fgf23 alleles ( Hbb +/+ Fgf23 +/+), Hbb th3/+ Fgf23 +/+ mice showed markedly elevated plasma levels of “total” FGF23 (sum of intact, active hormone and C-terminal cleaved fragments). Plasma total FGF23 levels in Hbb th3/+ Fgf23 +/+ and Hbb th3/+ Fgf23 +/eGFP mice were similar, indicating utility of the latter genotype for interrogating sites of increased Fgf23 expression in murine b-thalassemia. We therefore used anti-GFP immunohistochemistry in formalin-fixed bone marrow sections to assess Fgf23 eGFP reporter allele expression in the context of tissue architecture. Hbb th3/+ Fgf23 +/eGFP mice showed GFP expression in BM-SEC throughout the bone marrow, which was more intense than in non-anemic Hbb +/+ Fgf23 +/eGFP mice; controls lacking the Fgf23 eGFP allele confirmed anti-GFP antibody specificity. Hbb th3/+ mice also showed Fgf23 eGFP reporter expression in the thymic vasculature but not vasculature of the liver, spleen, or kidney. In contrast to their marked elevation in plasma total FGF23, Hbb th3/+ Fgf23 +/+ mice showed plasma levels of the intact, biologically-active FGF23 hormone that overlapped with levels in Hbb +/+ Fgf23 +/+ controls. Interestingly, compared with Hbb th3/+ Fgf23 +/+ mice, Hbb th3/+ Fgf23 +/eGFP mice showed 45% lower plasma intact FGF23, suggesting an effect of Fgf23 gene dosage. Given prior reported effects of FGF23 on hematopoiesis, we assessed if Fgf23 gene dosage modulated the severity of ineffective erythropoiesis in Hbb th3/+ mice. Compared to Hbb +/+ Fgf23 +/+ controls, Hbb th3/+ Fgf23 +/+ mice showed reductions in RBC, hemoglobin, and mean corpuscular hemoglobin, as well as increases in RDW and in spleen weight (reflecting extramedullary hematopoiesis). However, the severity of these parameters was not modified by heterozygous Fgf23 disruption ( Hbb th3/+ Fgf23 +/eGFP).While FGF23 has been reported to induce left ventricular hypertrophy [PMID:21985788], Hbb th3/+ Fgf23 +/+ and Hbb th3/+ Fgf23 +/eGFP mice showed similarly increased heart-to-body weight ratios compared to Hbb +/+ Fgf23 +/+ controls. In non-thalassemic mice, heterozygous Fgf23 disruption ( Hbb +/+ Fgf23 +/eGFP) caused a trend ( P=0.10) towards lower plasma intact FGF23 while not impacting hematological parameters or spleen weight. In summary, by showing that Fgf23 gene dosage modulates plasma intact FGF23 levels in Hbb th3/+ mice without altering severity of anemia or splenomegaly, our data suggest that moderate reductions in circulating levels of the intact FGF23 hormone do not alter the severity of ineffective erythropoiesis in Hbb th3/+mice at 8 weeks of age. Our finding that β-thalassemic mice exhibit Fgf23 upregulation in BM-SEC lays the groundwork for future investigation of the functional effects of locally-produced FGF23 in the thalassemic hematopoietic stem cell niche.

Fibroblast Growth Factor 23 and Risk of Heart Failure Subtype: The CRIC (Chronic Renal Insufficiency Cohort) Study

Heart failure (HF) is an important cause of morbidity and mortality among individuals with chronic kidney disease (CKD). A large body of evidence from preclinical and clinical studies implicates excess levels of fibroblast growth factor 23 (FGF23) in HF pathogenesis in CKD. It remains unclear whether the relationship between elevated FGF23 levels and HF risk among individuals with CKD varies by HF subtype. Prospective cohort study. A total of 3,502 participants were selected in the Chronic Renal Insufficiency Cohort study. Baseline plasma FGF23. Incident HF by subtype and total rate of HF hospitalization. HF was categorized as HF with preserved ejection fraction (HFpEF, ejection fraction [EF]≥ 50%), HF with reduced EF (HFrEF, EF<50%) and HF with unknown EF (HFuEF). Multivariable-adjusted cause-specific Cox proportional hazards models were used to investigate associations between FGF23 and incident hospitalizations for HF by subtype. The Lunn-McNeil method was used to compare hazard ratios across HF subtypes. Poisson regression models were used to evaluate the total rate of HF. During a median follow-up time of 10.8 years, 295 HFpEF, 242 HFrEF, and 156 HFuEF hospitalizations occurred. In multivariable-adjusted cause-specific Cox proportional hazards models, FGF23 was significantly associated with the incidence of HFpEF (HR, 1.41; 95% CI, 1.21-1.64), HFrEF (HR, 1.27; 95% CI, 1.05-1.53), and HFuEF (HR, 1.40; 95% CI, 1.13-1.73) per 1 standard deviation (SD) increase in the natural log of FGF23. The Lunn-McNeil method determined that the risk association was consistent across all subtypes. The rate ratio of total HF events increased with FGF23 quartile. In multivariable-adjusted models, compared with quartile 1, FGF23 quartile 4 had a rate ratio of 1.81 (95% CI, 1.28-2.57) for total HF events. Self-report of HF hospitalizations and possible lack of an echocardiogram at time of hospitalization. In this large multicenter prospective cohort study, elevated FGF23 levels were associated with increased risks for all HF subtypes. Heart failure (HF) is a prominent cause of morbidity and mortality in individuals with chronic kidney disease (CKD). Identifying potential pathways in the development of HF is essential in developing therapies to prevent and treat HF. In a large cohort of individuals with CKD, the Chronic Renal Insufficiency Cohort (N=3,502), baseline fibroblast growth factor-23 (FGF23), a hormone that regulates phosphorous, was evaluated in relation to the development of incident and recurrent HF with reduced, preserved, and unknown ejection fraction. In this large multicenter prospective cohort study, elevated FGF23 levels were associated with increased risk of all HF subtypes. These findings demonstrate the need for further research into FGF23 as a target in preventing the development of HF in individuals with CKD.

Relationship of Fibroblast Growth Factor 23 Serum Levels with Disease Characteristics in Systemic Lupus Erythematosus Patients.

Fibroblast growth factor 23 (FGF23), a hormone secreted by osteocytes and osteoblasts, is a major regulator of vitamin D and phosphate homeostasis. FGF23 has been associated with the disturbance of mineral homeostasis, and with kidney and cardiovascular diseases. Systemic lupus erythematosus (SLE) is an autoimmune disorder that can affect virtually any organ. In the present work, we set out to analyze the relationship of FGF23 with the expression of SLE, including patterns of activity, damage, and severity. A total of 284 well-characterized patients with SLE were recruited. Activity (SLEDAI), severity (Katz), and damage index (SLICC-DI) scores were determined. The serum levels of FGF23 were also assessed. Multivariable linear regression analysis was performed to study the relationship between disease characteristics and FGF23. FGF23 and 25(OH) vitamin D were negatively correlated. Furthermore, prednisone use was associated with higher circulating FGF23 after an adjustment for confounding factors. SLICC-DI was related to higher serum levels of FGF23 after a multivariable analysis. However, when the SLICC-DI index items and domains were analyzed separately, apart from proteinuria ≥3.5 gm/24 h, only the musculoskeletal domain, encompassing arthritis and osteoporosis, was significantly associated with higher serum levels of FGF23. In conclusion, an association is observed between elevated serum FGF23 levels and disease damage, particularly related to musculoskeletal complications and proteinuria, in patients with SLE.

Treating 'osteoporosis': a near miss in an unusual case of FGF-23-mediated hypophosphataemic osteomalacia.

We present the case of a 60-year-old female who developed repeated atraumatic stress fractures. She was initially diagnosed with osteoporosis based on her dual-energy X-ray absorptiometry (DXA) scan bone mineral density (BMD) T-scores and started on denosumab therapy. Secondary osteoporosis screen revealed abnormal myeloma screen and low serum phosphate levels. It was thought that the patient had multiple myeloma with associated Fanconi-related tubular dysfunction. However, fibroblast growth factor-23 (FGF-23) levels were grossly elevated, making Fanconi syndrome unlikely. The patient was subsequently diagnosed with two separate conditions, namely cardiac amyloid light-chain (AL) amyloidosis and FGF-23-related hypophosphataemia, likely due to tumour-induced osteomalacia. This case highlights the importance of excluding osteomalacia as a cause of low BMD and checking FGF-23 levels in the workup for hypophosphataemia. Tumour-induced osteomalacia is a difficult diagnosis as the tumour is often small and slow growing. Imaging may fail to identify a tumour, and treatment therefore consists of calcitriol and phosphate replacement. Tumour-induced osteomalacia should be suspected in the adult presenting with new-onset hypophosphataemia, elevated FGF-23 levels and isolated renal phosphate wasting. Serum phosphate is not part of the routine chemistry panels. Routinely checking phosphate levels prior to initiating antiresorptive therapy is warranted. DXA cannot distinguish low bone mineral density due to osteoporosis from osteomalacia. Antiresorptive therapy should be avoided in osteomalacia due to the risk of clinical and radiographic deterioration.

Lipocalin-2: a novel link between the injured kidney and the bone.

Fibroblast growth factor 23 (FGF23) excess is associated with left ventricular hypertrophy (LVH) and early mortality in patients with chronic kidney disease (CKD) and in animal models. Elevated Lipocalin-2 (LCN2), produced by the injured kidneys, contributes to CKD progression and might aggravate cardiovascular outcomes. The current review aims to highlight the role of LCN2 in CKD, particularly its interactions with FGF23. Inflammation, disordered iron homeostasis and altered metabolic activity are common complications of CKD, and are associated with elevated levels of kidney-produced LCN2 and bone-secreted FGF23. A recent study shows that elevated LCN2 increases FGF23 production, and contributes to cardiac injury in patients and animals with CKD, whereas LCN2 reduction in mice with CKD reduces FGF23, improves cardiovascular outcomes and prolongs lifespan. In this manuscript, we discuss the potential pathophysiological functions of LCN2 as a major kidney-bone crosstalk molecule, linking the progressive decline in kidney function to excessive bone FGF23 production. We also review associations of LCN2 with kidney, cardiovascular and bone and mineral alterations. We conclude that the presented data support the design of novel therapeutic approaches to improve outcomes in CKD.