Higher Fibroblast Growth Factor 23 Research Articles

Glucose Metabolic Abnormalities and Their Interaction With Defective Phosphate Homeostasis in Tumor-induced Osteomalacia.

Phosphate homeostasis was compromised in tumor-induced osteomalacia (TIO) due to increased fibroblast growth factor 23 (FGF23) secretion. Nevertheless, the glucose metabolic profile in TIO patients has not been investigated. This work aimed to clarify the glucose metabolic profiles in TIO patients and explore their interaction with impaired phosphate homeostasis. 20 TIO patients, 20 individuals with normal glucose tolerance, and 20 patients with type 2 diabetes mellitus (DM) were enrolled and underwent an oral glucose tolerance test (OGTT). Serum phosphate and FGF23 concentration were monitored during OGTT. In patients with TIO, 60% (12/20) exhibited impaired glucose tolerance (IGT) and 5% (1/20) had type 2 DM. Those with IGT or type 2 DM experienced more ambulatory difficulties (69.2% vs 42.9%), lower phosphate concentrations (0.43 ± 0.10 vs 0.53 ± 0.10, P = .042), and lower calcium concentrations (2.20 ± 0.08 vs 2.30 ± 0.40, P = .001) compared to TIO patients without these conditions. According to correlation analysis, serum phosphate levels were negatively correlated with plasma glucose levels at 60 minutes (P < .001), fasting plasma insulin levels (P < .05), and homeostasis model assessment for insulin resistance (P < .05). Those with high FGF23 levels had a higher glucose level at 60 minutes (10.5 [9.3, 12.3] vs 7.3 [6.4, 10.1], P = .048) than that of low group. After glucose loading, both FGF23 and phosphate levels exhibited a decreasing trend. The development of diabetes in TIO patients may be predisposed by ambulatory issues, low phosphate, and elevated FGF23 levels. Dysglycemia might further aggravate hypophosphatemia.

Role of serum fibroblast growth factor-23 and Klotho level in COVID-19 infection-related mortality: a prospective study.

This study investigated the role of fibroblast growth factor 23 (FGF23)/Klotho in the mortality of patients hospitalized with coronavirus disease 2019 (COVID-19), excluding those with chronic kidney disease (CKD). A prospective cross-sectional study was conducted from April 2021 to May 2022. Patients who tested positive for COVID-19 via polymerase chain reaction and were hospitalized, were classified into two groups (survivors and non-survivors) at the end of their hospital follow-up. Demographic data, clinical status, and prognosis were analyzed. A total of 66 patients (age 58.8 ± 17.0 years, 60.6% male) were included. The mean age of non-survivors (67.2 ± 1 years) was significantly higher than the survivors (49.2 ± 1 years; p < 0.0001). FGF23 was significantly elevated in non-survivors (301 ± 20 pg/mL), compared to survivors (160 ± 36 pg/mL; p < 0.0001). Factors with significant differences (p < 0.001) between the two groups were investigated as independent mortality predictors using logistic regression analysis. FGF23 (p = 0.01), age (p = 0.045), and oxygen saturation at admission (p = 0.02) were independent predictors of mortality. High serum FGF23 levels were associated with COVID-19-related mortality; Klotho levels were lower (p = 0.028). Vitamin D was not significantly different between the groups. Elevated serum FGF23 and parathyroid hormone (PTH), and lower Klotho levels, were associated with COVID-19-related mortality in patients without CKD. There was no association with serum vitamin D levels. Further studies are required to establish the relationship between mortality and FGF23/Klotho, PTH, and vitamin D levels.

Carotid intima-media thickness, fibroblast growth factor 23, and mineral bone disorder in children with chronic kidney disease

BackgroundCarotid intima-media thickness (cIMT) is a measure of atherosclerotic vascular disease and a surrogate biomarker for cardiovascular risk in patients with chronic kidney disease (CKD). Mineral and bone disorders (MBD) are complications of CKD, contributing to vascular calcification and accelerated atherosclerosis. Increased fibroblast growth factor 23 (FGF23)—the earliest detectable serum abnormality associated with CKD-MBD—has been linked with cardiovascular disease in patients with CKD. This study aimed to identify factors and analyze the relationship associated with high cIMT, high FGF23, and poor MBD control in children with CKD.MethodsA cross-sectional study was conducted in Yogyakarta, Indonesia recruiting children with CKD. The correlations and factors between cIMT, FGF23, and MBD were explored.ResultsWe recruited 42 children aged 2–18 years old with CKD stages 2 to 5D. There were no significant correlations between cIMT and factors including advanced CKD, use of dialysis, body mass index, hypertension, anemia, MBD, FGF23 levels, and left ventricular mass index (LVMI). Patients with advanced CKD had poorly controlled anemia, hypertension, and higher LVMI. In multivariate analysis, CKD stages, hypertension stages, the presence of MBD, and LVMI were associated with FGF23 levels (p < 0.05).ConclusionsFGF23 levels increased with CKD progression, and MBD was more prevalent in advanced kidney disease. Elevated FGF23 is potentially associated with increased MBD prevalence in late-stage CKD. A larger study is needed to confirm the factors affecting cIMT in children with CKD.

FGF21 modulates immunometabolic homeostasis via the ALOX15/15-HETE axis in early liver graft injury

Fibroblast growth factor 21 (FGF21) is essential for modulating hepatic homeostasis, but the impact of FGF21 on liver graft injury remains uncertain. Here, we show that high FGF21 levels in liver graft and serum are associated with improved graft function and survival in liver transplantation (LT) recipients. FGF21 deficiency aggravates early graft injury and activates arachidonic acid metabolism and regional inflammation in male mouse models of hepatic ischemia/reperfusion (I/R) injury and orthotopic LT. Mechanistically, FGF21 deficiency results in abnormal activation of the arachidonate 15-lipoxygenase (ALOX15)/15-hydroxy eicosatetraenoic acid (15-HETE) pathway, which triggers a cascade of innate immunity-dominated pro-inflammatory responses in grafts. Notably, the modulating role of FGF21/ALOX15/15-HETE pathway is more significant in steatotic livers. In contrast, pharmacological administration of recombinant FGF21 effectively protects against hepatic I/R injury. Overall, our study reveals the regulatory mechanism of FGF21 and offers insights into its potential clinical application in early liver graft injury after LT.

#2524 Impact of sevelamer hydrochloride on fibroblast growth factor-23 levels in patients undergoing hemodialysis

Abstract Background and Aims 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. Reduction of high intact FGF23 concentration is a strategy, possibly improving the consequences of CKD. We aimed to Assessing the Impact of Sevelamer Carbonate on Fibroblast Growth Factor-23 Levels. Method This case-control study enrolled 100 pre-existing hemodialysis patients, evenly divided into two groups of 50. Group I received a specific sevelamer hydrochloride (Renagel)® dose (2 tablets every 8 hrs), while Group II served as the control group and did not receive (Renagel)®. All patients received the same modality of dialysis with a consistent dialysate calcium concentration. Additionally, they received comprehensive dietary phosphate counseling as part of the standard dietary education provided to our dialysis patients. The levels of phosphorus, calcium, alkaline phosphatase, and FGF23 were assessed in all individuals at the beginning of the study (baseline) and again following 3 months of sevelamer therapy. Results While baseline FGF-23 levels were not statistically different, a highly significant divergence emerged after 3 months of treatment. The sevelamer group experienced a remarkable 38.4% decrease in FGF-23, compared to a mere 0.5% change in the control group, highlighting the pronounced effect of sevelamer on this key protein. Analysis of PO4 levels revealed a remarkable difference between the groups following treatment. While initial PO4 measurements were statistically comparable, the sevelamer group experienced a significantly larger decrease compared to the control group (p &amp;lt; 0.001). Both baseline and follow-up FGF-23 levels displayed highly statistically significant positive correlations with PO4, PTH, alkaline phosphatase, and hsCRP. Conclusion This study found that non-calcium-based phosphate binders were associated with a substantial reduction in FGF-23 in hemodialysis patients. This finding suggests that utilizing such binders may offer protection against the adverse effects of high FGF-23 levels, which are prevalent in this population.

#2611 Development of a predictive model for FGF-23 levels in children with chronic kidney disease

Abstract Background and Aims The global prevalence of Chronic Kidney Disease (CKD) among the population is approximately 10%, with this rate steadily increasing. Epidemiological data on CKD in childhood are scarce and show significant variability across different countries. One of the most serious complications is mineral and bone disorders (CKD-MBD), which worsen the clinical course and prognosis of patients. The understanding of the pathogenesis of CKD-MBD has undergone substantial changes since the discovery of Fibroblast growth factor 23 (FGF-23), a 32 kDa peptide produced by osteocytes and osteoblasts, has emerged as a key regulator of phosphate metabolism. It is acknowledged that FGF-23 levels in the serum gradually increase as renal function declines, i.e., with the progression of CKD. According to various studies, FGF-23 may also be associated with cardiovascular complications, such as left ventricular hypertrophy (LVH). There is evidence indicating that FGF-23 may be regarded as an independent risk factor for mortality. Considering the predictive abilities of FGF-23 in relation to the onset of complications and mortality in children with CKD, there is a need for its assessment in serum or plasma. However, the availability of the FGF-23 assay kit in Kazakhstan is not consistently ensured in clinical practice, and its logistics may be time-consuming and financially burdensome. Therefore, we aimed to develop a predictive model to estimate FGF-23 levels based on accessible clinical and laboratory parameters. Method 73 children with CKD were enrolled in the pilot study. The average age was 9.79 ± 0.58 years, 52.1% males and 47.9% females. The study adhered to the principles outlined in the Declaration of Helsinki. A comprehensive evaluation of all clinical and necessary laboratory characteristics was conducted. The estimated glomerular filtration rate (eGFR) was calculated according to the Schwartz formula. FGF-23 levels were measured in serum using a multimatrix ELISA kit (Biomedica Medizinprodukte GmbH, Austria). For the development of the predictive model, we employed the decision tree learning approach. Statistical analysis and modeling were conducted using SPSS version 27 (IBM, USA). Results Initially, we included all clinical and laboratory parameters showing statistically significant associations with FGF-23 as independent variables and created various models. Then, we selected the most accurate predictive model which included 3 predictors: phosphate, eGFR and LVH. We found out a correlation between FGF-23 with eGFR (r = −0,826, p = 0.000), with phosphate (r = 0.473, p = 0.000). LVH is also associated with high FGF-23 (p = 0.000). At the start of the algorithm, the phosphate level should be estimated, and if it is normal, the next step is to determine eGFR. When eGFR is more than 85.7 ml/min, in 92.9% of cases FGF-23 will be within normal limits. eGFR less than 28.3 ml/min predicts a 100% chance of high FGF-23 levels. If the eGFR is in the range from 28.3 to 85.7 ml/min, the next we should determine the presence of LVH in the child. So, if a patient has been diagnosed with LVH, this indicates a high level of FGF-23 in 100% of cases. On the contrary, if the patient does not have LVH, then this probability is reduced to 52.9%. In the case of initially elevated phosphate, there is a need to evaluate if the patient has LVH or not regardless of eGFR. If it is present, the probability of a high level of FGF-23 is 100%, and if absent, it is 55.6%. Our predictive model demonstrated a high sensitivity of 98%, an overall percentage of accuracy is 82.2 ± 4.5%. Conclusion A decision tree algorithm based on a limited set of available clinical and laboratory characteristics such as phosphate, eGFR and LVH might be considered as a useful tool for predicting FGF-23 levels. This algorithmic approach enables the identification and evaluation of individuals with elevated FGF-23 who are at high risk for complications associated with CKD.

#2421 Kidney injury in scleroderma: serum level of fibroblast growth factor-23, klotho and neutrophil gelatinase-associated lipocalin after iloprost infusion

Abstract Background and Aims Systemic sclerosis (SSc) is characterized by progressive derangement of the microcirculation leading to a state of chronic tissue hypoxia with release of several inflammatory cytokines such as neutrophil gelatinase-associated lipocalin (NGAL), fibroblast growth factor-23 (FGF-23) and Klotho. Renal scleroderma associated-vasculopathy is characterized by vascular damage with normal renal function and increased intrarenal stiffness, assessed by renal resistive index (RRI) Aim of this study was to evaluate at baseline serum levels of FGF-23, Klotho and NGAL in SSc patients and healthy controls (HC) and to correlate the serum levels of these markers with microvascular damage of skin and kidney. Secondary aim was to evaluate the serum levels of FGF-23, Klotho and NGAL after Iloprost infusion. Method Twenty-one SSc patients and 20 HC were enrolled. All patients had a 2-months wash-out of Iloprost infusion before of clinical, laboratory and instrumental assessment. Peripheral venous blood was collected at three different time points for SSc patients: t0 immediately before the first Iloprost infusion (after 2-months wash-out period), t1 immediately after the first Iloprost infusion and t2 the day of the next Iloprost infusion (about 14 days from the last infusion). Results SSc patients had higher serum level of FGF-23 [18.7 pg/mL (± 6.4) vs 3.6 pg/mL (± 2.2), p &amp;lt; 0.001], Klotho [5.1 pg/mL (±0.8) vs 2.3 pg/mL (±0.6), p &amp;lt; 0.001] and NGAL [20.9 pg/mL (±2.6) vs 14.5 pg/mL (±1.7), p &amp;lt; 0.001] compared to HC. The one-way repeated-measures ANOVA showed that mean FGF-23 [F (2,40) = 71.255, p &amp;lt; 0.001], Klotho [F (1.405, 28.103) = 195.095, p &amp;lt; 0.001] and NGAL [F (2,40) = 48.024, p &amp;lt; 0.001] differed significantly between time points. Conclusion SSc patients had higher FGF-23, Klotho and NGAL than HC. Our present data demonstrate that microvascular damage is associated to chronic hypoperfusion with increased circulating markers such as FGF-23, Klotho and NGAL. For the first time, we demonstrated that Iloprost infusion reduces significantly serum level of FGF-23, Klotho and NGAL and it has showed to be a key role in renal vasculopathy in SSc patients. In literature, there are no data about the modification of these serum markers before and after vasoactive treatment, especially of Iloprost infusion.

Iloprost infusion reduces serological cytokines and hormones of hypoxia and inflammation in systemic sclerosis patients

IntroductionSystemic sclerosis (SSc) is characterized by microvascular damage of skin and internal organs with chronic hypoxia and release of cytokines and hormones such as neutrophil gelatinase-associated lipocalin (NGAL), fibroblast growth factor-23 (FGF-23) and Klotho. Aim of the study was to evaluate FGF-23, Klotho and NGAL serum levels in SSc patients and healthy controls (HC) and to evaluate serum levels changes of FGF-23, Klotho and NGAL after Iloprost.MethodsTwenty-one SSc patients and 20 HC were enrolled. In SSc patients, peripheral venous blood samples were collected at the first day before the autumn Iloprost infusion (t0), 60 min (t1) and 14 days after Iloprost infusion (t2).ResultsSSc patients had higher serum level of FGF-23 [18.7 ± 6.4 pg/ml versus 3.6 ± 2.2 pg/ml, p < 0.001], Klotho [5.1 ± 0.8 pg/ml versus 2.3 ± 0.6 pg/ml, p < 0.001] and NGAL [20.9 ± 2.6 pg/ml versus 14.5 ± 1.7 pg/ml, p < 0.001] than HC.Iloprost infusion reduces serum level of FGF-23 (18.7 ± 6.4 pg/ml versus 10.4 ± 5.5 pg/ml, p < 0.001), Klotho (5.1 ± 0.8 pg/ml versus 2.5 ± 0.6 pg/ml, p < 0.001) and NGAL (20.9 ± 2.6 pg/ml versus 15.1 ± 2.3 pg/ml, p < 0.001) between t0 and t1. The Iloprost infusion reduces serum level of FGF-23 (18.7 ± 6.4 pg/ml versus 6.6 ± 5.1 pg/ml), Klotho (5.1 ± 0.8 pg/ml versus 2.3 ± 0.4 pg/ml) and NGAL (20.9 ± 2.6 pg/ml versus 15.5 ± 1.9 pg/ml) between t0 and t2.ConclusionsSSc patients had higher FGF-23, Klotho and NGAL than HC. Iloprost reduces serum levels of FGF-23, Klotho and NGAL.

Emerging concepts on the FGF23 regulation and activity.

Fibroblast growth factor 23 (FGF23) discovery has provided new insights into the regulation of Pi and Ca homeostasis. It is secreted by osteoblasts and osteocytes, and acts mainly in the kidney, parathyroid, heart, and bone. The aim of this review is to highlight the current knowledge on the factors modulating the synthesis of FGF23, the canonical and non-canonical signaling pathways of the hormone, the role of FGF23 in different pathophysiological conditions, and the anti-FGF23 therapy. This is a narrative review based on the search of PubMed database in the range of years 2000-2023 using the keywords local and systemic regulators of FGF23 synthesis, FGF23 receptors, canonical and non-canonical pathways, pathophysiological conditions and FGF23, and anti-FGF23 therapy, focusing the data on the molecular mechanisms. The regulation of FGF23 synthesis is complex and multifactorial. It is regulated by local factors and systemic regulators mainly involved in bone mineralization. The excessive FGF23 production is associated with different congenital diseases and with diseases occurring with a secondary high FGF23 production such as in chronic disease kidney and tumor-induced osteomalacia (TIO). The anti-FGF23 therapy appears to be useful to treat chromosome X-linked hypophosphatemia and TIO, but there are doubts about the handle of excessive FGF23 production in CKD. FGF23 biochemistry and pathophysiology are generating a plethora of knowledge to reduce FGF23 bioactivity at many levels that might be useful for future therapeutics of diseases associated with high-serum FGF23 levels.

A Retrospective Cohort of Tumor-Induced Osteomalacia and Case Series of Malignant Disease.

Tumor-induced osteomalacia (TIO) is a rare condition with evidence mostly derived from case reports and case series. We aimed to describe the clinical characteristics of a large cohort of patients diagnosed with TIO, with a focus on patients with nonlocalizing and malignant TIO. This is a retrospective cohort of patients with TIO in an academic medical center, diagnosed between January 1998 and May 2023. We describe their demographics, biochemistries, tumor features, localization, treatment, and complications. Of 68 patients diagnosed with TIO, 49 (72%) were localizing and 5 (7.4%) were malignant. Of 50 patients who attempted localizing procedures, 29 (58%) achieved cure. Twenty (40%) had persistent disease due to the wrong tumor targeted, or refractory or recurrent tumors, despite up to 6 procedural attempts. There was no difference in demographics, phosphorus, or baseline fibroblast growth factor-23 (FGF23) levels between localizing vs nonlocalizing groups, and malignant vs nonmalignant groups. The lower extremity was the commonest site of localization (37%), with 47% in bone and 53% in soft tissue. Sixty percent of malignant cases were located in the trunk. Tumor size correlated with peak FGF23 (R = 0.566, P < .001) but was not associated with malignancy risk (P = .479). A cut-off FGF23 of >20 times upper limit of normal in the presence of normal renal function (P = .025) and recurrence after initial cure (P = .013) were factors significantly associated with malignancy. The nonlocalizing group had lower survival than the localizing group (P = .0097). TIO is a condition with significant morbidity. Very high FGF23 levels and disease recurrence are associated with malignant disease. Reasons behind the observation of higher mortality in nonlocalizing TIO should be further explored.

Serum fibroblast growth factor 23 concentration and the risk of mortality in patients undergoing peritoneal dialysis.

Fibroblast growth factor 23 (FGF23) is a phosphate-regulating hormone that is secreted in large amounts early in chronic kidney disease. In this cohort, we aimed to investigate the association between serum FGF23 concentration and mortality in patients undergoing peritoneal dialysis (PD). Serum FGF23 level was determined by enzyme-linked immunosorbent assay (ELISA) in a large 15-year prospective cohort study of PD patients with stored serum samples at baseline. Kaplan-Meier survival curves and Cox proportional hazards models were performed to characterise the relationship of FGF23 with mortality. A total of 737 incident PD patients were analysed. The baseline median FGF23 concentration was 683.2 (518.5-896.2) pg/mL. Age, serum phosphorus, high-density lipoprotein cholesterol and high-sensitivity C-reactive protein were independently correlated with serum FGF23 concentration. During a median follow-up of 66.7 (41.1-95.4) months, 171 of the 737 participants (23.2%) died, including 84 (49.1%) cardiovascular disease-related and 50 (29.2%) infection-related deaths. Multivariable Cox regression analysis showed that the adjusted hazard ratios of the highest tertile of serum FGF23 compared with those in the lowest tertile were 1.36 (95% confidence interval (CI): 0.89-2.07; p = 0.154), 0.75 (95% CI: 0.40-1.38; p = 0.353) and 2.66 (95% CI: 1.15-6.15; p = 0.022) for all-cause, cardiovascular disease-related and infection-related mortality, respectively. High serum FGF23 concentration is associated with a higher risk of infection-related death for incident PD patients.

C-terminal fragment of fibroblast growth factor 23 improves heart function in murine models of high intact fibroblast growth factor 23.

Cardiovascular disease (CVD) is the major cause of death in chronic kidney disease (CKD) and is associated with high circulating fibroblast growth factor (FGF)23 levels. It is unresolved whether high circulating FGF23 is a mere biomarker or pathogenically contributes to cardiomyopathy. It is also unknown whether the C-terminal FGF23 peptide (cFGF23), a natural FGF23 antagonist proteolyzed from intact FGF23 (iFGF23), retards CKD progression and improves cardiomyopathy. We addressed these questions in three murine models with high endogenous FGF23 and cardiomyopathy. First, we examined wild-type (WT) mice with CKD induced by unilateral ischemia-reperfusion and contralateral nephrectomy followed by a high-phosphate diet. These mice were continuously treated with intraperitoneal implanted osmotic minipumps containing either iFGF23 protein to further escalate FGF23 bioactivity, cFGF23 peptide to block FGF23 signaling, vehicle, or scrambled peptide as negative controls. Exogenous iFGF23 protein given to CKD mice exacerbated pathological cardiac remodeling and CKD progression, whereas cFGF23 treatment improved heart and kidney function, attenuated fibrosis, and increased circulating soluble Klotho. WT mice without renal insult placed on a high-phosphate diet and homozygous Klotho hypomorphic mice, both of whom develop moderate CKD and clear cardiomyopathy, were treated with cFGF23 or vehicle. Mice treated with cFGF23 in both models had improved heart and kidney function and histopathology. Taken together, these data indicate high endogenous iFGF23 is not just a mere biomarker but pathogenically deleterious in CKD and cardiomyopathy. Furthermore, attenuation of FGF23 bioactivity by cFGF23 peptide is a promising therapeutic strategy to protect the kidney and heart from high FGF23 activity.NEW & NOTEWORTHY There is a strong correlation between cardiovascular morbidity and high circulating fibroblast growth factor 23 (FGF23) levels, but causality was never proven. We used a murine chronic kidney disease (CKD) model to show that intact FGF23 (iFGF23) is pathogenic and contributes to both CKD progression and cardiomyopathy. Blockade of FGF23 signaling with a natural proteolytic product of iFGF23, C-terminal FGF23, alleviated kidney and cardiac histology, and function in three separate murine models of high endogenous FGF23.

The effects of fibroblast growth factor-23 on diagnosis of cerebral infarction and vertebral basilar artery stenosis☆

ObjectivesThis study aimed to explore the correlation between Fibroblast Growth Factor-23 (FGF23) levels and Cerebral Infarction (CI), and to determine whether there is a significant relationship between FGF23 and the occurrence and severity of CI. MethodsThe study categorized Cerebral Infarction (CI) patients into severe and mild stenosis groups based on vertebrobasilar artery stenosis, using Digital Subtraction Angiography (DSA) and Magnetic Resonance Imaging (MRI). The study compared the levels of Fibroblast Growth Factor-23 (FGF23) in the serum of CI patients and healthy controls using a t-test and evaluated the diagnostic effectiveness of serum FGF23 using a Receiver Operating Characteristic (ROC) curve. Additionally, the study analyzed the correlation between FGF23 levels and CI severity after treatment using the National Institute of Health Stroke Scale score. ResultsThe study found a significant increase in serum Fibroblast Growth Factor-23 (FGF23) levels in patients with Cerebral Infarction (CI) compared to healthy volunteers, (p < 0.001). A higher serum FGF23 level was observed in the severe stenosis group than in the mild stenosis group (p < 0.001). Furthermore, the study showed that a high FGF23 level at admission was significantly related to more severe symptoms of CI as indicated by the National Institute of Health Stroke Scale (NIHSS) score on the 7th day after treatment (p < 0.001). ConclusionsThis study discovered a correlation between Fibroblast Growth Factor-23 (FGF23) levels, vertebrobasilar artery stenosis, and short-term prognosis in patients who had recently experienced acute Cerebral Infarction (CI).

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.

THU466 XLH During Pregnancy: A Closer Look Based On Real-World Experience

Abstract Disclosure: D.S. Ali: None. A.A. Khan: Advisory Board Member; Self; Amgen Inc, Takeda. Grant Recipient; Self; Alexion Pharmaceuticals, Inc., Amgen Inc, Radius Health, Inc, Takeda, Ultragenyx. Background: X-linked hypophosphatemia (XLH) is a genetic disorder caused by mutation in the PHEX gene leading to excess serum levels of the phosphate-regulating hormone fibroblast growth factor 23 (FGF23). High FGF23 causes renal phosphate wasting, decreased production of serum 1,25-dihydroxy vitamin D, and increased metabolism of 1,25-dihydroxy vitamin D, leading to hypophosphatemia. Maintaining normal serum phosphorus levels in pregnant women with XLH is critically important to ensure mineralization of the fetal skeleton. Multiple factors may influence phosphorus homeostasis in pregnancy, including an increase in PTHrP production and a tripling of calcitriol beginning in the first trimester. Case study: 30 years old Gravida 1 Para 0 with XLH, diagnosed at the age of 18 months. She has a pathogenic heterozygous mutation of the PHEX gene (c.1645+1G&amp;gt;A). Treated with phosphate and calcitriol since diagnosis. Had no history of neonatal seizure or respiratory distress, and no dental or renal manifestations. No prior fractures or corrective surgeries and has a normal BMD. No history of enthesopathy, however, has chronic joint pain &amp;gt; 1 year. The pregnancy progressed well with no issues; the patient chose not to undergo amniocentesis for fetal diagnosis. She was monitored closely every 3 weeks, aiming to maintain the serum phosphorus within the normal range to ensure adequate mineralization of the fetal skeleton. The requirements for phosphate increased by 50% in the 2nd trimester and by 125% in the 3rd trimester compared to baseline. While the calcitriol dose increased by 25% in the 3 trimesters compared to baseline. Because further increases in the calcitriol dose were associated with hypercalciuria, the dose was carefully titrated. The mean serum phosphorus level was maintained in the low normal reference range at 0.79 - 0.8 mmol/L (NR: 0.8-1.45), mean TmP/GFR 0.611 (NR: 0.96-1.44). She was induced at 37 weeks due to cholestasis, and delivered with a vaginal delivery. The baby boy weighed 2.690 kg and had slightly low serum phosphorus and calcium levels at birth, which corrected spontaneously. DNA analysis confirmed that the baby also has a pathogenic mutation of the PHEX gene. Conclusion: There was a noticeable variation in the serum phosphorus levels during the 1st and 2nd trimesters and less so in the 3rd trimester and during lactation. The dose of phosphate and active vitamin D required careful upward titration to maintain a normal serum phosphorus level. Therefore, close monitoring is essential. Although the rate of c-sections is higher (76%) amongst the XLH patient population compared to the normal population 27.1%, our patient delivered vaginally with no adverse skeletal outcomes in the mother or neonate. Presentation: Thursday, June 15, 2023

Impaired 1,25-dihydroxyvitamin D3 action underlies enthesopathy development in the Hyp mouse model of X-linked hypophosphatemia.

X-linked hypophosphatemia (XLH) is characterized by high serum fibroblast growth factor 23 (FGF23) levels, resulting in impaired 1,25-dihydroxyvitamin D3 (1,25D) production. Adults with XLH develop a painful mineralization of the tendon-bone attachment site (enthesis), called enthesopathy. Treatment of mice with XLH (Hyp) with 1,25D or an anti-FGF23 Ab, both of which increase 1,25D signaling, prevents enthesopathy. Therefore, we undertook studies to determine a role for impaired 1,25D action in enthesopathy development. Entheses from mice lacking vitamin D 1α-hydroxylase (Cyp27b1) (C-/-) had a similar enthesopathy to Hyp mice, whereas deletion of Fgf23 in Hyp mice prevented enthesopathy, and deletion of both Cyp27b1 and Fgf23 in mice resulted in enthesopathy, demonstrating that the impaired 1,25D action due to high FGF23 levels underlies XLH enthesopathy development. Like Hyp mice, enthesopathy in C-/- mice was observed by P14 and was prevented, but not reversed, with 1,25D therapy. Deletion of the vitamin D receptor in scleraxis-expressing cells resulted in enthesopathy, indicating that 1,25D acted directly on enthesis cells to regulate enthesopathy development. These results show that 1,25D signaling was necessary for normal postnatal enthesis maturation and played a role in XLH enthesopathy development. Optimizing 1,25D replacement in pediatric patients with XLH is necessary to prevent enthesopathy.

Maternal overweight and obesity modify the association of serum fibroblast growth factor 21 levels with gestational diabetes mellitus: A nested case-control study.

To examine the prospective association between fibroblast growth factor 21 (FGF21) and risk of gestational diabetes mellitus (GDM) and the modifying effect of overweight/obesity for this association. Serum FGF21 levels were measured at 6-15weeks of gestation among 332 GDM cases and 664 matched controls. Conditional logistic regression was used to evaluate its association with GDM risk. Interaction analyses on multiplicative and additive scales were conducted to investigate the modifying effect of overweight/obesity. Elevated FGF21 levels were associated with a higher risk of GDM in multivariable models, but the positive association was attenuated after further adjustment for pre-pregnancy body mass index (BMI). A significant multiplicative interaction was noted between FGF21 (both continuous and dichotomous) and pre-pregnancy BMI (p for interaction=0.049 and 0.03), and the association was only significant in participants with pre-pregnancy BMI ≥24kg/m2 . When participants were grouped based on pre-pregnancy BMI (≥24 and <24kg/m2 ) and FGF21 levels (≥median and <median), a significant association was observed in those with higher BMI and FGF21 levels (odds ratio, 2.12; 95% CI: 1.41, 3.20) but not in those with either higher BMI or higher FGF21, with a significant additive interaction (relative excess risk due to interaction=1.23; 95% CI: 0.27, 2.20). FGF21 was also correlated with unfavourable glucose and lipid biomarkers as well as adipokines. Elevated serum FGF21 levels in early pregnancy were associated with a higher risk of GDM, particularly among those with overweight/obesity.

Insight to the association among fibroblast growth factor 21, non-alcoholic fatty liver disease and cardiovascular outcomes: A population-based study

Insight to the association among fibroblast growth factor 21, non-alcoholic fatty liver disease and cardiovascular outcomes: A population-based study

#3959 ASSOCIATION BETWEEN AMORPHOUS CALCIUM-PHOSPHATE RATIOS IN CIRCULATING CALCIPROTEIN PARTICLES AND PROGNOSTIC BIOMARKERS IN HEMODIALYSIS PATIENTS

Abstract Background and Aims 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. Method 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. Results 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 were associated with increased mortality. Patients with low amorphous CaPi rate tended to have lower 2-year survival rates (p = 0.07). Conclusion This study suggests that low amorphous CaPi ratio in circulating CPPs is associated with poor prognosis in hemodialysis patients. Further investigation of the association with prognosis is warranted.

Abstract #1405323: A Rare Case of Multiple Fragility Fractures Caused by Tumor-Induced Osteomalacia

Abstract #1405323: A Rare Case of Multiple Fragility Fractures Caused by Tumor-Induced Osteomalacia