Higher Fibroblast Growth Factor 23 Levels Research Articles

#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.

FGF23 as a Potential Pathophysiological Factor in Peripheral Arterial Disease Associated with Chronic Kidney Disease.

Fibroblast growth factor 23 (FGF23) levels are often elevated in chronic kidney disease (CKD). FGF23 and inflammation are common characteristics in CKD, and both are associated with worse disease progression and the occurrence of complications. The existence of an interaction between FGF23 and inflammation has been suggested, each of which influences the expression and activity of the other, leading to a vicious feedback loop with adverse outcomes, including cardiovascular disease and mortality. In this work, we determined circulating FGF23 levels in a group of patients with CKD stages 3 and 4 subjected to elective femoral endarterectomy due to established peripheral artery disease (PAD), a condition resulting from an athero-inflammatory process, and we studied its associations with different inflammatory markers and mediators. We evaluated its association with serum tumor necrosis factor (TNF)α, interleukin (IL) 6, and IL10, as well as with the gene expression levels of these parameters and A disintegrin and metalloproteinase domain-containing protein (ADAM) 17 in femoral vascular tissue and peripheral blood circulating cells (PBCCs). We also analyzed its association with serum concentrations of C-reactive protein (CRP), the systemic immune inflammation index (SII), and the neutrophil-to-lymphocyte ratio (NLR). Finally, we determined the vascular immunoreactivity of protein TNFα in a subgroup of patients. FGF23 concentrations were independently associated with circulating and PBCC mRNA levels of TNFα. Worst kidney function and diabetes were also found to be contributing to FGF23 levels. Patients with higher levels of FGF23 also had greater vascular immunoreactivity for TNFα.

Relationship between fibroblast growth factor in plasma and carotid plaque neovascularization: a pilot study.

Unstable atherosclerotic carotid plaques with intraplaque neovascularization (IPN) carry a substantial risk for ischemic stroke. Conventional ultrasound methods fall short in detecting IPN, where superb microvascular imaging (SMI) has emerged as a promising tool for both visualizing and quantification. High levels of fibroblast growth factor 23 (FGF-23) have, in observational studies, been suggested as related to cardiovascular morbidity and mortality. The association of FGF-23 to atherosclerotic carotid plaque instability remains relatively unexplored. A cohort of twenty-nine patients with ≥50% atherosclerotic carotid stenosis underwent conventional carotid ultrasound, SMI, and blood tests, including measurement of FGF-23 in plasma. Nineteen patients were characterized as symptomatic and ten as asymptomatic. Our major findings were: i) Higher FGF-23 levels were strongly correlated with increased SMI-assessed IPN. ii) Neo-vessel count recorded by quantitative SMI was positively correlated to increased FGF-23 levels, but not with basic FGF levels. (iii) In contrast, traditional risk factors for plaque instability exhibited no noteworthy associations with SMI-assessed IPN or with FGF-23 levels. This pilot study suggest the potential of FGF-23 as a valuable marker for neovascularization and atherosclerotic carotid plaque instability as a risk factor for ischemic stroke. Further research involving larger cohorts and prospective data is necessary to understand FGF-23's role in this context comprehensively.

A retrospective cohort of tumor-induced osteomalacia and case series of malignant disease.

We aimed to describe the clinical characteristics of a large cohort of patients diagnosed with tumor-induced osteomalacia (TIO), with a focus on patients with non-localizing and malignant TIO. This is a retrospective cohort of TIO patients in an academic medical center, diagnosed between January 1998 to May 2023. We described 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. 20 (40%) had persistent disease due to 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 versus non-localizing groups, and malignant versus non-malignant groups. Lower extremity was the commonest site of localization (37%), with 47% in bone and 53% in soft tissue. 60% of malignant cases were located in the trunk. Tumor size correlated with peak FGF23 (R=0.566, p<0.001) but was not associated with malignancy risk (p=0.479). A cut-off FGF23 of >20 times upper limit of normal in the presence of normal renal function (p=0.025), and recurrence after initial cure (p=0.013) were factors significantly associated with malignancy. The non-localizing group had lower survival than localizing group (p=0.0097). TIO is a condition with significant morbidity. Very high FGF23 level and disease recurrence are associated with malignant disease. Reasons behind the observation of higher mortality in non-localizing TIO should be further explored.

Association of Fibroblast Growth Factor 23 with Blood Pressure in Primary Proteinuric Glomerulopathies

Introduction: Fibroblast growth factor 23 (FGF23) has direct effects on the vasculature and myocardium, and high levels of FGF23 are a risk factor for cardiovascular disease (CVD); however, the impact of FGF23 on CVD in primary proteinuric glomerulopathies has not been addressed. Methods: The associations of baseline plasma intact FGF23 levels with resting blood pressure (BP) and lipids over time among adults and children with proteinuric glomerulopathies enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) were analyzed using generalized estimating equation regression analyses. Models were adjusted for age, sex, glomerular diagnosis, follow-up time, estimated glomerular filtration rate, urine protein/creatinine ratio, obesity, and serum phosphorous levels. Results: Two hundred and four adults with median FGF23 77.5 (IQR 51.3–119.3) pg/mL and 93 children with median FGF23 62.3 (IQR 44.6–83.6) pg/mL were followed for a median of 42 (IQR 20.5–54) months. In adjusted models, each 1 µg/mL increase in FGF23 was associated with a 0.3 increase in systolic BP index at follow-up (p < 0.001). Greater baseline FGF23 was associated with greater odds of hypertensive BP (OR = 1.0003; 95% CI 1.001–1.006, p = 0.03) over time. Compared to tertile 1, tertile 2 (OR = 2.1; 95% CI 1.12–3.99, p = 0.02), and tertile 3 (OR = 3; 95% CI 1.08–8.08, p = 0.04), FGF23 levels were associated with greater odds of hypertensive BP over time. Tertile 2 was associated with greater triglycerides compared to tertile 1 (OR = 48.1; 95% CI 4.4–91.9, p = 0.03). Conclusion: Overall, higher baseline FGF23 was significantly associated with hypertensive BP over time in individuals with proteinuric glomerulopathies. Further study of FGF23 as a therapeutic target for reducing CVD in proteinuric glomerular disease is warranted.

NT-proBNP Mediates the Association Between FGF23 and All-Cause Mortality in Individuals With Type 2 Diabetes.

FGF23 (fibroblast growth factor 23) is associated with a higher mortality risk in type 2 diabetes, but the mechanism is unclear. We aimed to study whether NT-proBNP (N-terminal pro-brain natriuretic peptide) mediates the association between FGF23 and mortality. We analyzed C-terminal FGF23 and NT-proBNP levels in 399 patients with type 2 diabetes. Cox regression analyses were performed, followed by mediation analyses using Structural Equation Modeling. During follow-up of 9.2 [7.6-11.3] years, 117 individuals died. FGF23 was associated with all-cause mortality, independent of potential confounders (fully adjusted hazard ratio [HR], 2.32 [95% CI, 1.21-4.43], P=0.01). The association was lost upon further adjustment for NT-proBNP (HR, 1.84; 95% CI, 0.91-3.73). NT-proBNP accounted for 26% of the mediation effect between FGF23 and all-cause mortality. These findings suggest that a higher FGF23 level is associated with increased mortality in individuals with type 2 diabetes through an effect on volume homeostasis.

Extracellular sodium regulates fibroblast growth factor 23 (FGF23) formation

The bone-derived hormone fibroblast growth factor-23 (FGF23) has recently received much attention due to its association with chronic kidney disease and cardiovascular disease progression. Extracellular sodium concentration ([Na+]) plays a significant role in bone metabolism. Hyponatremia (lower serum [Na+]) has recently been shown to be independently associated with FGF23 levels in patients with chronic systolic heart failure. However, nothing is known about the direct impact of [Na+] on FGF23 production. Here, we show that an elevated [Na+] (+20 mM) suppressed FGF23 formation, whereas low [Na+] (-20 mM) increased FGF23 synthesis in the osteoblast-like cell lines UMR-106 and MC3T3-E1. Similar bidirectional changes in FGF23 abundance were observed when osmolality was altered by mannitol but not by urea, suggesting a role of tonicity in FGF23 formation. Moreover, these changes in FGF23 were inversely proportional to the expression of NFAT5 (nuclear factor of activated T cells-5), a transcription factor responsible for tonicity-mediated cellular adaptations. Furthermore arginine vasopressin (AVP), which is often responsible for hyponatremia, did not affect FGF23 production. Next, we performed a comprehensive and unbiased RNA-seq analysis of UMR-106 cells exposed to low vs. high [Na+], which revealed several novel genes involved in cellular adaptation to altered tonicity. Additional analysis of cells with Crisp-Cas9 mediated NFAT5 deletion indicated that NFAT5 controls numerous genes associated with FGF23 synthesis, thereby confirming its role in [Na+]-mediated FGF23 regulation. In line with these in vitro observations, we found that hyponatremia patients have higher FGF23 levels. Our results suggest that [Na+] is a critical regulator of FGF23 synthesis.

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.

Long-term effects of a fat-directed FGF21 gene therapy in aged female mice.

Fibroblast growth factor 21 (FGF21) has been developed as a potential therapeutic agent for metabolic syndromes. Moreover, FGF21 is considered a pro-longevity hormone because transgenic mice overexpressing FGF21 display extended lifespan, raising the possibility of using FGF21 to promote healthy aging. We recently showed that visceral fat directed FGF21 gene therapy improves metabolic and immune health in insulin resistant BTBR mice. Here, we used a fat directed rAAV-FGF21 vector in 17-month-old female mice to investigate whether long-term FGF21 gene transfer could mitigate aging-related functional decline. Animals with FGF21 treatment displayed a steady, significant lower body weight over 7-month of the study compared to age-matched control mice. FGF21 treatment reduced adiposity and increased relative lean mass and energy expenditure associated with almost 100 folds higher serum level of FGF21. However, those changes were not translated into benefits on muscle function and did not affect metabolic function of liver. Overall, we have demonstrated that a single dose of fat-directed AAV-FGF21 treatment can provide a sustainable, high serum level of FGF21 over long period of time, and mostly influences adipose tissue homeostasis and energy expenditure. High levels of FGF21 alone in aged mice is not sufficient to improve liver or muscle functions.

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.

Cord Blood FGF-21 and GDF-15 Levels Are Affected by Maternal Exposure to Moderate to Severe Anemia and Malaria.

Anemia and malaria are global health problems affecting >50% of pregnant women in sub-Saharan Africa and are associated with intrauterine growth restriction. The hormones fibroblast growth factor 21 (FGF-21) and growth differentiation factor 15 (GDF-15) are involved in metabolic regulation and are expressed in the placenta. No studies exist on FGF-21 and GDF-15 responses to exposures of malaria and anemia in pregnancy. Using a prospective, longitudinal pregnancy and birth cohort of women with an average age of 26 years from a rural region in northeastern Tanzania, we examined if FGF-21 and GDF-15 levels in maternal blood at week 33 ± 2 (n = 301) and in cord blood at birth (n = 353), were associated with anemia and malaria exposure at different time points in pregnancy and with neonatal anthropometry. Among mothers at gestation week 33 ± 2, lower FGF-21 levels were observed after exposure to malaria in the first trimester, but not anemia, whereas GDF-15 levels at week 33 ± 2 were not associated with malaria nor anemia. In cord blood, moderate to severe anemia at any time point in pregnancy was associated with higher levels of FGF-21, whereas malaria exposure in the third trimester was associated with lower FGF-21 levels in cord blood. Negative associations were observed between cord blood FGF-21 and GDF-15 levels and neonatal skinfold thicknesses and birthweight. Our results suggest that moderate to severe anemia throughout pregnancy associates with higher FGF-21 levels, and malaria in last trimester associates with lower FGF-21 levels, in the neonates, thereby potentially affecting the future cardiometabolic health of the child.

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

ObjectiveWe aimed to investigate whether there was a joint effect of fibroblast growth factor 21 (FGF21) and non-alcoholic fatty liver disease (NAFLD) or interaction on the incidence of cardiovascular diseases based on a community-dwelling population. MethodsSerum FGF21 levels were determined using an enzyme-linked immunosorbent method. NAFLD was diagnosed via ultrasonography. Multivariable-adjusted cox proportional hazards models were used to assess the joint effects of FGF21 and NAFLD on the major adverse cardiovascular events (MACE). ResultsA total of 1194 participants were enrolled in the final analysis. The multivariable-adjusted hazard ratio (HR) of MACE was 1.84 (95% confidence interval (CI) 1.18–2.86) in participants with diagnosed NAFLD at baseline, compared with those without NAFLD at baseline. The multivariable-adjusted HRs of MACE across quintiles of serum FGF21 levels at baseline were 1.00, 1.48 (95%CI 0.68–3.21), 2.01 (95%CI 0.98–4.13), 1.94 (95%CI 0.94–4.02) and 2.14 (95%CI 1.03–4.44) respectively. Participants with high FGF21 levels and NAFLD at baseline showed the highest risk of MACE with a significant interaction between the presence of NAFLD and serum FGF21 levels. ConclusionsBoth FGF21 and NAFLD were associated with MACE, while the association between FGF21 and MACE may be interacted by the presence of NAFLD at baseline.

Hepatocellular carcinoma induced by hepatocyte Pten deletion reduces BAT UCP-1 and thermogenic capacity in mice, despite increasing serum FGF-21 and iWAT browning.

Hepatocellular carcinoma (HCC) markedly enhances liver secretion of fibroblast growth factor 21 (FGF-21), a hepatokine that increases brown and subcutaneous inguinal white adipose tissues (BAT and iWAT, respectively) uncoupling protein 1 (UCP-1) content, thermogenesis and energy expenditure. Herein, we tested the hypothesis that an enhanced BAT and iWAT UCP-1-mediated thermogenesis induced by high levels of FGF-21 is involved in HCC-associated catabolic state and fat mass reduction. For this, we evaluated body weight and composition, liver mass and morphology, serum and tissue levels of FGF-21, BAT and iWAT UCP-1 content, and thermogenic capacity in mice with Pten deletion in hepatocytes that display a well-defined progression from steatosis to steatohepatitis (NASH) and HCC upon aging. Hepatocyte Pten deficiency promoted a progressive increase in liver lipid deposition, mass, and inflammation, culminating with NASH at 24 weeks and hepatomegaly and HCC at 48 weeks of age. NASH and HCC were associated with elevated liver and serum FGF-21 content and iWAT UCP-1 expression (browning), but reduced serum insulin, leptin, and adiponectin levelsand BAT UCP-1 content and expression of sympathetically regulated gene glycerol kinase (GyK), lipoprotein lipase (LPL), and fatty acid transporter protein 1 (FATP-1), which altogether resulted in an impaired whole-body thermogenic capacity in response to CL-316,243. In conclusion, FGF-21 pro-thermogenic actions in BAT are context-dependent, not occurring in NASH and HCC, and UCP-1-mediated thermogenesis is not a major energy-expending process involved in the catabolic state associated with HCC induced by Pten deletion in hepatocytes.

Fibroblast growth factor 21 resistance is associated with body shape in patients with type 2 diabetes complicating hypertension.

Obesity, especially abdominal obesity, increases the prevalence of metabolic and cardiovascular disease (CVD). Fibroblast growth factor 21 (FGF21) has been identified as a critical regulator playing a therapeutic role in diabetes and its complications. This study aims to evaluate the relationship between serum FGF21 levels and body shape parameters in patients with hypertension (HP) and type 2 diabetes mellitus (T2DM). Serum FGF21 levels were determined in 1,003 subjects, including 745 patients with T2DM, and 258 individuals were selected as a healthy control in this cross-sectional study. Serum FGF21 levels were significantly higher in T2DM patients with HP than those without [534.9 (322.6-722.2) vs. 220.65 (142.8-347.55) pg/ml, p < 0.001], and levels in both of these two groups were significantly increased compared with that of healthy control [123.92 (67.23-219.32) pg/ml, all p < 0.001]. These differences were also observed in body shape parameters, including weight, waistline, body mass index (BMI), body shape index (ABSI), and the percentage of abdominal obesity. Serum FGF21 levels in T2DM patients were positively correlated with body shape parameters, including weight, waistline, neck circumference, BMI, ABSI, percent of abdominal obesity, and triglyceride, while negatively with estimated glomerular filtration rate (all p < 0.01). The significance remained stable when adjusted for age and T2DM duration. In addition, both serum FGF21 concentrations and waistline were independently associated with HP in T2DM patients after the adjustment for risk factors (all p < 0.05). ROC analysis for FGF21 levels of 745 patients with T2DM identified 411.33 pg/ml as an optimal cut-off point to predict HP, with a sensitivity and specificity of 66.0% and 84.9%, respectively. FGF21 resistance occurs in patients of HP in T2DM, and positively correlates with body shape parameters (especially waistline and BMI). High levels of FGF21 may be a compensatory reaction to offset HP.

#3115 THE ASSOCIATION OF FIBROBLAST GROWTH FACTOR-23 AND CARDIORENAL SYNDROME IN PATIENTS WITH DIABETES MELLITUS

Abstract Background and Aims Previous studies suggest that interactions between the heart and the kidney can contribute to the progressive dysfunction of both organs. Recently, there has been an increase in the prevalence of cardiovascular disease (CVD) and chronic kidney disease (CKD) due to increasing diabetes mellitus rate. It is known that fibroblast growth factor-23 (FGF-23) has been found to be related to kidney metabolism especially as a biomarker and a key factor to be used in the kidney field. The aim of our study was to assess potential therapeutic approaches of the use of FGF-23 in clinical settings as a potential circulating biomarker for CVD and CKD. Method A total of 155 patients with DT2, aged 34 to 84 years (60 [60;72]), were examined. Control group included 94 healthy people the same age. All patients underwent standard clinical and laboratory examination, with an assessment of the levels of FGF-23 in baseline plasma samples. Renal function was assessed based on the levels of serum creatinine, cystatin C, eGFR, which was calculated according to the CKD-EPI formula, and albuminuria, which was assessed as albumin/creatinine ratio (A/C). An echocardiographic examination was conducted according to the standard protocol with the calculation of dimensional, volume and speed characteristics. Results The levels of FGF-23 were significantly higher in DT2 patients with CKD 5 in comparison with stages 1–4. There were positive strong significant association between FGF-23 and creatinine (r = 0.71, p&amp;lt;0.001). In both unadjusted and adjusted analyses, probability of decreased eGFR was associated strongly with FGF-23 (COR; 95% CI 1.890; 1.362-2.622, p&amp;lt;0,001). When evaluating the dependence of the probability of decreased eGFR on the FGF-23 using the ROC analysis, the cut-off value of FGF-23 was 0,9 pmol/l. The sensitivity and specificity of the method were 75.3% and 74.5%, respectively (AUC 0.832±0.035 with 95% CI: 0.764-0.901, p&amp;lt;0.001). DT2 patients with left ventricular hypertrophy (LVH) were characterized by higher levels of FGF-23 (2,45 [0,65;7,43] vs 0,57 [0,19;2,19] pmol/l in control group). DT2 patients with LVH and natriuretic peptides levels ≥ 35 pg/ml for BNP and/or ≥125 ng/ml for NT-proBNP had significantly high concentrations of FGF-23 than patients with normal levels of natriuretic peptides (3,22 [1,09;9,55] vs. 0,52 [0,27;1,08] pmol/l, p&amp;lt;0,0001). In order to assess the diagnostic significance of the FGF-23 for predicting left ventricular mass index (LVMI) thickening and increasing the proBNP concentration, a ROC analysis was performed. Thus, at the level of FGF-23 (AUC-0.702) = 0.9 pmol/l, the sensitivity and specificity for LVMI thickening were 66.9% and 67.3%. Conclusion Our study identifies FGF-23 as a promising target of novel therapeutic interventions in cardiorenal syndrome, which should be investigated in future clinical studies.

FGF-21 and GDF-15 are increased in migraine and associated with the severity of migraine-related disability

BackgroundMigraine is a prevalent disorder with significant socioeconomic impact. The impairment of metabolic homeostasis in migraine warrants further investigation. Changes in serum levels of Fibroblast-growth-factor 21 (FGF-21) and Growth-differentiation-factor 15 (GDF-15) are characteristic of some metabolic and mitochondrial diseases. This study aimed to assess whether the presence of migraine affects serum levels of FGF-21 and GDF-15, and taking metabolic disorders into account as potential confounding factors.MethodsWe collected serum samples from 221 migraine patients (153 episodic migraineurs and 68 chronic migraineurs) and 124 healthy controls. The serum concentrations of FGF-21 and GDF-15 were measured using an enzyme-linked immunosorbent assay (ELISA) based approach. Clinical variables, including monthly headache days, peak headache pain intensity, the 6-item Headache Impact Test (HIT-6), and the Migraine Disability Assessment (MIDAS), were also addressed. The associations between the clinical variables of migraine patients and serum levels of FGF-21 and GDF-15 were studied.ResultsIn the multiple regression that corrected for age, we found that the serum levels of FGF-21 and GDF-15 were significantly higher in migraine sufferers than in healthy controls. A significant elevation in serum concentration of FGF-21, but not GDF-15, was observed in patients with chronic migraine (CM) compared to those with episodic migraine (EM). Regarding migraine-related disability, higher scores on the HIT-6 and MIDAS were associated with higher levels of FGF-21 and GDF-15. For the receiver operating characteristic (ROC) analysis, the diagnosis of migraine using GDF-15 showed that the area under the ROC curve (AUC) was 0.801 and the AUC of chronic migraine was 0.880.ConclusionSerum GDF-15 and FGF-21 levels are increased in patients with migraine and associated with the severity of migraine-related disability.

Association of Serum Fibroblast Growth Factor 23 and FGF23 Gene Variants with Chronic Kidney Disease in Patients with Type 2 Diabetes and Essential Hypertension

Fibroblast growth factor 23 (FGF23) gene variants could influence the production of FGF23 in subjects at risk for chronic kidney disease (CKD). Our purpose was to analyze the association of serum levels of FGF23 and two FGF23 gene variants with metabolic and renal function parameters in Mexican patients with Type 2 Diabetes (T2D) and/or essential hypertension (HTN). The study included 632 individuals diagnosed with T2D and/or HTN, of which 269 (43%) were diagnosed with CKD. FGF23 serum levels were determined and FGF23 gene variants rs11063112 and rs7955866 were genotyped. Genetic association analysis included binary and multivariate logistic regressions adjusted for age and sex. Patients with CKD were older, had higher systolic blood pressure, uric acid, and glucose levels than those without CKD. Also, patients with CKD had higher FGF23 levels (106 vs. 73 pg/mL p=0.003). No correlation of any gene variants with FGF23 levels was found, but minor allele for rs11063112 and haplotype rs11063112A-rs7955866A were associated with low probability of CKD (Odds Ratio [OR]=0.62 and 0.58, respectively). Conversely, the haplotype rs11063112T-rs7955866A was associated with increased FGF23 levels and risk for CKD (OR=6.90). In addition to the traditional risk factors, levels of FGF23 are higher in Mexican patients with diabetes and/or essential hypertension and CKD, compared to those without renal damage. In contrast, the two minor alleles of two variants of the FGF23 gene, rs11063112 and rs7955866, as well as the haplotype carrying these two alleles, were found to be protective against renal disease in this Mexican patients' sample.

Fibroblast growth factor 21 and prognosis of patients with cardiovascular disease: A meta-analysis.

The role of fibroblast growth factor 21 (FGF21) in predicting the long-term prognosis of patients with cardiovascular disease (CVD) remains unknown. A comprehensive search in PubMed, Embase, and the Cochrane Library was performed to identify studies reporting the association between FGF21 and prognosis among patients with CVD. A meta-analysis was performed, with patients stratified by coronary artery disease (CAD) or heart failure (HF). The endpoint of CAD or HF was major adverse cardiovascular events defined by each study and a composite of death or HF readmission, respectively. The I2 method and linear regression test of funnel plot asymmetry were used to test heterogeneity (I2 > 50% indicates substantial heterogeneity) and publication bias (asymmetry P < 0.05, indicating publication bias). A total of 807 records were retrieved, and nine studies were finally included. Higher FGF21 levels were significantly associated with the risk of major adverse cardiovascular events in patients with CAD (multivariate hazard ratio [HR]: 1.77, 95% confidence interval [CI]: 1.40-2.23, P < 0.05, I2 = 0%, fixed-effect model). Increased FGF21 levels were also associated with the risk of all-cause death among patients with CAD (multivariate HR: 2.67, 95% CI: 1.25-5.72, P < 0.05, I2 = 64%, random-effect model). No association was found between FGF21 and the endpoint among patients with HF (HR: 1.57, 95% CI: 0.99-2.48, P > 0.05, random-effect model), but a large heterogeneity (I2 = 95%) and potential publication bias (Asymmetry P < 0.05) existed in the analysis. Increased FGF21 levels were independently associated with poor prognosis of CAD, whereas the role of FGF21 in predicting clinical outcomes of HF requires further investigation.

Tumor-induced Osteomalacia Secondary to Phosphaturic Mesenchymal Tumor.

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

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

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