Changes In Fibroblast Growth Factor 23 Research Articles

The Effect of Periodontitis on Fibroblast Growth Factor 23 Levels in Predialysis Chronic Kidney Disease Patients.

Introduction Chronic kidney disease (CKD) is known to cause an increase in fibroblast growth factor 23 (FGF23). Periodontitis, a condition recognized as a risk factor for CKD, is also potentially associated with the increment of FGF23. This study aims to compare FGF23 levels in CKD patients with and without periodontitisand non-CKDpatients with and without periodontitis. Correlation with serum phosphate, calcium, and intact parathyroid hormone (iPTH) was assessed. Additionally, associations between FGF23, calcium, phosphate, iPTH, creatinine, urea, plaque score, and bleeding score with periodontitis in CKD patients were determined. Method A total of 124 participants were categorized into four groups: CKD patients with periodontitis (n=31), CKD patients without periodontitis (n=32), periodontitis patients without CKD (n=32), and healthy population (n=29). The selected CKD patients include those from stages 3 and 4 (predialysis) patients. Serum levels of FGF23, calcium, phosphate, iPTH, creatinine, and urea were analyzed. Oral examinations were conducted to determine the presence and absence of periodontitis and assess plaque and bleeding scores. Result A significantly higher level of FGF23 was found in CKD compared to non-CKD groups; however, no difference was observed with the presence of periodontitis in both CKD and non-CKD. There was no significant correlation found between FGF23 and serum calcium, phosphate, or iPTH concerning periodontal status. Apart from the bleeding score, there was no association between FGF23, calcium, phosphate, iPTH, creatinine, urea, and plaque score with the presence of periodontitis in CKD patients. Conclusion The presence of periodontitis was not associated with higher FGF23 levels in CKD patients. Changes in FGF23, calcium, phosphate, iPTH, creatinine, urea, and plaque score could not be attributed to the presence of periodontitis in CKD patients.

Changes in body composition, adipokines, ghrelin, and FGF23 in growth hormone-deficient children during rhGH therapy.

Beyond growth acceleration, growth hormone (GH) therapy improves body composition of GH-deficient (GHD) children due to the interaction of GH with lipid and carbohydrate metabolism, possibly mediated by adipokines secreted by adipose tissue and ghrelin. To promote linear growth, it is essential to have normal phosphate homeostasis. Fibroblast growth factor 23 (FGF23) is a known regulator of serum phosphorus and may be responsible for the increased renal phosphorus reabsorption observed during GH therapy. This study aimed to assess the impact of one-year GH therapy on body composition, adipokines, acylated/unacylated ghrelin (AG/UAG), and FGF23 in GHD children. A prospective observational study of 42 prepubertal, non-obese GHD children followed up in the first year of GH replacement therapy, investigating changes in adipokine profiles, AG/UAG, FGF23, and body composition. Data before therapy onset were compared with measurements obtained after 6 and 12 months of GH therapy. All children with a mean age of 9.2 ± 2.6 years grew at an accelerated pace. Total body fat decreased significantly, while the lipid profile improved, and total bone mineral density (BMD) significantly increased over the 12 months of treatment. Leptin and UAG levels decreased significantly, whereas adiponectin and AG values increased. A significant increase in plasma FGF23 and insulin growth factor 1 (IGF1) was accompanied by increased serum phosphate. Changes in FGF23 concentration did not have an impact on BMD. The strong association of FGF23 with IGF1 and height standard deviation (SD) could reveal a role of FGF23 in linear growth. In regression analysis models, GH therapy influences the changes of leptin and adiponectin, but not ghrelin, independently of body composition - lean or fat mass. GH replacement therapy improves body composition and adipokine profile in GHD children and directly impacts leptin and adiponectin concentrations independently of body composition. Also, GHD children have increased serum phosphate, correlated with upregulation rather than with suppression of FGF23, an unexpected observation given the phosphaturic role of FGF23. Further research is needed to identify the molecular mechanisms by which the GH/IGF1 axis influences adipokines secretion and plasma changes of FGF23.

Abstract #1595981: Changes in Fibroblast Growth Factor-23 and the Klotho Protein Axis in Diabetic Nephropathy

Abstract #1595981: Changes in Fibroblast Growth Factor-23 and the Klotho Protein Axis in Diabetic Nephropathy

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.

1662-P: The Bidirectional Relationship of Fibroblast Growth Factor 23 and Glucose Homeostasis

Objective: To investigate potential cross-talk between the phosphate-regulating hormone fibroblast growth factor 23 (FGF23) and glucose homeostasis. Research Design and Methods: First, we investigated the effect of glucose loading on plasma FGF23 and its temporal relationship with changes in plasma phosphate (0-15-30-45-60-75-90-120-150-180-240-300-360-420-480 minutes) in 45 overweight (BMI 25-30) subjects using time-lag analyses. Second, we studied cross-sectional associations of plasma FGF23 with glucose homeostasis using multivariable linear regression in a population-based cohort. We also investigated associations of FGF23 with incident diabetes and obesity (BMI >30 kg/m2) in individuals without diabetes or obesity at baseline, respectively, using multivariable Cox regression analyses. Finally, we explored whether the association between FGF23 and diabetes depends on BMI. Results: After glucose loading, changes in FGF23 preceded changes in plasma phosphate (Ptime-lag=0.04). In the population-based cohort (N=5482; mean age 52 yrs, 52% women, median FGF23 69 RU/mL), FGF23 was associated with plasma glucose (est. β 0.13[0.03-0.23], P=0.01), insulin (est. β 0.10[0.03-0.17], P<0.001), and proinsulin (est. β 0.06[0.02-0.10], P=0.01) at baseline. Upon longitudinal analyses, a higher baseline FGF23 was independently associated with the development of diabetes (199 events (4%); fully adjusted HR 1.66[95% CI 1.06-2.60], P=0.03) and development of obesity (241 events (6%); fully adjusted HR 1.84[1.34-2.50], P<0.001). The association between FGF23 and incident diabetes lost significance after additional adjustment for BMI. Conclusions: Glucose loading has phosphate-independent effects on FGF23; vice versa, FGF23 is associated with glucose, insulin, proinsulin levels and obesity. These findings suggest deleterious cross-talk between FGF23 and glucose homeostasis, which may promote susceptibility to incident diabetes. Disclosure A.Van der vaart: None. C.Eelderink: None. A.Van beek: Advisory Panel; Novo Nordisk, Consultant; Novo Nordisk. S.J.Bakker: None. P.Van dijk: None. M.De borst: None.

Fibroblast growth factor 23, glucose homeostasis and incident diabetes: findings of two cohort studies.

The phosphate-regulating hormone fibroblast growth factor 23 (FGF23) has been linked to deregulations in glucose metabolism, but its role is insufficiently understood. This study investigates potential cross-talk between FGF23 and glucose homeostasis. First, we investigated the effect of glucose loading on plasma C-terminal FGF23 levels and its temporal relationship with changes in plasma phosphate in 45 overweight (BMI 25-30 kg/m2) subjects using time-lag analyses. Second, we studied cross-sectional associations of plasma C-terminal FGF23 levels with glucose homeostasis using multivariable linear regression in a population-based cohort. We also investigated associations of FGF23 with incident diabetes and obesity (BMI >30 kg/m2) in individuals without diabetes or obesity at baseline, respectively, using multivariable Cox regression analyses. Finally, we explored whether the association between FGF23 and diabetes depends on BMI. After glucose loading, changes in FGF23 preceded changes in plasma phosphate (Ptime-lag=0.04). In the population-based cohort (N=5482; mean age 52 yrs, 52% women, median FGF23 69 RU/mL), FGF23 was associated with plasma glucose (b 0.13[0.03-0.23], P=0.01), insulin (b 0.10[0.03-0.17], P<0.001), and proinsulin (b 0.06[0.02-0.10], P=0.01) at baseline. Upon longitudinal analyses, a higher baseline FGF23 was independently associated with development of diabetes (199 events (4%); fully adjusted HR 1.66[95% CI 1.06-2.60], P=0.03) and development of obesity (241 events (6%); fully adjusted HR 1.84[1.34-2.50], P<0.001). The association between FGF23 and incident diabetes lost significance after additional adjustment for BMI. Glucose loading has phosphate-independent effects on FGF23 and, vice versa, FGF23 is associated with glucose, insulin and proinsulin levels and obesity. These findings suggest cross-talk between FGF23 and glucose homeostasis, which may promote susceptibility to incident diabetes.

Effect of vitamin D supplementation on circulating fibroblast growth factor-23 concentration in adults with prediabetes.

Recent meta-analyses report that vitamin D supplementation increases blood fibroblast growth factor-23 (FGF23) level. To determine the effect of 4000IU/day of vitamin D3 for 12months on circulating FGF23 levels. We also examined the association of the achieved 25-hydroxyvitamin D level [25(OH)D] with the FGF23 level at 12months and with 12-month changes in FGF23. An ancillary analysis among adults 70years and older with prediabetes who participated in a trial comparing vitamin D3 4000IU/day with placebo. Plasma intact FGF23 and serum 25(OH)D were measured at baseline and month 12 (M12). Characteristics of the 52 participants (vitamin D3 n = 28; placebo n = 24) did not differ significantly aside from more women than men in the vitamin D3 group. Mean ± SD age was 73.8 ± 3.7years, BMI 31.3 ± 4.2kg/m2, and glomerular filtration rate (GFR) 76.3 ± 11.8mL/min/1.73m2 Baseline serum 25(OH)D level was 33.4 ± 10.8ng/mL and increased at M12 to 54.9 ± 14.8ng/mL in the vitamin D3 group versus 33.4 ± 14.9 in the placebo (p < 0.001). At baseline, GFR was inversely associated with FGF23 (r = -0.349, p = 0.011). Change in FGF23 level at M12 did not differ significantly between vitamin D3 and placebo. In all participants combined, the achieved serum 25(OH)D level at M12 was not significantly associated with the M12 plasma FGF23 or the M12 change in FGF23. In obese older adults with sufficient vitamin D status and normal renal function, vitamin D3 4000IU/day for 12months did not significantly alter plasma intact FGF23 levels. gov NCT 01,942,694, registered 9/16/2013.

Does Dapagliflozin influence arterial stiffness and levels of circulating anti-aging hormone soluble Klotho in people with type 2 diabetes and kidney disease? Results of a randomized parallel group clinical trial.

ObjectiveThe mechanisms that explain the cardio-renal benefits of sodium glucose co-transporter 2 (SGLT-2) inhibitors are unknown. The effect of SGLT-2 inhibitors on arterial aging, measured by Aortic Pulse Wave Velocity (Ao-PWV) and Soluble Klotho (s-Klotho), a circulating anti-aging biomarker of arterial health are also unclear.Design/SettingA 24-week single center randomized controlled trial (registry number/ EudraCT Number: 2013-004042-42) comparing Dapagliflozin and Ramipril (D+R) versus Ramipril (R) on the primary endpoint of urine albumin excretion rate (AER) and pre-specified secondary endpoints of Ao-PWV and biomarkers of arterial aging [s-Klotho and Fibroblast Growth Factor 23 (FGF-23)]. People with type 2 diabetes who had estimated glomerular filtration rate (eGFR) > 60 ml/min and residual microalbuminuria on maximum tolerated renin angiotensin system (RAS) inhibition were included in this study.ResultsIn total, 33 participants (male 73%) were randomized to either D+R (n = 17) or R (n = 16) arms. After 24 weeks of treatment, Ao-PWV (mean ± SD) did not change significantly from baseline D +R [9.06 ± 1.91 m/s to 9.13 ± 2.03 m/s], and R [9.88 ± 2.12 m/s to 10.0 ± 1.84 m/s]. AER fell significantly by 43.5% (95% CI: −57.36%, −29.56%; p < 0.01) in people in the D+ R arm only. We do not observe any significant changes in FGF-23 or s-Klotho. HbA1c and Angiotensin 1–7 fell significantly only in D + R arm.ConclusionsThe combination of Dapagliflozin and Ramipril had no effects on Ao-PWV and s-Klotho which are biomarkers of arterial aging and cardio-renal risk. Our data suggest that the early cardio-renal benefits observed with SGLT-2 inhibitors are unlikely to be related to an improvement in arterial aging.

FGF23 and Cardiovascular Structure and Function in Advanced Chronic Kidney Disease.

Fibroblast growth factor 23 (FGF23) is a bone-derived phosphatonin that is elevated in chronic kidney disease (CKD) and has been implicated in the development of cardiovascular disease. It is unknown whether elevated FGF23 in CKD is associated with impaired cardiovascular functional capacity, as assessed by maximum exercise oxygen consumption (VO2Max). We sought to determine whether FGF23 is associated with cardiovascular functional capacity in patients with advanced CKD and after improvement of VO2Max by kidney transplantation. We performed secondary analysis of 235 patients from the Cardiopulmonary Exercise Testing in Renal Failure and After Kidney Transplantation (CAPER) cohort, which recruited patients with stage 5 CKD who underwent kidney transplantation or were waitlisted and hypertensive controls. All patients underwent cardiopulmonary exercise testing (CPET) and echocardiography and were followed longitudinally for 1 year after study enrollment. Patients across FGF23 quartiles differed in BMI (P=0.004) and mean arterial pressure (P<0.001) but did not significantly differ in sex (P=0.5) or age (P=0.08) compared with patients with lower levels of FGF23. Patients with higher FGF23 levels had impaired VO2Max (Q1: 24.2±4.8 ml/min per kilogram; Q4: 18.6±5.2 ml/min per kilogram; P<0.001), greater left ventricular mass index (LVMI; P<0.001), reduced HR at peak exercise (P<0.001), and maximal workload (P<0.001). Kidney transplantation conferred a significant decline in FGF23 at 2 months (P<0.001) before improvement in VO2Max at 1 year (P=0.008). Multivariable regression modeling revealed that changes in FGF23 was significantly associated with VO2Max in advanced CKD (P<0.001) and after improvement after kidney transplantation (P=0.006). FGF23 was associated with LVMI before kidney transplantation (P=0.003), however this association was lost after adjustment for dialysis status (P=0.4). FGF23 was not associated with LVMI after kidney transplantation in all models. FGF23 levels are associated with alterations in cardiovascular functional capacity in advanced CKD and after kidney transplantation. FGF23 is only associated with structural cardiac adaptations in advanced CKD but this was modified by dialysis status, and was not associated after kidney transplantation.

Impact of etelcalcetide on fibroblast growth factor-23 and calciprotein particles in patients with secondary hyperparathyroidism undergoing haemodialysis.

Recently, we demonstrated the efficacy of etelcalcetide in the control of secondary hyperparathyroidism (SHPT). This post hoc analysis aimed to evaluate changes in fibroblast growth factor-23 (FGF23) and calciprotein particles (CPPs) after treatment with calcimimetics. The DUET trial was a 12-week multicenter, open-label, parallel-group, randomized (1:1:1) study with patients treated with etelcalcetide plus active vitamin D (E + D group; n= 41), etelcalcetide plus oral calcium (E + Ca group; n= 41), or control (C group; n= 42) under maintenance haemodialysis. Serum levels of FGF23 and CPPs were measured at baseline, and 6 and 12 weeks after the start. In the linear mixed model, serum levels of FGF23 in etelcalcetide users were significantly lower than those in non-users at week 6 (p< .001) and week 12 (p< .001). When compared the difference between the E + Ca group and the E + D group, serum levels of FGF23 in the E + Ca group were significantly lower than those in the E + D group at week 12 (p= .017). There were no significant differences in the serum levels of CPPs between etelcalcetide users and non-users at week 6 and week 12, while CPPs in the E + Ca group were significantly lower than those in the E + D group (p< .001) at week 12. Etelcalcetide may be useful through suppression of FGF23 levels among haemodialysis patients with SHPT. When correcting hypocalcaemia, loading oral calcium preparations could be more advantageous than active vitamin D for the suppression of both FGF23 and CPPs.

18-year change in serum intact fibroblast growth factor 23 from midlife to late life and risk of mortality: the ARIC Study.

Fibroblast growth factor 23 (FGF23) concentration increases in response to declining kidney function to preserve normal phosphate concentrations. However, the etiological association of change in FGF23 concentration with mortality has not been examined in the general population. We analyzed 5458 participants of the Atherosclerosis Risk in Communities Study who had intact FGF23 and estimated glomerular filtration rate (eGFR) assessed during midlife (visit 3, 1993-1995, mean age: 58 years) and late life (visit 5, 2011-2013, 76 years) to examine the association of FGF23 change over 18 years from mid-life to late life with the subsequent risk of mortality in late life using Cox regression models. The median 18-year change in intact FGF23 was +17.3 pg/mL. During a median follow-up of 7.2 years following visit 5, 1176 participants died. In multivariable Cox models, elevated mortality was seen in the highest quartile of FGF23 change (ΔFGF23: ≥31.3 pg/mL) (adjusted hazard ratio (aHR): 1.61 (95%CI: 1.36-1.90), or 1.37 (1.15-1.64) after additionally adjusting for eGFR change, compared with the lowest quartile (≤6.4 pg/mL)). When both FGF23 change and FGF23 in late life were simultaneously entered into the Cox model, FGF23 in late life, but not FGF23 change, was an independent predictor of mortality; however, we observed a high correlation between FGF23 change from midlife to late life and FGF23 in late life (r = 0.77). Serum intact FGF23 change from midlife to late life was associated with subsequent risk of mortality independent of decline in kidney function. Our findings further support the implications of FGF23 beyond its association with kidney function.

Fibroblast growth factor 23 as a risk factor for cardiovascular events and mortality in patients in the EVOLVE trial.

High mortality rates in patients with chronic kidney disease-mineral and bone disorder (CKD-MBD) receiving maintenance hemodialysis are largely due to cardiovascular (CV) events. We evaluated associations between MBD parameters, fibroblast growth factor 23 (FGF23) concentrations, and clinically adjudicated CV events from the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial. Patients enrolled in EVOLVE, who had not experienced any study endpoints between randomization and week 20 with evaluable baseline and week 20 values for key laboratory parameters (parathyroid hormone, calcium, phosphate, and FGF23), were assessed. We used adjusted Cox proportional hazards regression models to estimate relative risk of outcomes (primary composite, all-cause mortality, and CV events) based on FGF23 and MBD parameters. Laboratory values were modeled with linear terms and using natural cubic splines with two degrees of freedom. For the primary endpoint, patients assessed (N = 2309) were followed up over a mean duration of 3.1 years, during which 1037 CV events (497 deaths, 540 nonfatal events) occurred. Adjusted models showed an association between FGF23 and the risk of CV events. Hazard ratio per log unit of FGF23 at week 20 was 1.09 [95% CI: 1.03-1.16], and the hazard ratio per log unit change in FGF23 from week 0 to week 20 was 1.09 [95% CI: 1.00-1.17]. Our data highlight FGF23 as an independent CV risk factor and potential biomarker and therapeutic target for patients with CKD-MBD receiving maintenance hemodialysis.

Fibroblast growth factor 23 concentrations and modifying factors in children from age 12 to 24months.

Fibroblast growth factor 23 (FGF23) participates in phosphate, calcium and vitamin D metabolism. In children these interactions and modifying factors are largely unknown. This study evaluates temporal changes and modifiers of FGF23 concentrations from 12 to 24months, in healthy children, participating in a randomized vitamin D intervention (VIDI). Participants received vitamin D3 of 10 or 30μg/day from age 2weeks to 24months. At 12 and 24months, growth measurements and venous blood samples were obtained for analyses of intact (iFGF23) and C-terminal FGF23 (cFGF23), 25-hydroxyvitamin D (25-OHD), calcium, phosphate, parathyroid hormone, iron and ferritin. Changes in FGF23 and modifying factors were examined by linear mixed models. The study included 594 infants. Girls had higher iFGF23 than boys (p<0.001 for both 12 and 24months), cFGF23 did not differ between the sexes. Adjusted mean iFGF23 decreased from 41.4 to 38.1pg/mL in boys (p<0.001) and from 45.2 to 42.5pg/mL in girls (p=0.002). Adjusted mean cFGF23 decreased from 2.89 to 2.00pmol/L in boys (p<0.001) and from 2.92 to 1.93pmol/L in girls (p<0.001). Iron modified FGF23 in both sexes, associating positively with iFGF23 and inversely with cFGF23. In girls, 25-OHD modified iFGF23. In boys, season modified FGF23, possibly through seasonal differences in 25-OHD. Vitamin D intervention dose did not affect FGF23. FGF23 decreases from 12 to 24months. Girls have higher iFGF23 than boys, at both time points. Iron modifies FGF23 in both sexes.

Effect of Sixteen Weeks Combined Training on FGF-23, Klotho, and Fetuin-A Levels in Patients on Maintenance Hemodialysis.

Introduction. Fibroblast growth factor 23 (FGF-23) and its cofactor alfa klotho, are one of the most important factors, directly and indirectly, involved in the process of calcification and atherosclerosis. This study aimed to evaluate the efficacy of a combination of regular exercise during dialysis on quality of life and markers including FGF-23, alfa klotho, and fetuin-A levels. Methods. Forty-five hemodialysis patients aged 61 ± 9.02 years and weight 69 ± 11.25 kg were randomly divided into two training, EX (n = 24) and control groups, CON (n = 21). The EX group patients participated in a 16-week combined aerobic and resistance exercise program during dialysis. Bone markers including, FGF-23, klotho, fetuin-A, were measured before and at the end of the study in both groups. Statistical analysis for comparing data change during study by SPSS software and the P value was set at .05. Results. In the control group in the secondary assessment, reduction in quality of life was observed (P .05), however significant rising of klotho was observed in treated patients (P < .05). Also, combined training reduced the amount of phosphorus, parathyroid hormone; significantly (P < .05). Conclusion. This study showed that regular exercise during dialysis improves quality of life and physical functions. No significant change in FGF-23 and CRP were observed during the study. However significant rising of klotho and reduction of iPTH and phosphorous levels were observed in treated patients.

Change in FGF23 concentration over time and its association with all-cause mortality in patients treated with haemodialysis or haemodiafiltration.

BackgroundPrevious studies in patients on haemodialysis (HD) have shown an association of fibroblast growth factor 23 (FGF23) with all-cause mortality. As of yet, the result of FGF23 lowering on mortality is unknown in this population.MethodsFGF23 was measured in a subset of 404 patients from the Dutch CONvective TRansport STudy (CONTRAST study) [a randomized trial in prevalent dialysis patients comparing HD and haemodiafiltration (HDF) with clinical outcome] at baseline and Months 6 and 12. A substantial decline of FGF23 change over time was anticipated in patients randomized to HDF since HDF induces higher dialytic clearance of FGF23. The associations of both baseline FGF23 and 6-months change in FGF23 with all-cause mortality were analysed. In addition, the difference in FGF23 change between HD and HDF was explored. Furthermore, the role of dialysis modality in the association between FGF23 change and outcome was analysed.ResultsNo association was observed between quartiles of baseline FGF23 and all-cause mortality. Over 6 months, FGF23 declined in patients on HDF, whereas FGF23 remained stable in patients on HD. A decrease in FGF23 was not associated with improved survival compared with a stable FGF23 concentration. However, increasing FGF23 was associated with a significantly higher mortality risk, both in crude and fully adjusted models [hazard ratio 2.01 (95% confidence interval 1.30–3.09)].ConclusionWhereas no association between a single value of FGF23 and all-cause mortality was found, increasing FGF23 concentrations did identify patients at risk for mortality. Since lowering FGF23 did not improve outcome, this study found no argument for therapeutically lowering FGF23.

Klotho/FGF23 and Wnt Signaling as Important Players in the Comorbidities Associated with Chronic Kidney Disease.

Fibroblast Growth Factor 23 (FGF23) and Klotho play an essential role in the regulation of mineral metabolism, and both are altered as a consequence of renal failure. FGF23 increases to augment phosphaturia, which prevents phosphate accumulation at the early stages of chronic kidney disease (CKD). This effect of FGF23 requires the presence of Klotho in the renal tubules. However, Klotho expression is reduced as soon as renal function is starting to fail to generate a state of FGF23 resistance. Changes in these proteins directly affect to other mineral metabolism parameters; they may affect renal function and can produce damage in other organs such as bone, heart, or vessels. Some of the mechanisms responsible for the changes in FGF23 and Klotho levels are related to modifications in the Wnt signaling. This review examines the link between FGF23/Klotho and Wnt/β-catenin in different organs: kidney, heart, and bone. Activation of the canonical Wnt signaling produces changes in FGF23 and Klotho and vice versa; therefore, this pathway emerges as a potential therapeutic target that may help to prevent CKD-associated complications.

Higher plasma fibroblast growth factor 23 levels are associated with a higher risk profile in pulmonary arterial hypertension.

Metabolic abnormalities are proposed to contribute to pulmonary arterial as well as right ventricular remodelling in pulmonary arterial hypertension. Among the proposed abnormalities are altered glucose and lipid processing, mitochondrial malfunction, oxidative stress as well as vitamin D and iron abnormalities. In the present study, we investigated 11 metabolic plasma biomarkers, with the hypothesis that metabolic proteins may mirror disease severity in pulmonary arterial hypertension. Using proximity extension assays, plasma metabolic biomarkers were measured in 48 pulmonary arterial hypertension patients at diagnosis and, in 33 of them, at an early treatment follow-up, as well as in 16 healthy controls. Among the studied metabolic biomarkers, plasma fibroblast growth factor-23 (p < 0.001), fibroblast growth factor-21 (p < 0.001), fatty acid binding protein 4 (p < 0.001) and lectin-like oxidised low-density lipoprotein receptor 1 (p < 0.001) were increased and paraoxonase-3 was decreased (p < 0.001) in pulmonary arterial hypertension at diagnosis versus controls. Fibroblast growth factor-23 showed the strongest correlations to studied clinical parameters and was therefore selected for further analyses. Fibroblast growth factor-23 correlated specifically to mean right atrial pressure (r = 0.67, p < 0.001), six-min walking distance (r = −0.66, p < 0.001), NT-proBNP (r = 0.64, p < 0.001), venous oxygen saturation (r = −0.61, p < 0.001), cardiac index (r = −0.39, p < 0.007) and pulmonary vascular resistance (r = 0.37, p < 0.01). Fibroblast growth factor-23 correlated moreover to ESC/ERS (r = 0.72, p < 0.001) and the REVEAL risk score (r = 0.61, p < 0.001). Comparing early treatment follow-up with baseline, fibroblast growth factor-23 decreased (p < 0.02), with changes in fibroblast growth factor-23 correlating to changes in six-min walking distance (r = −0.56, p < 0.003), venous oxygen saturation (r = −0.46, p < 0.01), pulmonary vascular resistance (r = 0.43, p < 0.02), mean right atrial pressure (r = 0.38, p < 0.04) and cardiac index (r = −0.39, p < 0.04). Elevated plasma fibroblast growth factor-23 levels at pulmonary arterial hypertension diagnosis were associated with worse haemodynamics and a higher risk profile, and were decreased after the administration of pulmonary arterial hypertension-specific treatment.

Effects of Nicotinamide and Lanthanum Carbonate on Serum Phosphate and Fibroblast Growth Factor-23 in CKD: The COMBINE Trial

Higher serum phosphate and fibroblast growth factor-23 (FGF23) levels may be modifiable to prevent cardiovascular disease in CKD. Short-term studies have reported modest efficacy in phosphate and FGF23 reduction with intestinal phosphate binders in CKD. To investigate effects of lanthanum carbonate (LC; a phosphate binder) and/or nicotinamide (NAM; an inhibitor of active intestinal phosphate transport) on serum phosphate and FGF23 in stage 3b/4 CKD, we conducted a randomized trial among individuals with eGFR 20-45 ml/min per 1.73 m2 to NAM (750 mg twice daily) plus LC (1000 mg thrice daily), NAM plus LC placebo, LC plus NAM placebo, or double placebo for 12 months. Dual primary end points were change from baseline in serum phosphate and intact FGF23 concentrations. Mean eGFR for the 205 participants was 32ml/min per 1.73 m2. At baseline, serum phosphate was 3.7 mg/dl and median FGF23 was 99 pg/ml (10th, 90th percentiles: 59, 205). Mean rates of change in phosphate increased slightly over 12 months in all groups and did not differ significantly across arms. Similarly, percent changes in FGF23 per 12 months increased for all arms except LC plus placebo, and did not differ significantly across arms. Gastrointestinal symptoms limited adherence. Adverse events rates were similar across arms. LC and/or NAM treatment did not significantly lower serum phosphate or FGF23 in stage 3b/4 CKD over 12 months. Although these agents appeared safe, intestinal symptoms limited adherence. Reducing phosphate and FGF23 in nondialysis CKD will require new approaches.

Effects of etelcalcetide on fibroblast growth factor 23 in patients with secondary hyperparathyroidism receiving hemodialysis.

BackgroundEtelcalcetide is an intravenous calcimimetic approved for treatment of secondary hyperparathyroidism (sHPT) in patients receiving hemodialysis. Besides lowering parathyroid hormone (PTH), etelcalcetide also significantly reduces fibroblast growth factor 23 (FGF23), but the mechanisms are unknown.MethodsTo investigate potential mediators of etelcalcetide-induced FGF23 reduction, we performed secondary analyses of the 26-week randomized trials that compared the effects on PTH of etelcalcetide (n = 509) versus placebo (n = 514) and etelcalcetide (n = 340) versus cinacalcet (n = 343) in adults with sHPT receiving hemodialysis. We analyzed changes in FGF23 in relation to changes in PTH, calcium, phosphate and bone turnover markers. We also investigated how concomitant treatments aimed at mitigating hypocalcemia altered the FGF23-lowering effects of etelcalcetide.ResultsEtelcalcetide reduced FGF23 [median % change (quartile 1–quartile 3)] from baseline to the end of the trial significantly more than placebo [–56% (–85 to –7) versus +2% (–40 to +65); P < 0.001] and cinacalcet [–68% (–87 to –26) versus –41% (–76 to +25); P < 0.001]. Reductions in FGF23 correlated strongly with reductions in calcium and phosphate, but not with PTH; correlations with bone turnover markers were inconsistent and of borderline significance. Increases in concomitant vitamin D administration partially attenuated the FGF23-lowering effect of etelcalcetide, but increased dialysate calcium concentration versus no increase and increased dose of calcium supplementation versus no increase did not attenuate the FGF23-lowering effects of etelcalcetide.ConclusionThese data suggest that etelcalcetide potently lowers FGF23 in patients with sHPT receiving hemodialysis and that the effect remains detectable among patients who receive concomitant treatments aimed at mitigating treatment-associated decreases in serum calcium.

Fibroblast growth factor 23 levels decline following sleeve gastrectomy.

Levels of fibroblast growth factor 23 (FGF23) have been positively associated with measures of adiposity, cardiovascular disease and mortality. It is unclear whether the relationship of FGF23 with cardiovascular disease and mortality is confounded by obesity. We aimed to determine whether FGF23 concentrations decline following a reduction in adiposity after sleeve gastrectomy (SG). The effect of SG on FGF23 was evaluated in 22 obese adults (59% male) with type 2 diabetes. Fat mass, weight, BMI, plasma intact FGF23, parathyroid hormone (PTH) and leptin were determined at baseline and at 12months following SG. At baseline, median (IQR) age was 51 (43-54) years, fat mass 47.8 (41.0-59.4)kg, BMI 40.9 (36.9-46.9)kg/m2 and FGF23 66.2 (55.3-82.9)pg/mL. Significant changes in median BMI (-10.8kg/m2 , 95% CI: -12.9 to -7.2, P<0.0001), fat mass (-20.0kg, 95% CI: -26.7 to -12.4, P<0.0001) and weight (-34.7kg, 95% CI -40.0 to -23.1, P<0.0001) were observed after SG. FGF23 (-12.4pg/mL, 95% CI: -19.5 to 2.0, P=0.005), PTH (-1.1pmol/L, 95% CI: -1.7 to 0.2, P=0.009) and leptin (-1687pg/mL, 95% CI -4524 to -563, P=0.01) declined following SG. Change in FGF23 was not significantly associated with change in measures of adiposity, PTH or leptin. FGF23 concentrations decline in the setting of significant weight loss following SG, implying that increased FGF23 concentrations are a downstream consequence of obesity, which may confound its association with cardiometabolic dysfunction. Mediators of the relationship between adiposity and FGF23 require further elucidation.