Log Fibroblast Growth Factor-23 Research Articles

Vitamin D3 Repletion Improves Vascular Function, as Measured by Cardiorenal Biomarkers in a High-Risk African American Cohort.

Background: 25-hydroxy vitamin D (Vit D)-deficiency is common among patients with chronic kidney disease (CKD) and contributes to cardiovascular disease (CVD). African Americans (AAs) suffer disproportionately from CKD and CVD, and 80% of AAs are Vit D-deficient. The impact of Vit D repletion on cardio-renal biomarkers in AAs is unknown. We examined Vit D repletion on full-length osteopontin (flOPN), c-terminal fibroblast growth factor-23 (FGF-23), and plasminogen activator inhibitor-1 (PAI-1), which are implicated in vascular and kidney pathology. Methods: We performed a randomized, placebo-controlled study of high-risk AAs with Vit D deficiency, treated with 100,000 IU Vit D3 (cholecalciferol; n = 65) or placebo (n = 65) every 4 weeks for 12 weeks. We measured kidney function (CKD-EPI eGFR), protein-to-creatinine ratio, vascular function (pulse wave velocity; PWV), augmentation index, waist circumference, sitting, and 24-h-ambulatory blood pressure (BP), intact parathyroid hormone (iPTH) and serum calcium at baseline and study end, and compared Vit D levels with laboratory variables. We quantified plasma FGF-23, PAI-1, and flOPN by enzyme-linked immunosorbent assay. Multiple regression analyzed the relationship between log flOPN, FGF-23, and PAI-1 with vascular and renal risk factors. Results: Compared to placebo, Vit D3 repletion increased Vit D3 2-fold (p < 0.0001), decreased iPTH by 12% (p < 0.01) and was significantly correlated with PWV (p < 0.009). Log flOPN decreased (p = 0.03), log FGF-23 increased (p = 0.04), but log PAI-1 did not change. Multiple regression indicated association between log flOPN and PWV (p = 0.04) and diastolic BP (p = 0.02), while log FGF-23 was associated with diastolic BP (p = 0.05), and a trend with eGFR (p = 0.06). Conclusion: Vit D3 repletion may reduce flOPN and improve vascular function in high risk AAs with Vit D deficiency.

Association of Genetically Predicted Fibroblast Growth Factor-23 with Heart Failure: A Mendelian Randomization Study.

Elevated fibroblast growth factor-23 (FGF23) has been consistently associated with heart failure, particularly heart failure with preserved ejection fraction, among patients with CKD and in the general population. FGF23 may directly induce cardiac remodeling and heart failure. However, biases affecting observational studies impede robust causal inferences. Mendelian randomization leverages genetic determinants of a risk factor to examine causality. We performed a two-sample Mendelian randomization to assess causal associations between FGF23 and heart failure. Genetic instruments were genome-wide significant genetic variants associated with FGF23, including variants near PIP5K1B, RGS14, LINC01229, and CYP24A1. We analyzed data from the Heart Failure Molecular Epidemiology for Therapeutic Targets and BioVU biobanks to examine associations of the four variants with overall heart failure, heart failure with preserved ejection fraction, and heart failure with reduced and mid-range ejection fraction. We developed an eGFR polygenic risk score using summary statistics from the Chronic Kidney Disease Genetics Consortium (CKDGen) genome-wide association study of eGFR in >1 million individuals and performed stratified analyses across eGFR polygenic risk score strata. Genetically determined FGF23 was not associated with overall heart failure in the Heart Failure Molecular Epidemiology for Therapeutic Targets consortium (odds ratio, 1.13; 95% confidence interval, 0.89 to 1.42 per unit higher genetically predicted log FGF23) and the full BioVU sample (odds ratio, 1.32; 95% confidence interval, 0.95 to 1.84). In stratified analyses in BioVU, higher FGF23 was associated with overall heart failure (odds ratio, 3.09; 95% confidence interval, 1.38 to 6.91) among individuals with low eGFR-polygenic risk score (<1 SD below the mean), but not those with high eGFR-polygenic risk score (P interaction = 0.02). Higher FGF23 was also associated with heart failure with preserved ejection fraction among all BioVU participants (odds ratio, 1.47; 95% confidence interval, 1.01 to 2.14) and individuals with low eGFR-polygenic risk score (odds ratio, 7.20; 95% confidence interval, 2.80 to 18.49), but not those high eGFR-polygenic risk score (P interaction = 2.25 × 10-4). No significant associations were observed with heart failure with reduced and midrange ejection fraction. We found no association between genetically predicted FGF23 and heart failure in the Heart Failure Molecular Epidemiology for Therapeutic Targets consortium. In BioVU, genetically elevated FGF23 was associated with higher heart failure risk, specifically heart failure with preserved ejection fraction, particularly among individuals with low genetically predicted eGFR. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_07_28_CJN00960122.mp3.

Fibroblast Growth Factor-23 in Pre-Dialysis Chronic Kidney Disease Patients and its Correlation with Carotid Artery Calcification.

Fibroblast growth factor 23 (FGF-23) is a phosphate metabolism regulator in patients with chronic kidney disease (CKD). The present study is aimed to examine the FGF-23 level in pre-dialysis patients with CKD and its correlation with carotid artery calcification (CAAC). This cross-sectional study included patients with CKD and controls. The patients were compared with controls having similar distribution of age and sex to determine serum FGF-23 level in Indian healthy adult population. Detailed medical history, physical examination, and investigations were done for each patient. Atherosclerotic risk factors, cardiovascular comorbidities, and drug history were recorded. Carotid calcification was observed using carotid ultrasound. In total, 62 patients with a mean age of 50.0 years were enrolled. Majority of the patients had hypertension (66.1%), followed by diabetes (27.4%) and dyslipidemia (3.2%). Mean serum corrected calcium levels were significantly higher in patients with CAAC compared to the patients without CAAC (9.21 ± 1.34 vs. 8.53 ± 0.93 mg/dL; P = 0.014). The FGF-23 levels were significantly higher in patients with CAAC compared to those without CAAC (396.0 vs. 254.0 pg/mL; P = 0.008). CAAC was found to be present in both early and late stages of CKD. Multivariate analysis showed that log FGF-23 and serum corrected calcium remained as independent determinants of CAAC. The prevalence of CAAC increased with the ascending quartiles of FGF23. In conclusion, FGF-23 was found to be independently associated with CAAC in CKD.

MO796IMPACT OF ACTIVE VITAMIN D AND CALCIUM PREPARATION ON VASCULAR CALCIFICATION MARKERS IN HEMODIALYSIS PATIENTS WITH HYPOCALCEMIA INDUCED BY CALCIMIMETICS

Abstract Background and Aims Recently, we demonstrated the efficacy of etelcalcetide for control of secondary hyperparathyroidism (SHPT) in the DUET trial; a 12-week multicenter, open-label, randomized (1:1:1), parallel-group study treated with etelcalcetide + active vitamin D (Group E+D), etelcalcetide + oral calcium preparation (Group E+Ca), or control groups (Group C) in 124 subjects undergoing maintenance hemodialysis. Moreover, we also showed that active vitamin D was useful in correcting hypocalcemia induced by calcimimetics, but the oral calcium preparation was superior for suppression of hyperphosphatemia. In this post hoc analysis, we evaluated vascular calcification markers, fibroblast growth factor 23 (FGF23) and calciprotein particles (CPPs), in patients using etelcalcetide (n = 77) extracted from the registrants of the DUET trial. Method Serum levels of FGF23 and CPPs were measured at baseline, 6 weeks and 12 weeks after start of the trial. Skewed data (FGF23 and CPPs) were transformed to natural logarithm to achieve normal distribution prior to statistical analysis. The changes in log CPPs and log FGF23 were estimated in a linear mixed model with each treatment group, time point, and interaction of the treatment group and time point as the fixed effects. We compared these changes between treatment the groups using a linear mixed model and also the Tukey-Kramer method to correct for multiplicity. Additionally, we exploratory examined the correlations among changes of FGF23, CPPs and other biomarkers related to bone mineral metabolisms, iPTH, Ca, P, and calcium-phosphate product, tested by Spearman’s rank correlation coefficient. Results The decreases at the 12-week time point after the trial start in log FGF23 were estimated -1.13 pg/mL in Group E+Ca and -0.10 pg/mL in Group E+D in a linear mixed model, respectively. Similarly, the decreases in CPPs were estimated -1.60 AU in Group E+Ca and -0.82 AU in Group E+D, respectively. Changes of both FGF23 (P = 0.017) and CPPs (P &amp;lt; 0.001) in Group E+Ca significantly decreased compared with those in in Group E+D by Tukey-Kramer multiple-comparison test at 12 weeks after the trial start, while both changes in CPPs and FGF23 could not reach the significant differences between two groups at 6 weeks after the trial start (Figure 1). Reductions in FGF23 positively correlated with reductions in calcium (ρ = 0.42, P &amp;lt; 0.01) and phosphate (ρ = 0.48, P &amp;lt; 0.01) at 6 weeks after the trial start, and in calcium (ρ = 0.30, P &amp;lt; 0.01) and phosphate (ρ =0.70, P &amp;lt; 0.01) at 12 weeks after 6 weeks of the trial start), but there was no correlation with reductions in iPTH at any time point. Reductions in CPPs positively correlated with reductions only in phosphate at 6 weeks after the trial start (ρ = 0.47, P &amp;lt; 0.01) and at 12 weeks after 6 weeks of the trial start (ρ = 0.54, P &amp;lt; 0.01). Conclusion In this analysis, vascular calcification markers were significantly decreased in Group E+Ca compared to those in Group E+D. Further studies should be needed, our study suggests that oral calcium preparation may have an advantage against vascular calcification rather than active vitamin D for the correction of hypocalcemia induced by etelcalcetide in hemodialysis patients with SHPT.

Fibroblast Growth Factor 23 and Risk of Hospitalization with Infection in Chronic Kidney Disease: The Chronic Renal Insufficiency Cohort (CRIC) Study.

Risk of infectious disease is increased among individuals with CKD. Fibroblast growth factor 23 (FGF23) is often elevated in CKD, and may impair immune function directly or indirectly through proinflammatory and vitamin D-suppressing pathways. Whether FGF23 is associated with risk of infection has not been evaluated in a CKD population. In 3655 participants of the Chronic Renal Insufficiency Cohort study, we evaluated the association of baseline plasma levels of C-terminal FGF23 with time to first hospitalization with major infection, defined by hospital discharge with a diagnosis code for urinary tract infection, pneumonia, cellulitis/osteomyelitis, or bacteremia/septicemia. Multivariable Cox models were used to estimate hazard ratios (HRs) and adjust for confounding. During a median follow-up of 6.5 years, 1051 individuals (29%) were hospitalized with major infection. Multivariable Cox analysis indicated a graded increase in the risk of infection with higher levels of FGF23 (HR, 1.51; 95% CI, 1.23 to 1.85 with the highest quartile [≥235.9 RU/ml] versus lowest quartile [<95.3 RU/ml]; HR, 1.26; 95% CI, 1.18 to 1.35 per SD increment in log FGF23). The association was consistent across infection subtypes and demographic and clinical subgroups, and remained significant after additional adjustment for biomarkers of inflammation (IL-6, TNF-α, high-sensitivity C-reactive protein, fibrinogen, and albumin), and bone mineral metabolism (25-hydroxyvitamin D, phosphorus, calcium, and parathyroid hormone). The association was consistent across infection subtypes of urinary tract infection (482 cases), cellulitis/osteomyelitis (422 cases), pneumonia (399 cases), and bacteremia/septicemia (280 cases). Among individuals with CKD, higher FGF23 levels were independently and monotonically associated with an increased risk of hospitalization with infection.

Intravenous Maxacalcitol Therapy Correlates with Serum Fibroblast Growth Factor 23 Levels in Hemodialysis Patients Independent of Serum Phosphate or Calcium Levels.

Fibroblast growth factor 23 (FGF23) is a regulator of phosphate and vitamin D homeostasis that carries out primary bone- and mineral-related physiological functions to increase renal phosphate excretion and reduce 1α-hydroxylation of 25-hydroxyvitamin D. In a negative endocrine feedback loop, 1,25-dihydroxyvitamin D also stimulates FGF23 secretion. Previous studies have assessed the correlation between vitamin D receptor activator therapy and FGF23 concentrations, and to our knowledge, none has assessed the correlation between intravenous (i.v.) maxacalcitol therapy and FGF23 concentration in hemodialysis patients. Subjects included 148 patients on maintenance hemodialysis. Serum FGF23 concentrations were measured. The correlations among serum FGF23 concentrations with i.v. maxacalcitol therapy and other clinical parameters and medications were analyzed. Mean serum log FGF23 was 3.7 ± 0.8 pg/mL. After division into two equal groups based on median serum log FGF23 level, the percentages of patients administered i.v. maxacalcitol (60/74 [81.1%] vs. 45/74 [60.8%], p < 0.01) were significantly higher in the high log FGF23 group. The amounts of serum FGF23 concentrations had been significantly higher to the amounts of i.v. maxacalcitol per week dependency. Multivariate regression analysis showed that treatment with i.v. maxacalcitol was an independent predictor of serum FGF23 levels, regardless of phosphate or calcium concentrations. i.v. maxacalcitol correlates with serum FGF23 concentration in hemodialysis patients, independent of serum phosphate or calcium concentrations.

The FGF23\u2013Klotho axis and cardiac tissue Doppler imaging in pediatric chronic kidney disease\u2014a prospective cohort study

BackgroundChronic kidney disease-associated mineral bone disorder (CKD-MBD) is common in pediatric kidney disease patients and a risk factor for future cardiovascular disease (CVD). Fibroblast growth factor-23 (FGF23) and Klotho are novel key players in CKD-MBD, and has been suggested to be involved in the development of CVD.MethodsThis prospective cohort study included 74 pediatric patients; 31 with CKD (age range 0.8–18.8 years, glomerular filtration rate (GFR) range 9–68 mL/min/1.73 m2) and 43 transplanted patients (CKD-T; age range 3.3–17.7 years, GFR range 10–99 mL/min/1.73 m2) examined annually for 3 years. We assessed longitudinal patterns and predictors of FGF23 and soluble Klotho, as well as associations to cardiac remodeling and function using echocardiographic pulse wave Doppler (PWD) and color-coded tissue Doppler imaging (cc-TDI).ResultsThe prevalence of high FGF23 levels (≥95th percentile) was 60% in CKD and 42% in CKD-T patients, despite a low prevalence of hyperphosphatemia and normal Klotho levels. Low GFR at baseline was a predictor for high mean log FGF23 during follow-up in CKD and CKD-T patients (β = −0.2, p < 0.001). A high log FGF23 z-score longitudinally was borderline significantly associated with elevated left ventricular mass index (LVMI) in CKD patients (β = 1.8, p = 0.06). In addition, high log FGF23 (β = −0.43, p = 0.01) and low log Klotho (β = 0.44, p = 0.006) over time were associated with a worse left ventricular diastolic function (cc-TDI e′/a′) in CKD-T patients.ConclusionsIn pediatric CKD and CKD-T patients, the FGF23 level increase and Klotho level decrease with progressing renal failure, despite well-controlled phosphate levels. Following adjustments, both high FGF23 and low Klotho levels were strongly associated with a worse left ventricular diastolic function longitudinally. The potential role of FGF23 and Klotho in cardiac morbidity in pediatric CKD requires further investigation.

Associations of fibroblast growth factor 23 with urate metabolism in patients with chronic kidney disease

ObjectiveIn patients with preserved kidney function, a positive association of fibroblast growth factor 23 (FGF23) with serum uric acid (SUA) has been reported; however, the relationship in overall chronic kidney disease (CKD) patients has not been investigated. No report has examined the relationship between FGF23 and uric acid clearance (CUA). The aim of the present study was to determine whether FGF23 is independently associated with urate metabolism in patients with CKD stages 1–5. Materials and methodsIn this cross-sectional study, 537 CKD patients were enrolled. SUA, CUA, FGF23, parathyroid hormone (PTH), and 1,25-dihydroxyvitamin D (1,25(OH)2D) were measured. Multivariable linear regression analysis was applied to determine independent factors associated with SUA or CUA. ResultsIn all patients, both SUA and CUA were independently associated with male sex, use of diuretics, use of uric acid-lowering agents, estimated glomerular filtration rate, and log FGF23 (β=0.29, P<0.01 for SUA; β=−0.11, P<0.01 for CUA), but not with log PTH or log 1,25(OH)2D. Dyslipidemia and diabetes were also independent factors for SUA and CUA, respectively. In multivariable analyses by sex, log FGF23 was associated with SUA in both sexes (β=0.32, P<0.01 in males vs. β=0.20, P=0.02 in females). Conversely, log FGF23 was independently associated with CUA in males (β=−0.15, P<0.01), but not in females (β=−0.09, P=0.17). ConclusionsFGF23 was independently associated with urate metabolism in this population of CKD patients. FGF23 might also have a stronger association with urate metabolism in males compared with females.

Neutrophil Gelatinase-Associated Lipocalin, Fibroblast Growth Factor 23, and Soluble Klotho in Long-Term Kidney Donors

Background: The best treatment for end-stage renal disease (ESRD) is kidney transplantation. Twenty-seven percent of transplantations in Norway are from living donors. Recent studies have shown an increased risk of ESRD and increased mortality in donors. The aim of this study was to determine if the levels of the new biomarkers neutrophil gelatinase-associated lipocalin (NGAL), soluble Klotho (sKlotho), and fibroblast growth factor 23 (FGF23) are changed in kidney donors with normal kidney function defined as an estimated glomerular filtration rate (eGFR) >60 ml/min/1.73 m² compared to patients with chronic kidney disease (CKD) stages 3-5 and healthy controls. Methods: This is a cross-sectional, observational, single-center study including 35 kidney donors with an eGFR ≥60 ml/min/1.73 m² 5 years after donation, 22 patients with CKD stage 3 (eGFR 30-59 ml/min/1.73 m²), 18 patients with CKD stage 4 (eGFR 15-29 ml/min/1.73 m²), 20 patients with CKD stage 5 (eGFR <15 ml/min/1.73 m²), and 35 controls comparing levels of biomarkers in long-term kidney donors with those in CKD patients and healthy controls. Results: The level of log NGAL was significantly higher in donors than in healthy controls (2.02 ± 0.10 vs. 1.89 ± 0.10 ng/ml; p < 0.001), and the level increased with declining kidney function. The log FGF23 level was nonsignificantly higher in donors than in controls, but it significantly increased with declining kidney function. The log sKlotho levels were significantly lower in patients with CKD stages 4 and 5 than in controls, but no difference was revealed between controls and donors. Conclusion: Kidney donors have significantly higher levels of NGAL than healthy controls after a median of 15 years (range 5-38). NGAL could be a valuable diagnostic marker in the future. FGF23 and sKlotho were not significantly different between donors and controls.

Plasma FGF23 Is a Biomarker for Left Ventricular Hypertrophy and Mortality in Adults with Sickle Cell Anemia Chronic Kidney Disease

Sickle cell anemia (SCA) is characterized by end organ damage, especially in the kidney and heart, resulting in a high prevalence of chronic kidney disease (CKD), tricuspid regurgitation and left ventricular hypertrophy (LVH). In the general population, dysregulation of calcium/phosphate homeostasis by elevated plasma fibroblast growth factor 23 (FGF23) directly promotes LVH in end stage CKD without SCA. Accordingly, the high mortality associated with end stage renal disease is primarily cardiac, and is associated with ventricular remodeling and elevated plasma FGF23. However, FGF23 has not been investigated as a biomarker for CKD, LVH and mortality in SCA. Here, we assessed the relationships between CKD, LVH, plasma FGF23 and mortality in adults with SCA.First, we determined that LVH is a common entity in SCA-CKD using a nested case control study of all SS subjects with stage 3-5 CKD (eGFR<60) enrolled in the Bethesda Sickle Cell Cohort Study (ClinicalTrials.gov identifier: NCT00011648) and age and sex-matched SCA subjects with normal renal function. Of those with SCA-CKD (n=42), LVH defined by echocardiogram was present in 74% compared to 41% in those with normal kidney function (odds ratio 3.79; 95%CI 1.57 - 10.06; p=0.0039).We next measured plasma FGF23 levels in normal volunteers (n=37) and age and sex-matched SCA subjects with and without CKD (n=37), using ELISA. We observed a 3.5-fold increase in plasma FGF23 levels among subjects with SCA (p<0.0001) and a 22-fold increase in those with SCA-CKD (p<0.0001). FGF23 levels are elevated at baseline in adults with SCA which has not previously been reported. The much higher fold increase in SCA-CKD was not unexpected, based upon previously reported high plasma FGF23 associated with CKD in the absence of SCA. Spearman correlations between plasma FGF23 levels in adults with SCA were correlated with creatinine (r=0.52, p=0.0011), eGFR (r=-0.57, p=0.0003), left ventricular mass index (LVMI, r=0.48, p=0.0029), and tricuspid regurgitant velocity (TRV; r=0.44, p=0.01). These data suggest that as in CKD without SCA, plasma FGF23 is a biomarker associated with both a decline in renal function and an increase in the prevalence of LVH and tricuspid regurgitation.We next sought to determine if plasma FGF23 levels are a biomarker associated with mortality in the overall SCA patient population. Univariate Kaplan-Meier analyses showed that categorical FGF23 levels (above versus below log mean; hazard ratio=1.74, 95% confidence interval 1.09-2.85, p=0.02] and elevated TRV (≥2.5 m/s versus all others, hazard ratio=4.42, 95% confidence interval 2.60-7.52, p<0.0001) are significantly associated with increased mortality in 478 adults with SCA. LVH defined by sex adjusted echocardiographic thresholds for LVMI was not associated with an increased risk of death (p=0.71). Multivariable Cox proportional hazard analysis indicated that log FGF23 is an independent risk factor for death (hazard ratio=1.46, 95% confidence interval 1.01-2.10, p=0.04), in addition, to the known mortality association with elevated TRV (hazard ratio=4.90, 95% confidence interval 2.86-8.39, p<0.0001). The Cox analysis suggests that plasma FGF23 is a biomarker for mortality in SCA, although the echocardiographic abnormality associated with death in this model is TRV and not LVMI.In conclusion, we observed a high prevalence of LVH in adults with SCA-CKD (70.3%), and SCA-CKD is associated with a 22 fold increase in plasma FGF23 levels. One limitation of our study was the inability to assess associations between plasma FGF23, LVMI, TRV and mortality risk in SCA-CKD due to a limited number of CKD subjects. When FGF23 was investigated in all adults with SCA, plasma FGF23 was a significant risk factor for death, independent of TRV and other known risk factors. Larger SCA-CKD studies will be necessary in the future to better understand the relationships between TRV, LVH, FGF23 and mortality. Overall, plasma FGF23 is a potentially helpful biomarker to further elucidate the pathobiology of SCA-CKD end organ complications. DisclosuresNo relevant conflicts of interest to declare.

Relationship of FGF23 to indexed left ventricular mass in children with non-dialysis stages of chronic kidney disease.

The aim of this study was to evaluate the association of serum intact fibroblast growth factor 23 (FGF23) concentrations with indexed left ventricular mass in children with non-dialysis stages 3-5 of chronic kidney disease (CKD). The study cohort comprised 83 children (51 boys; mean age 12.1 ± 3.2 years) with a mean estimated glomerular filtration rate (eGFR) of 32.3 ± 14.6 ml/min/1.73 m(2) who underwent clinic and ambulatory blood pressure measurement (ABPM), echocardiography and evaluation of biochemical markers of CKD-associated mineral bone disease. The mean left ventricular mass index (LVMI) was 35.9 ± 8.5 g/m(2.7) (± standard deviation), with 30 (36.1 %) children showing left ventricular hypertrophy (LVH), all eccentric, as defined using age-specific criteria. For all subjects, the mean FGF23 concentration was 142.2 ± 204.4 ng/l and the normalised distribution following log transformation was 1.94 ± 0.39. There was significant univariate correlation of LVMI with GFR, body mass index (BMI) z-score and calcium intake, but not with 24-h systolic ABPM z-score, log intact parathyroid hormone or log FGF23. On multivariate analysis following adjustment for confounders, only elemental calcium content (g/kg/day) estimated from prescribed calcium-based phosphate binder dose (β = 154.9, p < 0.001) and BMI z-score (β = 2.397, p = 0.003) maintained a significant positive relationship with LVMI (model r (2) = 0.225). We observed no significant relationship of FGF23 with LVMI. Larger studies in children are needed to clarify the roles of calcium-containing phosphate binders and FGF23 with LV mass and their roles in the evolution of the development of adverse cardiovascular outcomes.

25-vitamin D, 1,25-vitamin D, parathyroid hormone, fibroblast growth factor-23 and cognitive function in men with advanced CKD: a veteran population.

. Cognitive impairment is common in advanced chronic kidney disease (CKD), but little is known about its relation with abnormalities in mineral metabolism. Methods: The longitudinal association between plasma 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)2D), intact parathyroid hormone (iPTH), and fibroblast growth factor-23 (FGF-23) levels and cognitive function was assessed in 605 patients (67 ± 12 years) with advanced CKD not requiring dialysis (n = 247) or end-stage renal disease (ESRD; n = 358) who participated in the Homocysteine Study Cognitive Function Substudy (HOSTCOG)). Cognitive function was assessed using the Telephone Interview for Cognitive Status-modified (TICSm; mean follow-up 3.1 years) and associated with baseline mineral metabolite levels using linear regression analyses. Results: In unadjusted analyses, increasing log 1,25(OH)2D and decreasing log iPTH and FGF-23 levels were associated with worse cognitive status (p < 0.05). In fully adjusted multivariate analyses, the associations were no longer significant. Log 25(OH)D levels were not associated with cognitive function in unadjusted or adjusted analyses. Results were similar when analyzed by tertile or separately within CKD and ESRD groups. Conclusions: These results suggest that mineral metabolism dysregulation does not mediate the impairment in cognitive function common in advanced CKD.

Relation Between Fetuin-A Levels and Fibroblast Growth Factor 23 With the Severity of Coronary Artery Disease Measured by SYNTAX Scores

Diagnosis of coronary artery disease requires invasive procedures that are typically not implemented until clinical warning signs are apparent. The goal of this study was todetermine the relation between the severity of coronary artery disease, as measured by the SYNTAX scoring system, with serum levels of fetuin-A and fibroblast growth factor 23 (FGF23) in the general population. We enrolled 165 patients who had stable angina and positive results on treadmill testing or abnormal results on thallium myocardial perfusion scanning showing perfusion defects or who had acute coronary syndromes. Patients were hospitalized for evaluation with angiography, with or without simultaneous percutaneous coronary intervention. SYNTAX Scores were calculated on the basis of the results of coronary angiography using a computer-based questionnaire of sequential and interactive self-guided questions. Univariate analysis was used to assess the significance of fetuin-A and FGF23, as well as gender, age, body mass index, waist circumference, diabetes, hypertension, creatinine, total cholesterol, cholesterol, triglycerides, and high-sensitivity C-reactive protein in relation to cardiovascular disease severity. Multivariate analysis with stepwise regression was used to assess the utility of fetuin-A and FGF23 as predictors of SYNTAX Score. Multivariate analysis showed log fetuin-A to be a significant predictor of SYNTAX Score (p <0.0001) after controlling for the significant factors gender, cholesterol levels, and log high-sensitivity C-reactive protein. Log FGF23 values were also shown by multivariate regression to significantly predict SYNTAX Score (p= 0.0137) after controlling for gender, creatinine, cholesterol, and log high-sensitivity C-reactive protein. In conclusion, fetuin-A and FGF23 can be considered in combination with noninvasive testresults as patient selection criteria for performing angiography.

Fibroblast growth factor 23 as a risk factor of left ventricular hypertrophy and vascular calcification in predialysis chronic kidney disease patients

Objective The objective of this study was to evaluate the possible role of fibroblast growth factor 23 (FGF23) in the occurrence of left ventricular hypertrophy and vascular calcification in predialysis chronic kidney disease (CKD) patients. Background FGF23 is a suggested risk factor for poor outcome of CKD. This raises the possibility that FGF23 is a hormone that controls calcium–phosphorus metabolism and is a real risk factor for cardiovascular mortality and morbidity in predialysis CKD patients. Materials and methods Thirty predialysis CKD patients with estimated glomerular filtration rate (90≥eGFR>15 ml/min/1.73 m 2 ) by the modification of diet in renal diseases formula were included in this study. Patients were recruited from the Internal Medicine Department, Menoufia University (Egypt). Our controls were 10 individuals with preserved kidney function of more than 90 ml/min/1.73 m 2 with normal BUN and creatinine matched by age and sex. Routine and specific investigations (serum FGF23 measurement using ELISA immunoassay, serum intact parathyroid hormone, conventional echocardiography, and lateral abdominal aortic radiograph for calcification) were performed. Results The mean log FGF23 level in CKD patients was 2.3±0.6 Ru/ml and was significantly higher than that of control participants, 1.7±0.1 Ru/ml ( P P P >0.05). Left ventricular mass index was correlated positively with log FGF23 ( r =0.44, P r =−0.4, P r =0.55, P r =0.36, P >0.05). Conclusion FGF23 could be an early risk factor for the occurrence of left ventricular hypertrophy even before an increase in serum phosphorus in predialysis CKD patients.

Associations of epicardial fat with coronary calcification, insulin resistance, inflammation, and fibroblast growth factor-23 in stage 3-5 chronic kidney disease.

BackgroundEpicardial fat, quantified in a single multi-slice computed tomography (MSCT) slice, is a reliable estimate of total epicardial fat volume (EFV). We sought to determine risk factors for EFV detected in a single-slice MSCT measurement (ssEFV) in pre-dialysis chronic kidney disease (CKD) patients. Our primary objective was to determine the association between ssEFV and coronary artery calcification (CAC).Methods94 pre-dialysis stage 3–5 CKD patients underwent MSCT to measure ssEFV and CAC. ssEFV was quantified at the level of the left main coronary artery. Measures of inflammation, traditional and kidney-related cardiovascular disease risk factors were collected.ResultsMean age: 63.7 ± 14 years, 56% male, 39% had diabetes, and mean eGFR: 25.1 ± 11.9 mL/min/1.73 m2. Mean ssEFV was 5.03 ± 2.4 cm3. By univariate analysis, body mass index (BMI) (r = 0.53; P = <0.0001), abdominal obesity (r = 0.51; P < 0.0001), high density lipoprotein (HDL) cholesterol (r = − 0.39; P = <0.0001), insulin resistance (log homeostasis model assessment of insulin resistance (log HOMA-IR)) (r = 0.38, P = 0.001), log interleukin-6 (IL-6) (r = 0.34; P = 0.001), and log urinary albumin to creatinine ratio (UACR) (r = 0.30, P = 0.004) demonstrated the strongest associations with ssEFV. Log coronary artery calcification (log CAC score) (r = 0.28, P = 0.006), and log fibroblast growth factor-23 (log FGF-23) (r = 0.23, P = 0.03) were also correlated with ssEFV. By linear regression, log CAC score (beta =0.40; 95% confidence interval (CI), 0.01-0.80; P = 0.045), increasing levels of IL-6 (beta = 0.99; 95% CI, 0.38 – 1.61; P = 0.002), abdominal obesity (beta = 1.86; 95% CI, 0.94 - 2.8; P < 0.0001), lower HDL cholesterol (beta = −2.30; 95% CI, – 3.68 to −0.83; P = 0.002) and albuminuria (log UACR, beta = 0.81; 95% CI, 0.2 to 1.4; P = 0.01) were risk factors for increased ssEFV.ConclusionsIn stage 3–5 CKD, coronary calcification and IL-6 and were predictors of ssEFV. Further studies are needed to clarify the mechanism by which epicardial fat may contribute to the pathogenesis of coronary disease, particularly in the CKD population.

Fibroblast growth factor 23 is associated with carotid artery calcification in chronic kidney disease patients not undergoing dialysis: a cross-sectional study

BackgroundFibroblast growth factor 23 (FGF23) is an important hormone in the regulation of phosphate metabolism. It is unclear whether FGF23 is associated with carotid artery calcification (CAAC) in predialysis patients. The present study aimed to clarify the relationship between FGF23 and CAAC in patients with chronic kidney disease (CKD) who were not on dialysis.MethodsOne-hundred ninety-five predialysis CKD patients were enrolled in this cross-sectional study. CAAC was assessed using multidetector computed tomography, and the prevalence of CAAC was examined. Intact FGF23 was measured in each patient. The risk factors for CAAC were evaluated using a logistic regression model.ResultsWe found CAAC in 66% of the patients. The prevalence of CAAC significantly increased across CKD stages: it was 37% in CKD stages 1–2, 58% in stage 3; 75% in stage 4, and 77% in stage 5 (p < 0.01). In multivariate analysis, smoking, diabetes mellitus and log FGF23 were each identified as risk factors for CAAC. The study population was divided in quartiles of FGF23 levels. Compared with the lowest FGF23 quartile, each subsequent quartile had a progressively higher odds ratio (OR) for CAAC, adjusted for confounders (ORs [95% confidence interval] of 2.34 [0.78 to 7.31], 5.28 [1.56 to 19.5], and 13.6 [2.92 to 74.6] for the second, third, and fourth quartiles, respectively.ConclusionsThe prevalence of CAAC is increased with the decline in the kidney function. FGF23 is independently related to CAAC in patients with CKD who are not on dialysis.

Investigating FGF-23 concentrations and its relationship with declining renal function in paediatric patients with pre-dialysis CKD Stages 3-5

The aims of our study were to investigate (i) the prevalence of elevated fibroblast growth factor-23 (FGF-23), (ii) the relationship between FGF-23 concentrations and level of renal dysfunction and (iii) the main determinants of elevation of FGF-23 concentration in children with pre-dialysis chronic kidney disease (CKD) Stages 3-5. In this single-centre prospective observational study, 71 children with pre-dialysis CKD Stages 3-5, aged 11.9 ± 3.1 years, had FGF-23 levels measured. Anthropometry and routine laboratory investigations were measured. Fourteen (19.7%) patients had normal FGF-23 concentrations defined as < 50 ng/L. FGF-23 [median (interquartile range)] concentrations were 78.7 (55.6-137.6) ng/L and following log transformation normalized data with log FGF-23 [mean (SD)] values of 1.96 ± 0.4 ng/L. Log FGF-23 concentrations had a negative reciprocal relationship with estimated glomerular filtration rate (eGFR) (P < 0.0001) and 1,25 vitamin D3 levels (P = 0.01) and a positive relationship with phosphate (P = 0.03) and percent fractional excretion of phosphate (P = 0.01) but not with log-intact parathyroid hormone (PTH) (P = 0.22). Multiple linear regression demonstrated a strong relationship between log FGF-23 and eGFR only. Elevated FGF-23 concentrations were observed in the majority of a carefully managed cohort of children with non-dialysis CKD with a dominant effect on FGF-23 concentrations with glomerular filtration rate (GFR). These data allow the potential confounding effects of PTH and phosphate elevation with declining GFR to be removed, leaving a clearer picture of the FGF-23-GFR relationship.

FGF23, Albuminuria, and Disease Progression in Patients with Chronic IgA Nephropathy

Fibroblast growth factor-23 (FGF23) regulates mineral metabolism. Circulatory FGF23 levels are increased and predict outcomes in CKD. However, the relation of FGF23 to albuminuria and disease progression in patients with CKD and one underlying diagnosis is unknown. Prospective, observational study in 180 patients with IgA nephropathy (IgAN), CKD stage 1-4, and median 55-month follow-up (range, 12-177 months). Primary outcomes were (1) time-averaged albuminuria, (2A) progression to CKD stage 5 or ≥50% loss of estimated GFR, (2B) progression to CKD stage 5 or ≥25% loss of estimated GFR within 10 years, and (3) annual loss of estimated GFR. FGF23 was independently associated with baseline and time-averaged albuminuria (change in 1 g/24 hour albuminuria per increase in log FGF23: β = 0.26; P=0.02). Log FGF23 predicted CKD progression in crude models and after adjustment for mineral metabolites (endpoints 2A and 2B). It remained significant after adjustments for age, sex, serum albumin, calcium, phosphate, parathyroid hormone, 25-hydroxyvitamin D, baseline albuminuria, baseline estimated GFR, mean arterial BP, body mass index, and angiotensin-converting enzyme inhibitors/angiotensin-receptor blocker use in endpoint 2B (hazard ratio, 2.53; P=0.02) but not endpoint 2A (hazard ratio, 2.01; P=0.43). Log FGF23 predicted annual loss of estimated GFR in the same model (change in ml/min per 1.73 m(2) per increase in log FGF23, 1.50; P=0.008). In patients with CKD and IgAN, FGF23 was associated with albuminuria and CKD progression, a finding that suggests its role as a potential biomarker in IgAN.

Combined Use of Vitamin D Status and FGF23 for Risk Stratification of Renal Outcome

Hyperphosphatemia, vitamin D deficiency, hyperparathyroidism, and high serum fibroblast growth factor 23 (FGF23) levels, when studied separately, were found to predict the progression of CKD. However, studies with simultaneous measurement of mineral bone disorder (MBD)-related factors were scarce. This study aimed to identify factors predicting renal outcome independent of other factors. This was a prospective cohort study of 738 Japanese predialysis outpatients in the nephrology departments of two hospitals. The outcome was defined as a doubling of serum creatinine or initiation of dialysis. Mean estimated GFR (eGFR) was 35 ml/min per 1.73 m(2). At enrollment, the increase in intact FGF23 with decreasing eGFR was the earliest among changes in MBD-related factors, followed by 1,25-dihydroxyvitamin D decrease, parathyroid hormone increase, and phosphate increase. During a median duration of 4.4 years, 213 patients reached the endpoint. In a multivariable Cox model, high FGF23 and low 25-hydroxyvitamin D (25D) levels were the only MBD-related factors associated with a higher risk of renal endpoint (adjusted hazard ratio [95% confidence interval] per unit change of log FGF23 and 10 ng/ml of 25D: 1.83 [1.28-2.61] and 0.61 [0.41-0.90], respectively). There was no significant interaction between 25D and FGF23 (P=0.11). Active vitamin D therapy, serum phosphate, 1,25-dihydroxyvitamin D, and parathyroid hormone levels were not related to the renal endpoint. Treating death as a competing risk or multiple imputation for missing values yielded similar results. Combined use of two markers is useful for the risk stratification of renal outcome.

Relationship of serum fibroblast growth factor 23 with cardiovascular disease in older community-dwelling women

Although fibroblast growth factor 23 (FGF23) has been implicated in the pathogenesis of cardiovascular disease, the relationship between FGF23 and cardiovascular disease has not been well characterized in the general population. The aim of this study was to determine whether serum FGF23 is independently associated with cardiovascular disease in older community-dwelling women. A cross-sectional design was used to examine the relationship between serum FGF23 and cardiovascular disease. The subjects consisted of a population-based sample of 659 women, aged 70-79 years, who participated in the Women's Health and Aging Studies in Baltimore, Maryland. Prevalent cardiovascular disease (coronary heart disease, stroke, congestive heart failure, and peripheral artery disease) was assessed through diagnostic algorithms and physician adjudication. Of the 659 women, 185 (28.1%) had cardiovascular disease. Median (25th, 75th percentile) intact serum FGF23 was 34.6 (25.2, 46.2) pg/ml. The prevalence of cardiovascular disease in the lowest, middle, and highest tertile of serum FGF23 was 22.6, 24.9, and 36.7% respectively (P=0.002). Serum log FGF23 was associated with cardiovascular disease (odds ratio per 1 s.d. increase=1.23, 95% confidence interval 1.17, 1.30; P<0.0001) in a multivariable logistic regression model, adjusting for age, race, smoking, education, body mass index, cognition, diabetes, hypertension, physical activity, total cholesterol, high-density lipoprotein cholesterol, and renal function. Elevated serum FGF23 concentrations are independently associated with prevalent cardiovascular disease in older community-dwelling women. Further studies are needed to elucidate the potential biological mechanisms by which FGF23 may be involved in the pathogenesis of cardiovascular disease.