Phosphate Transporter Regulator That Prevents Abnormal Hyperphosphatemia.

Renal type II sodium-dependent inorganic phosphate (Pi) transporters NaPi2a and NaPi2c cooperate with other organs to strictly regulate the plasma Pi concentration. A high Pi load induces the phosphaturic hormones parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23), enhances urinary Pi excretion and prevents the onset of hyperphosphatemia. How FGF23 is induced from the bones by a high Pi load and the setpoint of the plasma Pi concentration, however, are unclear. Here, we investigated the role of transporter-associated protein (TRAP), found in gene co-expression networks in NaPi2a and NaPi2c function. TRAP is localized in the renal proximal tubules and interacts with NaPi2a. In TRAP-knockout (KO) mice, the serum FGF23 concentration was markedly increased but increased Pi excretion and hypophosphatemia were not observed. In addition, TRAP-KO mice exhibit reduced NaPi2a responsiveness to FGF23 and PTH administration. Furthermore, a dietary Pi load causes marked hyperphosphatemia and abnormal NaPi2a regulation in TRAP-KO mice. Thus, TRAP is thought to be associated with FGF23 induction in bones and the regulation of NaPi2a to prevent an increase in the plasma Pi concentration due to a high Pi load and kidney injury.

SUN-359 Antenatal Oral Iron Supplementation, FGF23 and Bone Metabolism in Kenyan Women and Their Offspring: A Randomised Controlled Trial

Objectives: FGF23 decreases reabsorption and increases phosphate excretion in the kidney and regulates vitamin D metabolism. Maternal iron deficiency may be implicated in the pathogenesis of hypophosphataemia-driven rickets in offspring through perturbed FGF23 expression. We aimed to determine the effect of antenatal oral iron supplementation on maternal and neonatal markers of bone mineral regulation. Methods: 470 rural Kenyan women with singleton pregnancies and haemoglobin concentrations ≥90g/L were randomly allocated to daily, supervised supplementation iron (60mg as ferrous fumarate) or placebo from 13–23 weeks gestational age until 1 month postpartum. We analysed maternal and neonatal plasma samples collected at birth, with primary outcomes being concentrations of FGF23 in its intact form (I-FGF23, the phosphate- and vitamin D-regulating hormone) and its C-terminal fragment (C-FGF23). Results: In mothers and neonates, antenatal iron supplementation reduced C-FGF23 concentration by 62.6% (95%CI: -70.3% to -53.0%) and 15.2% (-28.4% to 0.3%), respectively; increased neonatal I-FGF23 concentration by 21.6% (1.2% to 46.1%); increased maternal hepcidin concentration by 136%, (86% to 200%); and decreased maternal 25-hydroxyvitamin D concentrations by 6.1nmol/L (1.2 to 11.0nmol/L). We found no effect on markers of bone turnover in either mothers or neonates. The magnitude of the effect of antenatal iron supplementation on concentrations of C-FGF23, I-FGF23 and phosphate, and on estimated glomerular filtration rate (a measure of kidney glomerular function) depended on maternal iron status at baseline Conclusions: Antenatal iron supplementation may provide health benefits to pregnant women and their offspring beyond increasing iron status. Whether iron supplementation reduces present and future infant risk of rickets remains unclear.

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

Background Previous 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. Methods FGF23 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. Results No 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)]. Conclusion Whereas 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.

The role of vitamin D replacement therapy in serum FGF23 concentration in children with myelomeningocele compared with healthy children – a preliminary study

Background Fibroblast growth factor 23 (FGF23) is a recently discovered bone-derived regulator of vitamin D metabolism and phosphate homeostasis. It inhibits phosphate reabsorption and calcitriol production by the kidney. Myelomeningocele (MMC) remains the most severe form of neural tube defects involving serious locomotor disability, osteoporosis and pathologic fractures. We aimed to investigate the influence of vitamin D replacement therapy on serum FGF23 concentration in children with MMC and compare the results with healthy participants. Methods This prospective analysis was conducted on 16 children with MMC and 20 healthy children. Serum FGF23 levels were measured; for the studied group, before and after vitamin D replacement therapy with cholecalciferol (vitamin D3). The children’s medical charts were analyzed to determine age, sex, anthropometric measurements, calcium and phosphate, cholecalciferol and renal function parameters. Results There were significant differences in vitamin D and FGF23 serum concentrations between the studied groups. The median vitamin D levels in the MMC group increased during replacement therapy (7 vs. 18.5 ng/mL, p = 0.29) in comparison to the median of 25.5 ng/mL in the control group. In MMC children we found a significant decrease in median serum FGF23 after vitamin D replacement therapy (from 42.1 to 0 RU/mL, p < 0.001). FGF23 correlated positively with albumin, serum and urine phosphate levels and negatively with alkaline phosphatase. Conclusions 1. Serum concentration of FGF-23 is increased in MMC children in comparison to a healthy control group. 2. Vitamin D replacement therapy decreases FGF23 concentrations in MMC children, although further studies are still warranted to gain detailed insight on the FGF23 in the MMC population. 3. Children with MMC present vitamin D deficiency. Nutrition supplemented with low doses of cholecalciferol (vitamin D3) (intakes reaching recommended daily allowances) was insufficient to correct 25(OH)-D level in that population of patients.

Genetic Variants Associated with Circulating Fibroblast Growth Factor 23

BackgroundFibroblast growth factor 23 (FGF23), a bone-derived hormone that regulates phosphorus and vitamin D metabolism, contributes to the pathogenesis of mineral and bone disorders in CKD and is an emerging cardiovascular risk factor. Central elements of FGF23 regulation remain incompletely understood; genetic variation may help explain interindividual differences.MethodsWe performed a meta-analysis of genome-wide association studies of circulating FGF23 concentrations among 16,624 participants of European ancestry from seven cohort studies, excluding participants with eGFR<30 ml/min per 1.73 m2 to focus on FGF23 under normal conditions. We evaluated the association of single-nucleotide polymorphisms (SNPs) with natural log–transformed FGF23 concentration, adjusted for age, sex, study site, and principal components of ancestry. A second model additionally adjusted for BMI and eGFR.ResultsWe discovered 154 SNPs from five independent regions associated with FGF23 concentration. The SNP with the strongest association, rs17216707 (P=3.0×10−24), lies upstream of CYP24A1, which encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D. Each additional copy of the T allele at this locus is associated with 5% higher FGF23 concentration. Another locus strongly associated with variations in FGF23 concentration is rs11741640, within RGS14 and upstream of SLC34A1 (a gene involved in renal phosphate transport). Additional adjustment for BMI and eGFR did not materially alter the magnitude of these associations. Another top locus (within ABO, the ABO blood group transferase gene) was no longer statistically significant at the genome-wide level.ConclusionsCommon genetic variants located near genes involved in vitamin D metabolism and renal phosphate transport are associated with differences in circulating FGF23 concentrations.

Abstract 9902: Serum FGF23 Concentration is Associated With Cardiac Hypertrophy and Decreased Systolic Function Among Both CKD and Non-CKD Cardiac Patients

Introduction: Purpose: Serum concentrations of fibroblast growth factor-23 (FGF23) are increased in response to elevated serum phosphate levels among patients with renal dysfunction. Besides regulating circulating phosphate levels, FGF23 may induce cardiac hypertrophy; thus, enhanced FGF23 excretion may underlie the heart failure observed among patients with chronic kidney disease (CKD). Here we examined whether FGF23 concentrations are associated with cardiac hypertrophy among cardiac patients regardless of the presence or absence of CKD. Methods: The present study enrolled 480 cardiac patients admitted to our cardiology department between January 2012 and December 2012. Serum FGF23 level was measured by an ELISA method. Left ventricular mass index (LVMI) was used as a marker of cardiac hypertrophy. Results: Of the 480 patients, 132 (27.5%) had an estimated glomerular filtration rate (eGFR) of <60 mL/min/m2 (no-CKD group) and the remaining 348 (72.5%) had an eGFR of 60 or greater (CKD group). FGF23 was correlated with eGFR in the CKD group, but not in the no-CKD group. Stepwise multivariate linear regression analysis was performed using LVMI as a dependent variable, and sex, age, eGFR, serum calcium and phosphate, and log(FGF23) as independent variables. Log(FGF23) was selected as an independent variable that had a significant association with LVMI with a standardized correlation coefficient of 0.26 in the no-CKD group (P<0.01) and 0.25 in the CKD group (P<0.01). When left ventricular ejection fraction was used as an independent variable in this model, log(FGF23) was selected as significant predictor with a standardized correlation coefficient of -0.20 in the no-CKD group (P<0.05) and -0.18 in the CKD group (P<0.01). Conclusions: Among cardiac patients, serum FGF23 concentration was associated positively with left ventricular mass and negatively with left ventricular ejection fraction not only in patients with CKD, but also in those without CKD.

Predictors of intact and C-terminal fibroblast growth factor 23 in Gambian children

Elevated C-terminal fibroblast growth factor 23 (C-FGF23) concentrations have been reported in Gambian children with and without putative Ca-deficiency rickets. The aims of this study were to investigate whether i) elevated C-FGF23 concentrations in Gambian children persist long term; ii) they are associated with higher intact FGF23 concentrations (I-FGF23), poor iron status and shorter 25-hydroxyvitamin D half-life (25OHD-t1/2); and iii) the persistence and predictors of elevated FGF23 concentrations differ between children with and without a history of rickets. Children (8–16 years, n=64) with a history of rickets and a C-FGF23 concentration >125 RU/ml (bone deformity (BD), n=20) and local community children with a previously measured elevated C-FGF23 concentration (LC+, n=20) or a previously measured C-FGF23 concentration within the normal range (LC−, n=24) participated. BD children had no remaining signs of bone deformities. C-FGF23 concentration had normalised in BD children, but remained elevated in LC+ children. All the children had I-FGF23 concentration within the normal range, but I-FGF23 concentration was higher and iron status poorer in LC+ children. 1,25-dihydroxyvitamin D was the strongest negative predictor of I-FGF23 concentration (R2=18%; P=0.0006) and soluble transferrin receptor was the strongest positive predictor of C-FGF23 concentration (R2=33%; P≤0.0001). C-FGF23 and I-FGF23 concentrations were poorly correlated with each other (R2=5.3%; P=0.07). 25OHD-t1/2 was shorter in BD children than in LC− children (mean (s.d.): 24.5 (6.1) and 31.5 (11.5) days respectively; P=0.05). This study demonstrated that elevated C-FGF23 concentrations normalised over time in Gambian children with a history of rickets but not in local children, suggesting a different aetiology; that children with resolved rickets had a shorter 25OHD-t1/2, suggesting a long-standing increased expenditure of 25OHD, and that iron deficiency is a predictor of elevated C-FGF23 concentrations in both groups of Gambian children.