Browsing by Subject "Fibroblast growth factor 23 (FGF23)"

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    FGF23 and Cardiovascular Structure and Function in Advanced Chronic Kidney Disease
    (Wolters Kluwer, 2022-07-05) Halim, Arvin; Burney, Heather N.; Li, Xiaochun; Li, Yang; Tomkins, Claudia; Siedlecki, Andrew M.; Lu, Tzong-shi; Kalim, Sahir; Thadhani, Ravi; Moe, Sharon; Ting, Stephen M.S.; Zehnder, Daniel; Hiemstra, Thomas F.; Lim, Kenneth; Medicine, School of Medicine
    Background: 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. Methods: 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. Results: 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. Conclusions: 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.
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    Novel PHEX gene locus-specific database: Comprehensive characterization of vast number of variants associated with X-linked hypophosphatemia (XLH)
    (Wiley, 2022) Sarafrazi, Soodabeh; Daugherty, Sean C.; Miller, Nicole; Boada, Patrick; Carpenter, Thomas O.; Chunn, Lauren; Dill, Kariena; Econs, Michael J.; Eisenbeis, Scott; Imel, Erik A.; Johnson, Britt; Kiel, Mark J.; Krolczyk, Stan; Ramesan, Prameela; Truty, Rebecca; Sabbagh, Yves; Medicine, School of Medicine
    X-linked hypophosphatemia (XLH), the most common form of hereditary hypophosphatemia, is caused by disrupting variants in the PHEX gene, located on the X chromosome. XLH is inherited in an X-linked pattern with complete penetrance observed for both males and females. Patients experience lifelong symptoms resulting from chronic hypophosphatemia, including impaired bone mineralization, skeletal deformities, growth retardation, and diminished quality of life. This chronic condition requires life-long management with disease-specific therapies, which can improve patient outcomes especially when initiated early in life. To centralize and disseminate PHEX variant information, we have established a new PHEX gene locus-specific database, PHEX LSDB. As of April 30, 2021, 870 unique PHEX variants, compiled from an older database of PHEX variants, a comprehensive literature search, a sponsored genetic testing program, and XLH clinical trials, are represented in the PHEX LSDB. This resource is publicly available on an interactive, searchable website (https://www.rarediseasegenes.com/), which includes a table of variants and associated data, graphical/tabular outputs of genotype-phenotype analyses, and an online submission form for reporting new PHEX variants. The database will be updated regularly with new variants submitted on the website, identified in the published literature, or shared from genetic testing programs.
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    OR13-3 Effects of Iron Isomaltoside versus Ferric Carboxymaltose on Hormonal Control of Phosphate Homeostasis: The PHOSPHARE-IDA04/05 Randomized Controlled Trials
    (Oxford University Press, 2019-04-15) Wolf, Myles; Rubin, Janet; Achebe, Maureen; Econs, Michael; Peacock, Munro; Imel, Erik; Thomsen, Lars; Carpenter, Thomas; Weber, Thomas; Zoller, Heinz; Medicine, School of Medicine
    Iron isomaltoside (IIM) and ferric carboxymaltose (FCM) are newer intravenous iron preparations that can be administered in high-doses to rapidly correct iron deficiency anemia (IDA). FCM can cause hypophosphatemia due to fibroblast growth factor 23 (FGF23) mediated renal phosphate wasting, which has been associated with osteomalacia, but the comparative effects of IIM are unknown. In two separate, identically designed, open label randomized controlled trials, we 1:1 randomized 245 adults with IDA to receive IIM (single infusion of 1000 mg) or FCM (FDA-approved dosing schedule: 2 infusions of 750 mg administered 1 week apart). We compared the incidence, severity and duration of hypophosphatemia, and effects on renal phosphate excretion, FGF23, PTH, vitamin D, and biomarkers of bone turnover measured in blood and urine samples collected at study visits at baseline (day 0) and on days 1, 7, 8, 14, 21, and 35. In pooled analyses of both trials, the incidence of hypophosphatemia <2 mg/dL was higher in the FCM versus IIM group (74.4% versus 8.0%, p<0.0001). Hypophosphatemia persisted at day 35 in 43.0% of FCM-treated patients compared to 0.9% of IIM-treated patients (p<0.0001). Severe hypophosphatemia ≤1 mg/dL occurred in 11.3% of FCM-treated patients compared to 0.0% of IIM-treated patients (p<0.0001). FCM significantly increased intact FGF23 compared to IIM (p<0.0001): on day 1, which was one day after the first infusion, FCM increased mean intact FGF23 from 49.9 pg/mL at baseline to 149.5 pg/mL; by day 8, which was one day after the second infusion, FCM increased intact FGF23 to 327.9 pg/mL; the corresponding figures for IIM were 59.9 pg/mL at baseline, 58.3 pg/mL by day 1 and 66.9 pg/mL by day 8. Compared to treatment with IIM, FCM significantly: increased urinary fractional phosphate excretion; decreased serum 1,25-(OH)2 vitamin D; decreased ionized calcium; and increased PTH, which persisted through day 35. These changes after FCM treatment were accompanied by significant increases in both total and bone specific alkaline phosphatase that also persisted through day 35. Correction of IDA was comparable between the two treatments. Serious or severe hypersensitivity reactions occurred in 0.8% in the IIM group and 1.7% in the FCM group. Compared to IIM, FCM induced high rates of FGF23-mediated hypophosphatemia, which was frequently severe and often persisted for >35 days. FCM but not IIM also induced changes in vitamin D and calcium homeostasis that triggered secondary hyperparathyroidism, which likely contributed to persistence of hypophosphatemia. Consistent with case reports of pathological fractures following FCM use, FCM also induced significant elevations of biomarkers of bone turnover that are associated with osteomalacia.