Browsing by Subject "phosphate"

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    Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial
    (Elsevier, 2019-06-15) Imel, Erik A.; Glorieux, Francis H.; Whyte, Michael P.; Munns, Craig F.; Ward, Leanne M.; Nilsson, Ola; Simmons, Jill H.; Padidela, Raja; Namba, Noriyuki; Cheong, Hae Il; Pitukcheewanont, Pisit; Sochett, Etienne; Högler, Wolfgang; Muroya, Koji; Tanaka, Hiroyuki; Gottesman, Gary S.; Biggin, Andrew; Perwad, Farzana; Mao, Meng; Chen, Chao-Yin; Skrinar, Alison; Martin, Javier San; Portale, Anthony A.; Medicine, School of Medicine
    Background X-linked hypophosphatemia in children is characterized by elevated serum FGF23, hypophosphatemia, rickets, lower extremity bowing, and growth impairment. We compared the efficacy and safety of continuing conventional therapy, consisting of oral phosphate and active vitamin D, versus switching to burosumab, a fully human monoclonal antibody against FGF23, in pediatric X-linked hypophosphatemia. Methods In this randomised, active-controlled, open-label, phase 3 trial at 16 clinical sites, we enrolled children with X-linked hypophosphataemia aged 1–12 years. Key eligibility criteria were a total Thacher rickets severity score of at least 2·0, fasting serum phosphorus lower than 0·97 mmol/L (3·0 mg/dL), confirmed PHEX (phosphate-regulating endopeptidase homolog, X-linked) mutation or variant of unknown significance in the patient or a family member with appropriate X-linked dominant inheritance, and receipt of conventional therapy for at least 6 consecutive months for children younger than 3 years or at least 12 consecutive months for children older than 3 years. Eligible patients were randomly assigned (1:1) to receive either subcutaneous burosumab starting at 0·8 mg/kg every 2 weeks (burosumab group) or conventional therapy prescribed by investigators (conventional therapy group). Both interventions lasted 64 weeks. The primary endpoint was change in rickets severity at week 40, assessed by the Radiographic Global Impression of Change global score. All patients who received at least one dose of treatment were included in the primary and safety analyses. The trial is registered with ClinicalTrials.gov, number NCT02915705. Findings Recruitment took place between Aug 3, 2016, and May 8, 2017. Of 122 patients assessed, 61 were enrolled. Of these, 32 (18 girls, 14 boys) were randomly assigned to continue receiving conventional therapy and 29 (16 girls, 13 boys) to receive burosumab. For the primary endpoint at week 40, patients in the burosumab group had significantly greater improvement in Radiographic Global Impression of Change global score than did patients in the conventional therapy group (least squares mean +1·9 [SE 0·1] with burosumab vs +0·8 [0·1] with conventional therapy; difference 1·1, 95% CI 0·8–1·5; p<0·0001). Treatment-emergent adverse events considered possibly, probably, or definitely related to treatment by the investigator occurred more frequently with burosumab (17 [59%] of 29 patients in the burosumab group vs seven [22%] of 32 patients in the conventional therapy group). Three serious adverse events occurred in each group, all considered unrelated to treatment and resolved. Interpretation Significantly greater clinical improvements were shown in rickets severity, growth, and biochemistries among children with X-linked hypophosphataemia treated with burosumab compared with those continuing conventional therapy. Funding Ultragenyx Pharmaceutical Inc. and Kyowa Kirin International
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    Erythropoietin and a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHDi) lowers FGF23 in a model of chronic kidney disease (CKD)
    (Wiley, 2020-03-31) Noonan, Megan L.; Clinkenbeard, Erica L.; Ni, Pu; Swallow, Elizabeth A.; Tippen, Samantha P.; Agoro, Rafiou; Allen, Matthew R.; White, Kenneth E.; Medical and Molecular Genetics, School of Medicine
    Iron‐deficiency anemia is a potent stimulator of the phosphaturic hormone Fibroblast growth factor‐23 (FGF23). Anemia, elevated FGF23, and elevated serum phosphate are significant mortality risk factors for patients with chronic kidney disease (CKD). However, the contribution of anemia to overall circulating FGF23 levels in CKD is not understood. Our goal was to investigate the normalization of iron handling in a CKD model using the erythropoiesis stimulating agents (ESAs) Erythropoietin (EPO) and the hypoxia‐inducible factor prolyl hydroxylase inhibitor (HIF‐PHDi) FG‐4592, on the production of, and outcomes associated with, changes in bioactive, intact FGF23 (“iFGF23”). Our hypothesis was that rescuing the prevailing anemia in a model of CKD would reduce circulating FGF23. Wild‐type mice were fed an adenine‐containing diet to induce CKD, then injected with EPO or FG‐4592. The mice with CKD were anemic, and EPO improved red blood cell indices, whereas FG‐4592 increased serum EPO and bone marrow erythroferrone (Erfe), and decreased liver ferritin, bone morphogenic protein‐6 (Bmp‐6), and hepcidin mRNAs. In the mice with CKD, iFGF23 was markedly elevated in control mice but was attenuated by >70% after delivery of either ESA, with no changes in serum phosphate. ESA treatment also reduced renal fibrosis markers, as well as increased Cyp27b1 and reduced Cyp24a1 mRNA expression. Thus, improvement of iron utilization in a CKD model using EPO and a HIF‐PHDi significantly reduced iFGF23, demonstrating that anemia is a primary driver of FGF23, and that management of iron utilization in patients with CKD may translate to modifiable outcomes in mineral metabolism.
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    Hypophosphatemic rickets: Revealing Novel Control Points for Phosphate Homeostasis
    (Springer US, 2014-09) White, Kenneth E.; Hum, Julia M.; Econs, Michael J.; Department of Medical & Molecular Genetics, IU School of Medicine
    Rapid and somewhat surprising advances have recently been made towards understanding the molecular mechanisms causing heritable disorders of hypophosphatemia. The results of clinical, genetic, and translational studies have interwoven novel concepts underlying the endocrine control of phosphate metabolism, with far-reaching implications for treatment of both rare, Mendelian diseases as well as common disorders of blood phosphate excess such as chronic kidney disease (CKD). In particular, diseases caused by changes in the expression and proteolytic control of the phosphaturic hormone Fibroblast growth factor-23 (FGF23) have come to the forefront in terms of directing new models explaining mineral metabolism. These hypophosphatemic disorders, as well as others resulting from independent defects in phosphate transport or metabolism, will be reviewed herein, and implications for emerging therapeutic strategies based upon these new findings will be discussed.
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    Iron and fibroblast growth factor 23 in X-linked hypophosphatemia
    (Elsevier B.V., 2014-03) Imel, Erik A.; Gray, Amie; Padgett, Leah; Econs, Michael J.; Department of Medicine, IU School of Medicine
    Background Excess fibroblast growth factor 23 (FGF23) causes hypophosphatemia in autosomal dominant hypophosphatemic rickets (ADHR) and X-linked hypophosphatemia (XLH). Iron status influences C-terminal FGF23 (incorporating fragments plus intact FGF23) in ADHR and healthy subjects, and intact FGF23 in ADHR. We hypothesized that in XLH serum iron would inversely correlate to C-terminal FGF23, but not to intact FGF23, mirroring the relationships in normal controls. Methods Subjects included 25 untreated outpatients with XLH at a tertiary medical center and 158 healthy adult controls. Serum iron and plasma intact FGF23 and C-terminal FGF23 were measured in stored samples. Results Intact FGF23 was greater than the control mean in 100% of XLH patients, and >2SD above the control mean in 88%, compared to 71% and 21% respectively for C-terminal FGF23. In XLH, iron correlated negatively to log-C-terminal FGF23 (r= −0.523, p<0.01), with a steeper slope than in controls (p<0.001). Iron was not related to log-intact FGF23 in either group. The log-ratio of intact FGF23 to C-terminal FGF23 was higher in XLH (0.00 ± 0.44) than controls (−0.28 ± 0.21, p<0.01), and correlated positively to serum iron (controls r= 0.276, p<0.001; XLH r= 0.428, p<0.05), with a steeper slope in XLH (p<0.01). Conclusion Like controls, serum iron in XLH is inversely related to C-terminal FGF23 but not intact FGF23. XLH patients are more likely to have elevated intact FGF23 than C-terminal FGF23. The relationships of iron to FGF23 in XLH suggest altered regulation of FGF23 cleaving may contribute to maintaining hypophosphatemia around an abnormal set-point.
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    Time-richness and phosphatic microsteinkern accumulation in the Cincinnatian (Katian) Ordovician, USA: An example of polycyclic phosphogenic condensation
    (Elsevier, 2019-12) Dattilo, Benjamin F.; Freeman, Rebecca L.; Zubovic, Yvonne; Brett, Carlton E.; Straw, Amanda; Frauhiger, Mason; Hartstein, Amanda; Shoemaker, Lincoln; Biology, School of Science
    Millimeter-scale phosphatic steinkern preservation is a feature of the taxonomically enigmatic Early Cambrian “small shelly faunas”, but this style of preservation is not unique to the Cambrian; it is ubiquitous, if infrequently reported, from the Phanerozoic record. The polycyclic phosphogenic condensation (PPC) model envisions both the genesis and concentration of phosphatic microsteinkerns as natural outcomes of shell bed genesis through episodic sediment starvation. This model predicts that more reworked and condensed shell bed limestones will contain more phosphatic microsteinkerns, but that even the least reworked limestones may contain some phosphatic particles. We test this model through examination of vertical thin sections densely collected through a 10-meter interval from the classic Cincinnatian (upper Katian, middle Maysvillian North American Stage) upper Fairview Formation, Miamitown Shale, and lower Grant Lake formations at four localities near Cincinnati, Ohio. For each of approximately 50 distinguishable limestone depositional units in each locality, a 2 × 2 cm square was selected for study. Each square was assigned a textural classification (mud content of intergranular space) and a breakage rank (pristine to comminuted). Phosphatic particle distribution was quantified both by visual estimation and by particle counting, with counts ranging from none detected to over 1000 per 4 cm2. Our analyses show a strong positive relationship between phosphate content and both textural maturity and fragmentation. This positive relationship is consistent with the PPC model and confirms that textural maturity can reflect the degree of condensation as well as depth-related environmental energy. This finding suggests that shell bed processes of repeated deposition and reworking make a significant contribution to the generation and accumulation of phosphatic particles. If local-scale sedimentary processes and conditions can control this accumulation, temporal changes in phosphatic sediment deposition rates may be linked to earth changes more complexly than through changing ocean chemistry on a global scale.