Browsing by Author "Wolf, Myles"

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    Coupling fibroblast growth factor 23 production and cleavage: iron deficiency, rickets, and kidney disease
    (Ovid Technologies (Wolters Kluwer) - Lippincott Williams & Wilkins, 2014-07) Wolf, Myles; White, Kenneth E.; Department of Medical & Molecular Genetics, IU School of Medicine
    PURPOSE OF REVIEW: High levels of fibroblast growth factor 23 (FGF23) cause the rare disorders of hypophosphatemic rickets and are a risk factor for cardiovascular disease and death in patients with chronic kidney disease (CKD). Despite major advances in understanding FGF23 biology, fundamental aspects of FGF23 regulation in health and in CKD remain mostly unknown. RECENT FINDINGS: Autosomal dominant hypophosphatemic rickets (ADHR) is caused by gain-of-function mutations in FGF23 that prevent its proteolytic cleavage, but affected individuals experience a waxing and waning course of phosphate wasting. This led to the discovery that iron deficiency is an environmental trigger that stimulates FGF23 expression and hypophosphatemia in ADHR. Unlike osteocytes in ADHR, normal osteocytes couple increased FGF23 production with commensurately increased FGF23 cleavage to ensure that normal phosphate homeostasis is maintained in the event of iron deficiency. Simultaneous measurement of FGF23 by intact and C-terminal assays supported these breakthroughs by providing minimally invasive insight into FGF23 production and cleavage in bone. These findings also suggest a novel mechanism of FGF23 elevation in patients with CKD, who are often iron deficient and demonstrate increased FGF23 production and decreased FGF23 cleavage, consistent with an acquired state that mimics the molecular pathophysiology of ADHR. SUMMARY: Iron deficiency stimulates FGF23 production, but normal osteocytes couple increased FGF23 production with increased cleavage to maintain normal circulating levels of biologically active hormone. These findings uncover a second level of FGF23 regulation within osteocytes, failure of which culminates in elevated levels of biologically active FGF23 in ADHR and perhaps CKD.
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    Effects of etelcalcetide on fibroblast growth factor 23 in patients with secondary hyperparathyroidism receiving hemodialysis
    (Oxford University Press, 2019-04-26) Wolf, Myles; Block, Geoffrey A.; Chertow, Glenn M.; Cooper, Kerry; Fouqueray, Bruno; Moe, Sharon M.; Sun, Yan; Tomlin, Holly; Vervloet, Marc; Oberbauer, Rainer; Medicine, School of Medicine
    Background: Etelcalcetide 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. Methods: To 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. Results: Etelcalcetide 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. Conclusion: These 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.
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    Effects of Iron Isomaltoside vs Ferric Carboxymaltose on Hypophosphatemia in Iron-Deficiency Anemia: Two Randomized Clinical Trials
    (American Medical Association, 2020-02-04) Wolf, Myles; Rubin, Janet; Achebe, Maureen; Econs, Michael J.; Peacock, Munro; Imel, Erik A.; Thomsen, Lars L.; Carpenter, Thomas O.; Weber, Thomas; Brandenburg, Vincent; Zoller, Heinz; Medicine, School of Medicine
    Importance Intravenous iron enables rapid correction of iron-deficiency anemia, but certain formulations induce fibroblast growth factor 23–mediated hypophosphatemia. Objective To compare risks of hypophosphatemia and effects on biomarkers of mineral and bone homeostasis of intravenous iron isomaltoside (now known as ferric derisomaltose) vs ferric carboxymaltose. Design, Setting, and Participants Between October 2017 and June 2018, 245 patients aged 18 years and older with iron-deficiency anemia (hemoglobin level ≤11 g/dL; serum ferritin level ≤100 ng/mL) and intolerance or unresponsiveness to 1 month or more of oral iron were recruited from 30 outpatient clinic sites in the United States into 2 identically designed, open-label, randomized clinical trials. Patients with reduced kidney function were excluded. Serum phosphate and 12 additional biomarkers of mineral and bone homeostasis were measured on days 0, 1, 7, 8, 14, 21, and 35. The date of final follow-up was June 19, 2018, for trial A and May 29, 2018, for trial B. Interventions Intravenous administration of iron isomaltoside, 1000 mg, on day 0 or ferric carboxymaltose, 750 mg, infused on days 0 and 7. Main Outcomes and Measures The primary end point was the incidence of hypophosphatemia (serum phosphate level <2.0 mg/dL) between baseline and day 35. Results In trial A, 123 patients were randomized (mean [SD] age, 45.1 [11.0] years; 95.9% women), including 62 to iron isomaltoside and 61 to ferric carboxymaltose; 95.1% completed the trial. In trial B, 122 patients were randomized (mean [SD] age, 42.6 [12.2] years; 94.1% women), including 61 to iron isomaltoside and 61 to ferric carboxymaltose; 93.4% completed the trial. The incidence of hypophosphatemia was significantly lower following iron isomaltoside vs ferric carboxymaltose (trial A: 7.9% vs 75.0% [adjusted rate difference, –67.0% {95% CI, –77.4% to –51.5%}], P < .001; trial B: 8.1% vs 73.7% [adjusted rate difference, –65.8% {95% CI, –76.6% to –49.8%}], P < .001). Beyond hypophosphatemia and increased parathyroid hormone, the most common adverse drug reactions (No./total No.) were nausea (iron isomaltoside: 1/125; ferric carboxymaltose: 8/117) and headache (iron isomaltoside: 4/125; ferric carboxymaltose: 5/117). Conclusions and Relevance In 2 randomized trials of patients with iron-deficiency anemia who were intolerant of or unresponsive to oral iron, iron isomaltoside (now called ferric derisomaltose), compared with ferric carboxymaltose, resulted in lower incidence of hypophosphatemia over 35 days. However, further research is needed to determine the clinical importance of this difference.
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    Metabolic Changes with Base-Loading in CKD
    (American Society of Nephrology, 2018-08-07) Scialla, Julia J.; Brown, Landon; Gurley, Susan; Corcoran, David L.; Bain, James R.; Muehlbauer, Michael J.; O’Neal, Sara K.; M. O’Connell, Thomas; Wolf, Myles; Melamed, Michal L.; Hostetter, Thomas H.; Abramowitz, Matthew K.; Otolaryngology -- Head and Neck Surgery, School of Medicine
    In small, randomized studies, treatment with sodium bicarbonate slowed kidney function decline in patients with CKD, possibly by lowering urine ammonium or inhibiting the renin-angiotensin-aldosterone or endothelin-1 pathways (1). Understanding the metabolic effects of alkali supplementation may reveal new candidate mechanisms. With this goal in mind, we profiled changes in systemic metabolites after treatment with sodium bicarbonate within a previously performed crossover trial of oral sodium bicarbonate (2).
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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.