High-Dose Ferric Carboxymaltose in Patients With HFrEF Induces Significant Hypophosphatemia

Limited role for fibroblast growth factor 23 in assessing prognosis in heart failure patients: data from the TIME‐CHF trial

“…Since these associations were specifically strong for cFGF23 rather than for iFGF23 levels, we speculate that such co‐existing conditions could primarily influence the rate of FGF23 degradation rather than its synthesis. This hypothesis is supported by recent findings that iFGF23 and cFGF23 levels react differently to intravenous iron replenishment in HF patients with iron deficiency . How exactly co‐existing conditions influence FGF23 metabolism needs to be determined and the biological relevance is still unclear.…”

“…Fourteen samples would be needed to estimate an individual's homeostatic set point (within 10%) for iFGF23 compared with only three samples for cFGF23 . The degradation of iFGF23 towards cFGF23 underlies external influences which might add to this variability …”

Randomized trial of intravenous iron-induced hypophosphatemia

“…Coincident with increased utilization of intravenous iron, reports are accumulating of patients who developed severe hypophosphatemia with serious musculoskeletal complications following their administration, including osteomalacia, fragility fractures, and hypoxemia (3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Although the molecular mechanism of hypophosphatemia is not fully understood, certain forms of intravenous iron may increase circulating concentrations of fibroblast growth factor 23 (FGF23) (13)(14)(15)(16). Constitutively elevated serum FGF23 concentrations in rare prototypical diseases of primary FGF23 excess, including hereditary hypophosphatemic rickets and tumor-induced osteomalacia, cause hypophosphatemia and bone demineralization by stimulating renal phosphate wasting and suppressing serum concentrations of 1,25-dihydroxyvitamin D (14,15,(17)(18)(19)(20).…”

Sharp rises in FGF23 and hypophosphatemia after intravenous iron administration do not cause myocardial damage

“…As reported before, FCM infusion significantly increased iFGF23 levels up to 11-fold within one day, returning back to baseline levels after four weeks, in a subgroup of 11 patients with normal renal function (eGFR 74.8 ± 12.8 ml/ min/m 2 ). In parallel to this iFGF23 rise, 60% of these patients developed significant hypophosphatemia (mean decrease 28% ± 16% from baseline) [1]. Thus, FCM-induced increases in FGF23, paralleled by a relevant hypophosphataemia, may compound to cause (additional) myocardial damage in patients with heart failure constituting a previously underestimated (transient) post-infusion risk in these patients before the beneficial long-term effects of iron replenishment occur.…”

“…Current guidelines recommend intravenous iron replenishment (specifically by ferric carboxymaltose [FCM]) in iron-deficient patients with heart failure and reduced ejection fraction (HFrEF). We have previously shown that the administration of FCM in HFrEF patients with normal kidney function leads to an acute increase in circulating intact FGF23 (iFGF23) with a significant and concurrent hypophosphataemia that persists over the span of several weeks [IRON-TURTLE trial (NCT03079518)] [1]. Numerous human cohort studies have postulated an independent association between elevated serum levels of FGF23 and an increased risk for cardiovascular disease and mortality [2].…”