Iron deficiency is a frequent comorbidity in up to 50% of patients who have heart failure with reduced ejection fraction (HFrEF)(1). Intravenous iron replenishment (specifically by ferric carboxymaltose [FCM]) increases exercise tolerance and quality of life in HFrEF patients with iron deficiency (1). FCM is currently graded as a Class IIa recommendation by heart failure guidelines in iron-deficient HFrEF patients (2, 3). However, preliminary data have linked FCM administration to the development of hypophosphatemia (4). Since circulating fibroblast growth factor (FGF)-23 is a key regulator of phosphate and vitamin D metabolism, we sought to determine if FCM modifies FGF-23 levels and how this associates with hypophosphatemia induction. Our single-center prospective interventional pilot trial included 23 stable iron-deficient HFrEF patients (NCT03079518). Patients were divided into groups based on presence or absence of chronic kidney disease (CKD)(cut-off estimated glomerular filtration rate 60 ml/min/1.73 m2): group HFrEF (þ) CKD (n ž 12), and group HFrEF (Ā) CKD (n ž 11). Iron deficiency was defined as ferritin< 100 mg/dl or ferritin 100 to 300 mg/dl and transferrin saturation (TSAT)< 20%. Patients received a single dose of 1,000 mg FCM intravenously. We assessed FGF-23 levels by both intact FGF-23 (iFGF-23) as well as the degraded C-terminal FGF-23 (c-termFGF-23)(both by enzymelinked immunosorbent assay) over a period of 28 days. Furthermore, we measured serum phosphate, 1, 25-OH vitamin D, parathyroid hormone, tartrateresistant acid phosphatase 5b, and bone-specific alkaline phosphatase as well as fractional excretion of phosphate (FEPi).

FCM infusion resulted in a concordant increase in ferritin and TSAT. Baseline serum phosphate, iFGF-23, c-termFGF-23, and FEPi were higher in HFrEF (þ) CKD compared to HFrEF (Ā) CKD patients. iFGF-23 levels rose rapidly in both groups reaching their peak at day 1 (in HFrEF [þ] CKD patients by a factor of 1.8; p ž NS; in HFrEF [Ā] CKD patients by a factor of 11; p< 0.001). In HFrEF (Ā) CKD patients, iFGF23 remained significantly elevated until day 28. c-termFGF23 levels decreased constantly toward day 28 in both groups. Serum phosphate significantly decreased only in HFrEF (Ā) CKD patients (nadir at day 14, mean decrease 0.33 Æ 0.2 mmol/l compared to baseline) and returned to baseline at day 28. FEPi was induced in both groups, although more in the HFrEF (Ā) CKD group. Transient hypophosphatemia (< 0.8 mmol/l) developed in 14 of 23 patients (9 HFrEF [Ā] CKD patients and 5 HFrEF [þ] CKD). Levels of 1, 25-OH vitamin D significantly decreased in both groups by more than 50% with a