Ferric Citrate Reduces Intravenous Iron and Erythropoiesis-Stimulating Agent Use in ESRD

Abstract

Ferric citrate (FC) is a phosphate binder with shown efficacy and additional effects on iron stores and use of intravenous (iv) iron and erythropoiesis-stimulating agents (ESAs). We provide detailed analyses of changes in iron/hematologic parameters and iv iron/ESA use at time points throughout the active control period of a phase 3 international randomized clinical trial. In all, 441 subjects were randomized (292 to FC and 149 to sevelamer carbonate and/or calcium acetate [active control (AC)]) and followed for 52 weeks. Subjects on FC had increased ferritin and transferrin saturation (TSAT) levels compared with subjects on AC by week 12 (change in ferritin, 114.1629.35 ng/ml; P,0.001; change in TSAT, 8.62%61.57%; P,0.001). Change in TSAT plateaued at this point, whereas change in ferritin increased through week 24, remaining relatively stable thereafter. Subjects on FC needed less iv iron compared with subjects on AC over 52 weeks (median [interquartile range] dose=12.9 [1.0-28.9] versus 26.8 [13.4-47.6] mg/wk; P,0.001), and the percentage of subjects not requiring iv iron was higher with FC (P,0.001). Cumulative ESA over 52 weeks was lower with FC than AC (median [interquartile range] dose=5303 [2023-9695] versus 6954 [2664-12,375] units/wk; P=0.04). Overall, 90.3% of subjects on FC and 89.3% of subjects on AC experienced adverse events. In conclusion, treatment with FC as a phosphate binder results in increased iron parameters apparent after 12 weeks and reduces iv iron and ESA use while maintaining hemoglobin over 52 weeks, with a safety profile similar to that of available binders.

New Options for Iron Supplementation in Maintenance Hemodialysis Patients

“…11 In contrast to conventional oral iron preparations, the iron-based phosphate binder ferric citrate has been shown to be highly effective in increasing serum ferritin, TSAT, and hemoglobin values and significantly reduced IV iron and ESA requirements. 77,78 Ferric pyrophosphate citrate, iron that is delivered by dialysate, has been shown to be highly effective in maintaining TSAT and reducing IV iron and ESA requirements without increasing serum ferritin levels. Given the immediate side effects and potential longterm adverse effects of IV iron products and adverse cardiovascular effects of high ESA doses, alternate routes for iron administration that decrease IV iron and ESA requirements seem worthy of consideration.…”

“…The cumulative ESA dose over 52 weeks was lower with ferric citrate than active control (median weekly epoetin dose, 5,303 vs 6,954 U; P 5 0.04). 78 An editorial 79 accompanying the report raised the concern of whether long-term ferric citrate use has the potential to result in iron overload. Of note, for adequate control of serum phosphorus levels, the daily dose of ferric citrate contains 2,000 mg of elemental iron, though it is not clear how much of this iron is absorbed.…”

“…However, the sum of all adverse events (serious and nonserious) was similar between ferric citrate and active control groups (90.3% and 89.3%, respectively). 77,78 The reason for the greater bioavailability of iron in ferric citrate than in conventional oral iron preparations is unclear and requires further investigation. Possible mechanisms include but are not limited to differences in the nature of the accompanying anion (citrate vs others), possible vesicular or paracellular transport of ferric citrate as opposed to the tightly regulated DMT-1 (divalent metal transporter 1) pathway, extended sites of absorption beyond the duodenum/proximal jejunum, and uremia-induced changes in the structure and function of the gut epithelial barrier.…”

Effects of Ferric Citrate in Patients with Nondialysis-Dependent CKD and Iron Deficiency Anemia

“…13,14 Prior studies in patients receiving dialysis and a phase 2 study in patients with NDD-CKD found ferric citrate to increase transferrin saturation, serum ferritin, and hemoglobin. 13,15,16 The current phase 3 trial was designed to evaluate the safety and efficacy of ferric citrate for treatment of iron deficiency anemia in patients with NDD-CKD (stages 3-5).…”

Iatrogenic iron overload and its potential consequences in patients on hemodialysis

“…HIF, a key regulatory protein which stimulates erythropoietin and transferrin production, reduces hepcidin production, and thereby modulates iron absorption and metabolism, although the direct or indirect influence (via erythropoietin) of HIF on hepcidin modulation is still an open question [89]. In addition to HIF stabilizers, iron administration via the dialysate ferric pyrophosphate citrate (Triferic ® ) and a ferric citrate-based phosphate binder (Auryxia ® ) are new therapeutic options for compensating iron deficiency related to blood loss in hemodialysis patients and for providing the iron required for erythropoiesis [90][91][92][93]. Ferric pyrophosphate citrate (Triferic ® ) rapidly delivers iron directly and safely to the bone marrow (5-7 mg iron) during hemodialysis sessions via the dialysate, efficiently matching the amount of iron required by ESA to generate red blood cells, without increasing ferritin levels [90].…”