Ferric pyrophosphate citrate administered via dialysate reduces erythropoiesis-stimulating agent use and maintains hemoglobin in hemodialysis patients

Ajay Gupta, Vivian Lin, Carrie Guss, Raymond Pratt, T Alp Ikizler, Anatole Besarab, Ajay Gupta, Vivian Lin, Carrie Guss, Raymond Pratt, T Alp Ikizler, Anatole Besarab

Abstract

Ferric pyrophosphate citrate (FPC) is a water-soluble iron salt administered via dialysate to supply iron directly to transferrin. The PRIME study tested whether treatment with FPC could reduce prescribed erythropoiesis-stimulating agent (ESA) use and maintain hemoglobin in hemodialysis patients. This 9-month, randomized, placebo-controlled, double-blind, multicenter clinical study included 103 patients undergoing hemodialysis 3-4 times weekly. The FPC group received dialysate containing 2 μmol/l of iron. The placebo group received standard dialysate. A blinded central anemia management group facilitated ESA dose adjustments. Intravenous iron was administered according to the approved indication when ferritin levels fell below 200 μg/l. The primary end point was the percentage change from baseline in prescribed ESA dose at end of treatment. Secondary end points included intravenous iron use and safety. At the end of treatment, there was a significant 35% reduction in prescribed ESA dose in FPC-treated patients compared with placebo. The FPC patients used 51% less intravenous iron than placebo. Adverse and serious adverse events were similar in both groups. Thus, FPC delivered via dialysate significantly reduces the prescribed ESA dose and the amount of intravenous iron needed to maintain hemoglobin in chronic hemodialysis patients.

Trial registration: ClinicalTrials.gov NCT01286012.

Conflict of interest statement

AG, VL, RP, and CG are employees of Rockwell Medical, the sponsor of the study. AG holds the rights to the patent on parenteral delivery of FPC, including via the dialysis solutions, and a pending patent on FPC sparing the need for ESAs. AG, RP, and CG hold a patent pending for FPC-sparing ESA usage in ESA-hyporesponsive hemodialysis patients. TAI received grant funding from Rockwell Medical (study sponsor) during the conduct of the study for measurement of inflammatory and oxidative stress markers. AB received grants from Rockwell Medical (study sponsor) during the conduct of the study. AB also received grants from Akebia and Fibrogen and consulting fees from Amgen, Fibrogen, Bayer, and Pharmacosmos. He is currently an employee of Fibrogen.

Figures

Figure 1
Figure 1
Patient disposition—CONSORT diagram. ESA, erythropoiesis-stimulating agent; FPC, ferric pyrophosphate citrate; mITT, modified intent-to-treat.
Figure 2
Figure 2
Serum iron parameters and measurements. Bars indicate s.d. (a) Serum iron parameters (total Fe, UIBC, and TSAT) before and after dialysis at the end of treatment. (b) Serum iron concentration before and after dialysis over the course of the study. Fe, iron; FPC, ferric pyrophosphate citrate; HD, hemodialysis; TSAT, transferrin saturation; UIBC, unsaturated iron binding capacity.
Figure 3
Figure 3
Erythropoiesis-stimulating agent use, intravenous iron use, serum ferritin, and hemoglobin over time. Bars indicate s.e.m. (a) Prescribed ESA percentage change from baseline. (b) Number of patients receiving i.v. iron and i.v. iron administration over time. (c) Serum ferritin concentrations and change from baseline in hemoglobin concentration over time. BL, baseline; EoT, end of treatment; ESA, erythropoiesis-stimulating agent; Fe, iron; FPC, ferric pyrophosphate citrate; Hgb, hemoglobin; i.v., intravenous; pt, patient; wk, week.
Figure 4
Figure 4
Change from baseline reticulocyte hemoglobin over time. Bars indicate s.e.m. CHr, reticulocyte hemoglobin; EoT, end of treatment; FPC, ferric pyrophosphate citrate.
Figure 5
Figure 5
Biomarkers of inflammation and oxidative stress. Biomarkers of inflammation (interleukin-6) and oxidative stress (malondialdehyde) measured before dialysis at baseline and at week 36, and the difference between measurements. Bars indicate s.d. P is not significant for all comparisons. FPC, ferric pyrophosphate citrate; IL-6, interleukin-6; MDA, malondialdehyde; Wk, week.

References

    1. 1Babitt JL, Lin HY. Mechanisms of anemia in CKD. J Am Soc Nephrol 2012; 23: 1631–1634.
    1. 2Sargent JA, Acchiardo SR. Iron requirements in hemodialysis. Blood Purif 2004; 22: 112–123.
    1. 3Goodnough LT, Nemeth E, Ganz T. Detection, evaluation, and management of iron-restricted erythropoiesis. Blood 2010; 116: 4754–4761.
    1. 4Zumbrennen-Bullough K, Babitt JL. The iron cycle in chronic kidney disease (CKD): from genetics and experimental models to CKD patients. Nephrol Dial Transplant 2014; 29: 263–273.
    1. 5Ganz T. Hepcidin and iron regulation, 10 years later. Blood 2011; 117: 4425–4433.
    1. 6Thomas DW, Hinchliffe RF, Briggs C et al. Guideline for the laboratory diagnosis of functional iron deficiency. Br J Haematol 2013; 161: 639–648.
    1. 7Auerbach M, Coyne D, Ballard H. Intravenous iron: from anathema to standard of care. Am J Hematol 2008; 83: 580–588.
    1. 8Fishbane S, Mathew AT, Wanchoo R. Intravenous iron exposure and outcomes in patients on hemodialysis. Clin J Am Soc Nephrol 2014; 9: 1837–1839.
    1. 9Vaziri ND. Understanding iron: promoting its safe use in patients with chronic kidney failure treated by hemodialysis. Am J Kidney Dis 2013; 61: 992–1000.
    1. 10Gupta A, Amin NB, Besarab A et al. Dialysate iron therapy: infusion of soluble ferric pyrophosphate via the dialysate during hemodialysis. Kidney Int 1999; 55: 1891–1898.
    1. 11Gupta A, Crumbliss AL. Treatment of iron deficiency anemia: are monomeric iron compounds suitable for parenteral administration? J Lab Clin Med 2000; 136: 371–378.
    1. 12Huebers HA, Finch CA. The physiology of transferrin and transferrin receptors. Physiol Rev 1987; 67: 520–582.
    1. 13Rostoker G, Griuncelli M, Loridon C et al. Hemodialysis-associated hemosiderosis in the era of erythropoiesis-stimulating agents: a MRI study. Am J Med 2012; 125: 991–9 e1.
    1. 14Kosch M, Bahner U, Bettger H et al. A randomized, controlled parallel-group trial on efficacy and safety of iron sucrose (Venofer) vs iron gluconate (Ferrlecit) in haemodialysis patients treated with rHuEpo. Nephrol Dial Transplant 2001; 16: 1239–1244.
    1. 15United States Renal Data SystemUSRDS 2013 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases: Bethesda, MD, 2013.
    1. 16Cowart RE, Swope S, Loh TT et al. The exchange of Fe3+ between pyrophosphate and transferrin. Probing the nature of an intermediate complex with stopped flow kinetics, rapid multimixing, and electron paramagnetic resonance spectroscopy. J Biol Chem 1986; 261: 4607–4614.
    1. 17Cervato G, Viani P, Gatti P et al. Further studies on the antioxidant role of pyrophosphate in model membranes. Chem Phys Lipids 1993; 66: 87–92.

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