Ferric Pyrophosphate Citrate (Triferic™) Administration Via the Dialysate Maintains Hemoglobin and Iron Balance in Chronic Hemodialysis Patients

Steven N. Fishbane; Ajay K. Singh; Serge H. Cournoyer; Kailash K. Jindal; Paolo Fanti; Carrie D. Guss; Vivian H. Lin; Raymond D. Pratt; Ajay Gupta

Disclosures

Nephrol Dial Transplant. 2015;30(12):2019-2026. 

In This Article

Abstract and Introduction

Abstract

Background. Administration of ferric pyrophosphate citrate (FPC, Triferic™) via hemodialysate may allow replacement of ongoing uremic and hemodialysis-related iron losses. FPC donates iron directly to transferrin, bypassing the reticuloendothelial system and avoiding iron sequestration.

Methods. Two identical Phase 3, randomized, placebo-controlled trials (CRUISE 1 and 2) were conducted in 599 iron-replete chronic hemodialysis patients. Patients were dialyzed with dialysate containing 2 μM FPC-iron or standard dialysate (placebo) for up to 48 weeks. Oral or intravenous iron supplementation was prohibited, and doses of erythropoiesis-stimulating agents were held constant. The primary efficacy end point was the change in hemoglobin (Hgb) concentration from baseline to end of treatment (EoT). Secondary end points included reticulocyte hemoglobin content (CHr) and serum ferritin.

Results. In both trials, Hgb concentration was maintained from baseline to EoT in the FPC group but decreased by 0.4 g/dL in the placebo group (P < 0.001, combined results; 95% confidence interval [CI] 0.2–0.6). Placebo treatment resulted in significantly larger mean decreases from baseline in CHr (−0.9 pg versus −0.4 pg, P < 0.001) and serum ferritin (−133.1 μg/L versus −69.7 μg/L, P < 0.001) than FPC treatment. The proportions of patients with adverse and serious adverse events were similar in both treatment groups.

Conclusions. FPC delivered via dialysate during hemodialysis replaces iron losses, maintains Hgb concentrations, does not increase iron stores and exhibits a safety profile similar to placebo. FPC administered by hemodialysis via dialysate represents a paradigm shift in delivering maintenance iron therapy to hemodialysis patients.

Introduction

In patients with hemodialysis-dependent Stage 5 chronic kidney disease (CKD-5HD), iron needs are increased because of elevated erythroid iron requirements resulting from the use of erythropoiesis-stimulating agents (ESAs) and dialysis-associated blood losses, including frequent blood sampling and overt or occult gastrointestinal bleeding.[1–3] At the same time, iron supply is suppressed by the chronic inflammation of renal failure, which stimulates hepatic production of the systemic iron regulatory hormone, hepcidin.[3,4] To counterbalance increased iron losses and hepcidin-induced sequestration of iron, most hemodialysis patients are currently administered intravenous (IV) iron.[5] Intravenous iron may increase the risks of inflammation, oxidative stress, endothelial dysfunction, cardiovascular disease, immune deficiency and bacterial infections[6] and further exacerbate iron sequestration.

Ferric pyrophosphate citrate (FPC, Triferic™) is a carbohydrate-free, water-soluble, complex iron salt that was first demonstrated to deliver iron via dialysate in 1999, allowing maintenance of hemoglobin (Hgb) concentration and iron balance while reducing the need for IV iron by about 80%.[7]

FPC is added to liquid bicarbonate concentrate at the clinic. The bicarbonate concentrate with FPC subsequently mixes with acid concentrate and water in the hemodialysis machine to generate dialysate containing 2 μM iron. FPC crosses the dialyzer membrane, enters the blood, donates its iron directly to transferrin and is rapidly cleared from circulation. This provides for iron utilization for erythropoiesis and avoids iron sequestration within reticuloendothelial macrophages,[7,8] thereby avoiding hepcidin-induced iron sequestration.

The ContinuousReplacement Using Iron Soluble Equivalents (CRUISE 1 and 2) studies tested the hypothesis that FPC administered via dialysate can sustain iron delivery for erythropoiesis and is more effective than placebo in maintaining Hgb concentration in hemodialysis.

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