Iron Therapy in Chronic Kidney Disease: Days of Future Past

Abstract

Anemia affects millions of patients with chronic kidney disease (CKD) and prompt iron supplementation can lead to reductions in the required dose of erythropoiesis-stimulating agents, thereby reducing medical costs. Oral and intravenous (IV) traditional iron preparations are considered far from ideal, primarily due to gastrointestinal intolerability and the potential risk of infusion reactions, respectively. Fortunately, the emergence of novel iron replacement therapies has engendered a paradigm shift in the treatment of iron deficiency anemia in patients with CKD. For example, oral ferric citrate is an efficacious and safe phosphate binder that increases iron stores to maintain hemoglobin levels. Additional benefits include reductions in fibroblast growth factor 23 levels and the activation of 1,25 dihydroxyvitamin D. The new-generation IV iron preparations ferumoxytol, iron isomaltoside 1000, and ferric carboxymaltose are characterized by a reduced risk of infusion reactions and are clinically well tolerated as a rapid high-dose infusion. In patients undergoing hemodialysis (HD), ferric pyrophosphate citrate (FPC) administered through dialysate enables the replacement of ongoing uremic and HD-related iron loss. FPC transports iron directly to transferrin, bypassing the reticuloendothelial system and avoiding iron sequestration. Moreover, this paper summarizes recent advancements of hypoxia-inducible factor prolyl hydroxylase inhibitors and future perspectives in renal anemia management.

Keywords: anemia; chronic kidney disease; ferric citrate; hypoxia-inducible factor; iron therapy.

Figure 1

Illustration of iron metabolism. Dietary iron is absorbed from the duodenum. In plasma, iron is bound to transferrin for transport. Some of the iron is stored in the liver through binding to ferritin. The remaining iron is transported to bone marrow for red blood cell (RBC) production, a process stimulated by erythropoietin (EPO), which is secreted by the kidney. EPO transcription is upregulated by hypoxia inducible factors (HIFs), which are transcription factors stabilized under hypoxic conditions. The process involves recruitment of coactivators, such as p300, and binding of HIF and p300 to the hypoxia-response element (HRE) of the EPO gene. RBCs are destroyed at the end of their lifespan by macrophages in the reticuloendothelial system (e.g., in the spleen), and their iron is then recycled. Hepcidin, mainly produced by the liver, plays a central role in the regulation of iron metabolism by downregulating iron absorption and iron utilization under conditions of infection and inflammation.

Figure 2

Illustration of the proposed mechanisms of action of ferric citrate (FC). FC binds dietary phosphorus in the gastrointestinal tract, thus controlling serum phosphate levels, which results in reduced fibroblast growth factor 23 (FGF23) production. The resulting reduction of FGF23 levels leads to increased 1,25-dihydroxyvitamin D levels, which subsequently improves bone mineral density. Blocking FGF23 activity also stimulates renal erythropoietin production. FC also enhances intestinal iron absorption and utilization, thereby activating red blood cell (RBC) production in bone marrow and improving hemoglobin (Hgb) levels and cardiac functional capacity. “↑” (means increase), “↓” (means decrease).