Modulation of Iron Metabolism and Hepcidin Release by HFE Mutations in Chronic Hemodialysis Patients: Pathophysiological and Therapeutic Implications

Routine monitoring of body iron stores is an essential component of the management of patients with end-stage renal disease (ESRD) receiving chronic hemodialysis treatment (CHD). Maintenance of adequate iron stores is important for the prevention of iron overload as well as for the treatment of iron deficiency and anemia, and this goal is generally achieved by intravenous iron administration. Despite regular iron supplementation, anemia due to renal failure, blood losses related to the procedure, and chronic inflammation is a typical finding in CHD patients, and is associated with increased mortality, reduced physical and mental function, and poor quality of life. Treatment often requires the administration of erythropoiesis stimulating agents (ESAs), but many patients do not respond adequately and/or require high doses of these medications, with potential adverse cardiovascular and infective events. A correct iron balance is required for the functionality of catalytic enzymes and proteins crucial for DNA synthesis, transport and storage of oxygen via hemoglobin and myoglobin, transport of electrons and cell respiration, oxidative phosphorylation, tricarboxylic acid cycle, and many other biochemical pathways. On the other hand, excess free iron is toxic to the cells due to its ability to catalyze free radical generation. Therefore, specialized transport systems and membrane carriers have evolved to keep iron in a soluble state that is suitable for circulation into the blood and transfer across cell membranes. Additionally, the absence of a physiological excretion mechanism requires systemic iron homeostasis to be regulated by intestinal absorption and iron recycling from erythrophagocytosis of senescent red cells. Iron metabolism is frequently altered in CHD due to decreased saturation of transferrin (TF), the plasma iron carrier, resulting in reduced iron availability for erythropoiesis, because of chronic inflammation and/or blood losses. Furthermore, inflammation and oxidative stress induce iron retention in macrophages and the transcription of ferritin, a protein with antioxidant activity, and hyperferritinemia indicating increased iron stores, and chronic inflammation is frequently observed in these patients. Hyperferritinemia, reflecting iron overload, oxidative stress, and genetic factors, is associated with imminent death risk, mainly related to cardiovascular events, the leading cause of death in these subjects.