Intravenous iron therapy and the cardiovascular system: risks and benefits

Abstract

Anaemia is a common complication of chronic kidney disease (CKD). In this setting, iron deficiency is frequent because of the combination of increased iron needs to sustain erythropoiesis with increased iron losses. Over the years, evidence has accumulated on the involvement of iron in influencing pulmonary vascular resistance, endothelial function, atherosclerosis progression and infection risk. For decades, iron therapy has been the mainstay of therapy for renal anaemia together with erythropoiesis-stimulating agents (ESAs). Despite its long-standing use, grey areas still surround the use of iron therapy in CKD. In particular, the right balance between either iron repletion with adequate therapy and the avoidance of iron overload and its possible negative effects is still a matter of debate. This is particularly true in patients having functional iron deficiency. The recent Proactive IV Iron Therapy in Haemodialysis Patients trial supports the use of intravenous (IV) iron therapy until a ferritin upper limit of 700 ng/mL is reached in haemodialysis patients on ESA therapy, with short dialysis vintage and minimal signs of inflammation. IV iron therapy has also been proven to be effective in the setting of heart failure (HF), where it improves exercise capacity and quality of life and possibly reduces the risk of HF hospitalizations and cardiovascular deaths. In this review we discuss the risks of functional iron deficiency and the possible benefits and risks of iron therapy for the cardiovascular system in the light of old and new evidence.

Keywords: anaemia; cardiovascular disease; chronic kidney disease; ferritin; haemodialysis; heart failure; iron.

FIGURE 1

Iron and PAH. There is experimental and clinical evidence linking iron deficiency to PAH. In humans, iron chelation has been associated with PAH, while in PAH patients, iron deficiency was observed. In contrast, iron supplementation was associated with decreased pulmonary artery SBP. Additionally, hepcidin induced cultured pulmonary smooth muscle cell proliferation. In rats, iron deficiency was also associated with PAH and promoted endothelin-1 secretion by pulmonary smooth muscle cells. However, chronic administration of iron dextran was also potentially deleterious, decreasing nitrous oxide bioavailability.

FIGURE 2

Iron and atherosclerosis. Iron availability has been linked to atherosclerosis. (A) In humans, iron excess or supplementation has been associated with increased serum levels of vascular adhesion molecules and increased intima–media thickness, while symptomatic atherosclerotic plaques are rich in iron. (B) In experimental animals, iron restriction was associated with milder atherosclerosis while there are inconclusive studies regarding the impact of iron supplementation on atherosclerosis. Increased iron availability had inconclusive effects on smooth muscle cell proliferation while it promoted LDL accumulation and oxidation as well as phenotypic changes in monocytes. In endothelial cells, increased iron availability increased the expression of adhesion molecules.