Iron Sucrose Promotes Endothelial Injury and Dysfunction and Monocyte Adhesion/Infiltration

Abstract

Background/Aims: Intravenous (IV) iron preparations are widely used in the management of anemia in ESRD populations. Recent changes in reimbursement policy have dramatically increased the use of IV iron to lower the use of costly erythropoiesis-stimulating agents. These preparations are frequently administered with insufficient attention to the total body iron stores or presence of inflammation which is aggravated by excess iron. Endothelial injury and dysfunction are critical steps in atherosclerosis, thrombosis and cardiovascular disease. IV iron preparations raise plasma non-transferrin-bound iron which can promote oxidative stress, endothelial damage and dysfunction. We explored the effect of an IV iron preparation on endothelial cells, monocytes and isolated arteries. Methods: Primary cultures of human aortic endothelial cells (HAEC) were treated with pharmacologically relevant concentrations of iron sucrose (10–100 µg/ml) for 4–24 h. Endothelial cell morphology, viability, and monocyte adhesion were tested. Endothelial function was assessed by measuring the vasorelaxation response to acetylcholine in normal rat thoracic aorta rings preincubated with iron sucrose (200 µg/ml). Results: In contrast to the control HAEC which showed normal cobblestone appearance, cells treated with iron sucrose (50–100 µg/ml) for 4 h showed loss of normal morphological characteristics, cellular fragmentation, shrinkage, detachment, monolayer disruption and nuclear condensation/fragmentation features signifying apoptosis. HAEC exposure to iron sucrose (10–100 µg/ml) increased monocyte adhesion 5- to 25-fold. Incubation in media containing 200 µg/ml iron sucrose for 3 h caused marked reduction in the acetylcholine-mediated relaxation in phenylephrine-precontracted rat aorta. Conclusion: Pharmacologically relevant concentration of iron sucrose results in endothelial injury and dysfunction and marked increase in monocyte adhesion.

Safety Issues in Iron Treatment in CKD

“…In fact, IV iron products significantly reduce acetylcholine-induced vasorelaxation in isolated artery rings. 13,21 Similar responses have been identified in normal human subjects. 20,22 Increased plasma asymmetric dimethylarginine levels potentially predict cardiovascular events in ESRD patients.…”

“…For example, in cultured human endothelial cells, exposure to IV iron products inhibited proliferation, induced apoptosis, and up-regulated monocyte adhesion. 13,20 Endothelial dysfunction and injury play a central part in the pathogenesis of atherosclerosis, thrombosis, and CVD. Oxidative stress induces endothelial dysfunction via ROS-mediated inactivation of nitric oxide, depletion of nitric oxide synthase co-factor (tetrahydrobiopterin), and accumulation of the nitric oxide synthase inhibitor asymmetric dimethylarginine.…”

“…Numerous in vitro and in vivo studies have shown the ability of IV iron compounds to promote oxidative stress and cell injury/death in cultured renal proximal tubular epithelial cells and endothelial cells. 13,14 Studies in CKD rats have shown persistent oxidative stress in the aorta, myocardium, and other organs several weeks after IV iron administration. 9,15 IV iron products, evaluated in a relatively small number of patients with ESRD, have shown significant increases in biomarkers of oxidative stress including lipid, protein, and DNA oxidation products and inflammatory mediators.…”

New Options for Iron Supplementation in Maintenance Hemodialysis Patients

“…Although IV iron preparations are effective, their indiscriminate use can have serious adverse consequences that may go undetected in short-term clinical trials. As described in a recent review, 9 use of IV iron preparations can increase the risk for infection, 10,11 cause oxidative stress, [12][13][14][15][16][17][18][19] promote cardiovascular disease, 11,[20][21][22][23][24] and lead to iron overload. [25][26][27][28] In addition, some IV iron preparations cause life-threatening anaphylactic reactions in susceptible individuals.…”

Mechanistic and Therapeutic Studies Related to Anemia of Chronic Disease and Inflammation

“…A high proportion of patients show suboptimal responses to Epo as well as the development of resistance to erythropoietin [34]. IV iron poses risks for septicemia, iron overload, endothelial damage, and anaphylactic reactions [11,35,36]. As a consequence of these drawbacks, tremendous resources have been invested in designing next generation ESAs, which include hypoxiainducible factor (HIF) stabilizers, hepcidin antagonists, Epo mimetics, and new iron formulations [7,37].…”