Iron Toxicity: Relevance for Dialysis Patients
Cardiovascular disease is the leading cause of death in hemodialysis patients, so any negative effect of intravenous iron is highly relevant. Theoretically, oxidative stress induced by IV iron could damage vascular endothelium and accelerate atherosclerosis. Evidence is present from several sources examining this subject. In endothelial tissue culture, iron products, at relevant pharmacologic concentrations, stimulate cellular apoptosis, inhibit proliferation and cause monocyte adhesion. In an isolated arterial ring model, iron inhibited vascular relaxation. Similarly, in humans, after injection of 100 mg of iron sucrose to normal volunteers, there was inhibition of vascular relaxation. In apolipoprotein E-deficient mice, atherosclerotic lesions contain significant amounts of iron. A low iron diet reduces the iron content and the size of the plaques and increases plaque stability. In humans, there is a strong positive correlation between iron content and protein oxidation products in atherosclerotic plaques. Serum ferritin in humans directly correlates with the amount of iron and lipid peroxides in carotid endarterectomy specimens from patients with atherosclerosis. Iron may play an important role in arterial remodeling and arteriosclerosis as evidenced by experiments finding the inhibition of intimal thickening and vascular smooth muscle cell proliferation by iron chelation in rabbits. Moreover, iron and lipoproteins interact to induce vascular foam cell apoptosis and plaque instability, a phenomenon related to acute cardiovascular events. Drüeke et al. studied the effects of IV iron-induced oxidation on the vasculature. They found that a clinical measure of atherosclerosis, increased carotid artery media-intima thickness, was directly proportional to the annual dose of IV iron. Recently, van der Weerd et al. studied hepcidin-25 as a predictor of cardiovascular mortality in 405 hemodialysis patients. Hepcidin-25 is a key regulator of iron status, increased by iron overload as well as by inflammation. The investigators found hepcidin-25 to be significantly associated with fatal and nonfatal cardiovascular (CV) events [hazard ratio 1.24 per 10 nmol/L, 95% confidence interval (CI) 1.05–1.46, P = 0.01]. This was true even after adjustment for inflammation, suggesting a possible role for iron overload. Taken together, these observations indicate a potential role of IV iron and iron overload in endothelial dysfunction and atherosclerosis.
Despite the potential risks of iron in relation to cardiovascular disease, it is interesting that IV iron treatment has been found to have benefit among patients with congestive heart failure (95% CI 0.13–9.80), but no relationship was found on mortality (odds ratio 0.66, 95% CI 0.30–1.44). Some of these studies have evaluated important patient-centered outcomes. A recent meta-analysis was conducted by Kapoor et al.. Five randomized controlled trials involving 631 patients were analyzed. Patients treated with intravenous iron in these trials were found to have reductions in hospitalizations, improvement in New York Heart Association class and left ventricular ejection fraction, but no significant improvement in mortality.
Iron and Cardiovascular Disease
Cardiovascular disease is the leading cause of death in hemodialysis patients, so any negative effect of intravenous iron is highly relevant. Theoretically, oxidative stress induced by IV iron could damage vascular endothelium and accelerate atherosclerosis. Evidence is present from several sources examining this subject. In endothelial tissue culture, iron products, at relevant pharmacologic concentrations, stimulate cellular apoptosis, inhibit proliferation and cause monocyte adhesion. In an isolated arterial ring model, iron inhibited vascular relaxation. Similarly, in humans, after injection of 100 mg of iron sucrose to normal volunteers, there was inhibition of vascular relaxation. In apolipoprotein E-deficient mice, atherosclerotic lesions contain significant amounts of iron. A low iron diet reduces the iron content and the size of the plaques and increases plaque stability. In humans, there is a strong positive correlation between iron content and protein oxidation products in atherosclerotic plaques. Serum ferritin in humans directly correlates with the amount of iron and lipid peroxides in carotid endarterectomy specimens from patients with atherosclerosis. Iron may play an important role in arterial remodeling and arteriosclerosis as evidenced by experiments finding the inhibition of intimal thickening and vascular smooth muscle cell proliferation by iron chelation in rabbits. Moreover, iron and lipoproteins interact to induce vascular foam cell apoptosis and plaque instability, a phenomenon related to acute cardiovascular events. Drüeke et al. studied the effects of IV iron-induced oxidation on the vasculature. They found that a clinical measure of atherosclerosis, increased carotid artery media-intima thickness, was directly proportional to the annual dose of IV iron. Recently, van der Weerd et al. studied hepcidin-25 as a predictor of cardiovascular mortality in 405 hemodialysis patients. Hepcidin-25 is a key regulator of iron status, increased by iron overload as well as by inflammation. The investigators found hepcidin-25 to be significantly associated with fatal and nonfatal cardiovascular (CV) events [hazard ratio 1.24 per 10 nmol/L, 95% confidence interval (CI) 1.05–1.46, P = 0.01]. This was true even after adjustment for inflammation, suggesting a possible role for iron overload. Taken together, these observations indicate a potential role of IV iron and iron overload in endothelial dysfunction and atherosclerosis.
Despite the potential risks of iron in relation to cardiovascular disease, it is interesting that IV iron treatment has been found to have benefit among patients with congestive heart failure (95% CI 0.13–9.80), but no relationship was found on mortality (odds ratio 0.66, 95% CI 0.30–1.44). Some of these studies have evaluated important patient-centered outcomes. A recent meta-analysis was conducted by Kapoor et al.. Five randomized controlled trials involving 631 patients were analyzed. Patients treated with intravenous iron in these trials were found to have reductions in hospitalizations, improvement in New York Heart Association class and left ventricular ejection fraction, but no significant improvement in mortality.