Acute Injury with Intravenous Iron and Concerns Regarding Long-Term Safety

Abstract

Intravenous iron is widely used to maintain adequate iron stores and prevent iron deficiency anemia in patients with chronic kidney disease, yet concerns remain about its long-term safety with respect to oxidative stress, kidney injury, and accelerated atherosclerosis, which are the subjects of this review. Three parenteral iron formulations are available for use in the United States: Iron dextran, iron gluconate, and iron sucrose. Iron dextran, especially the high molecular form, has been linked with anaphylactoid and anaphylactic reactions, and its use has been declining. A portion of intravenous iron preparations is redox-active, labile iron available for direct donation to transferrin. In vitro tests show that commonly available intravenous iron formulations have differing capacities to saturate transferrin directly: Iron gluconate > iron sucrose > iron dextran. Intravenous iron treatment produces oxidative stress, as demonstrated by increases in plasma levels of lipid peroxidation products (malondialdehyde), at a point that is much earlier than the time to peak concentration of catalytically active iron, suggesting a direct effect of iron sucrose on oxidative stress. Furthermore, iron sucrose infusion produces endothelial dysfunction that seems to peak earlier than the serum level of free iron. Intravenous iron sucrose infusion also has been shown to produce acute renal injury and inflammation as demonstrated by increased urinary albumin, enzyme (N-acetyl-␤-glucosaminidase), and cytokine (chemokine monocyte chemoattractant protein-1) excretions. Although the long-term dangers of intravenous iron are unproved, these data call for examination of effects of intravenous iron on the potential for long-term harm in patients with chronic kidney disease.

Lipid Peroxidation Products Formation with Various Intravenous Iron Preparations in Chronic Kidney Disease

“…While the use of parenteral iron in treating anemia of CKD in predialysis or dialysis patients on epoetin has been firmly established, [1] fears frequently expressed but rarely allayed [2] are the risks of short-term adverse events, like anaphylaxis, and long-term toxic effects, like oxidative stress and inflammation and its effect on atherosclerosis and cardiovascular disease (CVD) in CKD. CVD is the primary cause of death in ESRD patients, [6] primarily because CKD is a pro-oxidative state that leads to accelerated atherosclerosis.…”

“…[2] Possible long-term effects of intravenous iron include increased oxidative stress, inflammation, and renal tubular injury, which Agarwal [3] showed was due to unbound and catalytically active iron. Stocker and Keaney [4] showed CKD to be a state of accelerated atherosclerosis contributed largely by a pro-oxidant milieu.…”

“…Stocker and Keaney [4] showed CKD to be a state of accelerated atherosclerosis contributed largely by a pro-oxidant milieu. Bishu and Agarwal [2] showed that intravenous iron is an important contributor to oxidative stress and endothelial dysfunction in CKD. However, few clinical studies are available to assess the extent of lipid peroxidation products formation with different forms of parenteral iron.…”

ESAs in Dialysis Patients

“…11 Iron use will also rise with aggressive attempts to reduce ESA dosage. Exposure to large amounts of intravenously administered iron, over the long-term, raises safety concerns, 24 although observational studies have been reassuring. 25 In the absence of additional RCTs, clinicians are faced with making decisions on what to do with managing anemia in dialysis patients.…”

Use of parenteral iron products and serious anaphylactic‐type reactions

“…Long-term safety studies have not been done [31]. To help differentiate risk among the parenteral iron products, the brand name of the product always should be provided on medical records, death certificates, and adverse drug reaction reports (submitted via http:// www.fda.gov/medwatch or 1-800-FDA-1088).…”