Complement Activation-Related Pseudo-Allergy: A Fresh Look at Hypersensitivity Reactions to Intravenous Iron

iron preparations, and the one that started giving IV iron a bad name, was iron dextran. An early report in JAMA [2] reported 3 life-threatening immediate anaphylactic and 8 severe delayed reactions in 471 adult patients and 10 adult prisoner volunteers, who between them received 2,099 administrations of IV iron dextran (Imferon). Imferon was a high molecular weight (HMW) iron dextran preparation, and it is now clear that the incidence of severe immediate hypersensitivity reactions to HMW IV iron compounds (also including Dexferrum) was unacceptably high; both products have subsequently been withdrawn from the market. The cause of these anaphylactic-type reactions was believed to be IgE-mediated, and classified as a type I hypersensitivity reaction using the classical scheme of Gell and Coombs, originally described in 1968. Patients were known to have circulating anti-dextran antibodies, even before exposure to IV iron, and thus there was a neat biological rationale for this assumption. Other mechanisms were also considered, such as immune complex formation and complement activation, but no evidence was found to implicate these biological pathways [3] . The assumption that immediate hypersensitivity reactions were antibody-mediated persisted with other IV iron preparations, such as iron sucrose and iron sodium Intravenous (IV) iron has been available as a therapeutic agent for well over 50 years, with much of its use preceding the modern-day regulatory control of drugs by agencies such as the FDA, European Medicines Agency and others. In nephrological practice, there was an exponential interest in IV iron coinciding with the introduction of recombinant human erythropoietin in the late 1980s, when it was realized that, firstly, there was a need for supplemental iron to support increased erythropoiesis, and secondly, oral iron supplementation was largely ineffective in many patients with chronic kidney disease (particularly those on dialysis). Although unquestionably efficacious in increasing the body’s stores of iron, there have always been concerns about the use of IV iron, particularly in relation to allergic or hypersensitivity reactions. The first description of administering parenteral iron to man was in 1932 [1] , and the severe and toxic reactions described in this paper led the authors to suggest that extremely low amounts of iron, if any, should be given to humans in this manner. This shortfall was revolutionized with the development of iron preparations in which an iron salt, iron oxyhydroxide, was encased in a carbohydrate shell to allow iron to leach out slowly enough in the circulation to be taken up by circulating transferrin molecules. One of the older IV Published online: November 29, 2016 Nephrology American Journal of