Distinct in vitro Complement Activation by Various Intravenous Iron Preparations

Abstract

Background: Intravenous (IV) iron preparations are widely used in the treatment of anemia in patients undergoing hemodialysis (HD). All IV iron preparations carry a risk of causing hypersensitivity reactions. However, the pathophysiological mechanism is poorly understood. We hypothesize that a relevant number of these reactions are mediated by complement activation, resulting in a pseudo-anaphylactic clinical picture known as complement activation-related pseudo allergy (CARPA). Methods: First, the in-vitro complement-activating capacity was determined for 5 commonly used IV iron preparations using functional complement assays for the 3 pathways. Additionally, the preparations were tested in an ex-vivo model using the whole blood of healthy volunteers and HD patients. Lastly, in-vivo complement activation was tested for one preparation in HD patients. Results: In the in-vitro assays, iron dextran, and ferric carboxymaltose caused complement activation, which was only possible under alternative pathway conditions. Iron sucrose may interact with complement proteins, but did not activate complement in-vitro. In the ex-vivo assay, iron dextran significantly induced complement activation in the blood of healthy volunteers and HD patients. Furthermore, in the ex-vivo assay, ferric carboxymaltose and iron sucrose only caused significant complement activation in the blood of HD patients. No in-vitro or ex-vivo complement activation was found for ferumoxytol and iron isomaltoside. IV iron therapy with ferric carboxymaltose in HD patients did not lead to significant in-vivo complement activation. Conclusion: This study provides evidence that iron dextran and ferric carboxymaltose have complement-activating capacities in-vitro, and hypersensitivity reactions to these drugs could be CARPA-mediated.

The available intravenous iron formulations: History, efficacy, and toxicology

“…It is extremely unlikely that anyone reading this review was not taught that there is a serious risk of anaphylaxis with the use of parenteral iron. It is clear that this risk has been overstated for decades, with a big difference between the very rare serious allergic reactions which can lead to anaphylaxis (seen mainly in the 1970s and 1980s) and the uncommon, self‐limiting, minor hypersensitivity reactions that may be complement‐mediated or due to labile free iron in circulation . In the early 20th century, parenteral iron was thought to have prohibitive toxicity following the use of the intravenous (IV) colloidal ferric hydroxide, the carbohydrate core of which did not bind elemental iron tightly.…”

Involvement of complement activation in the pulmonary vasoactivity of polystyrene nanoparticles in pigs: unique surface properties underlying alternative pathway activation and instant opsonization

“…Based on the association of complement (C) activation with many of these adverse reactions, the term "complementactivation-related pseudoallergy" (CARPA) was introduced 1 and with time increasingly considered as a clinically relevant concept in liposomal chemotherapy and other areas of IV pharmacotherapy, [2][3][4][5] most recently in the medical use of nanoparticulate iron. 6,7 Nevertheless, a recent review questioned the pseudoallergic nature of these HSRs, the role of C, and the use of pigs as a relevant model. 8 The review concluded that "at present, current experimentally derived evidence is more in support of the rapid phagocytic response (RPR) hypothesis" (vs CARPA), essentially claiming that macrophage "bulimia" explains the HSRs independently of C activation.…”

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

“…Given that hypersensitivity reactions to IV iron are much less common than are seen with monoclonal antibodies or liposomal preparations, this is clearly much more difficult to demonstrate. Nevertheless, Hempel et al [5] , in this issue of Am J Nephrol , have attempted to provide some preliminary evidence that CARPA may be implicated in hypersensitivity reactions seen with IV iron, using a number of methods, including complement activation by 5 different IV iron preparations in vitro using functional complement assays, as well as studying complement activation in a group of hemodialysis patients receiving IV ferric carboxymaltose.…”

“…The design of the experiments by Hempel et al [5] did not allow the authors to determine whether the complement activation seen was due to the iron itself or the carbohydrate shell. The expanding body of literature on nanoparticles [6] , however, suggests that it is more likely to be related to the carbohydrate shell.…”

“…The study by Hempel et al [5] has a few limitations, but the authors should be congratulated for providing preliminary data to suggest that CARPA could be implicated in the pathogenesis of IV iron hypersensitivity. It is time for nephrologists to bury the hatchet of IgE-induced anaphylaxis seen with the older HMW IV iron dextran preparations, and concentrate on this new mechanism of IV iron-induced hypersensitivity, which we call CARPA.…”