Distinct in vitro Complement Activation by Various Intravenous Iron Preparations

• Published in: American journal of nephrology Vol. 45; no. 1; pp. 49 - 59
• Main Authors: Hempel, Julia Cordelia, Poppelaars, Felix, Gaya da Costa, Mariana, Franssen, Casper F.M., de Vlaam, Thomas P.G., Daha, Mohamed R., Berger, Stefan P., Seelen, Marc A.J., Gaillard, Carlo A.J.M.
• Format: Journal Article
• Language: English
• Published: Basel, Switzerland 01.01.2017
• Subjects: Administration, Intravenous; Anemia, Iron-Deficiency - complications; Anemia, Iron-Deficiency - drug therapy; Complement Activation - drug effects; Complement C1q - drug effects; Complement C1q - metabolism; Complement C3d - drug effects; Complement C3d - metabolism; Complement Membrane Attack Complex - drug effects; Complement Membrane Attack Complex - metabolism; Disaccharides - pharmacology; Disaccharides - therapeutic use; Ferric Compounds - pharmacology; Ferric Compounds - therapeutic use; Ferrosoferric Oxide - pharmacology; Ferrosoferric Oxide - therapeutic use; Glucaric Acid - pharmacology; Glucaric Acid - therapeutic use; Hematinics - pharmacology; Hematinics - therapeutic use; Humans; In Vitro Techniques; Iron Compounds - pharmacology; Iron Compounds - therapeutic use; Iron-Dextran Complex - pharmacology; Iron-Dextran Complex - therapeutic use; Kidney Failure, Chronic - complications; Kidney Failure, Chronic - therapy; Maltose - analogs & derivatives; Maltose - pharmacology; Maltose - therapeutic use; Mannose-Binding Lectin - drug effects; Mannose-Binding Lectin - metabolism; Original Report: Laboratory Investigation; Properdin - drug effects; Properdin - metabolism; Renal Dialysis; Iron sucrose; Complement activation; Complement activation related pseudo allergy; Intravenous iron; Iron dextran; Hypersensitivity reaction
• ISSN: 0250-8095; 1421-9670
• DOI: 10.1159/000451060

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.