title: Distinct in vitro Complement Activation by Various Intravenous Iron Preparations.
abstract: 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).
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Julia Cordelia
authors.initials: JC
authors.lastname: Hempel
authors.forename: Felix
authors.initials: F
authors.lastname: Poppelaars
authors.forename: Mariana
authors.initials: M
authors.lastname: Gaya da Costa
authors.forename: Casper F M
authors.initials: CF
authors.lastname: Franssen
authors.forename: Thomas P G
authors.initials: TP
authors.lastname: de Vlaam
authors.forename: Mohamed R
authors.initials: MR
authors.lastname: Daha
authors.forename: Stefan P
authors.initials: SP
authors.lastname: Berger
authors.forename: Marc A J
authors.initials: MA
authors.lastname: Seelen
authors.forename: Carlo A J M
authors.initials: CA
authors.lastname: Gaillard
mesh_terms: D061605:Administration, Intravenous; D018798:Anemia, Iron-Deficiency / Q000150:complications / Q000188:drug therapy*; D003167:Complement Activation / Q000187:drug effects*; D015922:Complement C1q / Q000187:drug effects / Q000378:metabolism; D015933:Complement C3d / Q000187:drug effects / Q000378:metabolism; D015938:Complement Membrane Attack Complex / Q000187:drug effects / Q000378:metabolism; D004187:Disaccharides / Q000494:pharmacology / Q000627:therapeutic use; D005290:Ferric Compounds / Q000494:pharmacology / Q000627:therapeutic use; D000077605:Ferric Oxide, Saccharated; D052203:Ferrosoferric Oxide / Q000494:pharmacology / Q000627:therapeutic use; D005937:Glucaric Acid / Q000494:pharmacology / Q000627:therapeutic use; D006397:Hematinics / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D066298:In Vitro Techniques; D058085:Iron Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D007505:Iron-Dextran Complex / Q000494:pharmacology / Q000627:therapeutic use; D007676:Kidney Failure, Chronic / Q000150:complications / Q000628:therapy*; D008320:Maltose / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D037601:Mannose-Binding Lectin / Q000187:drug effects / Q000378:metabolism; D011414:Properdin / Q000187:drug effects / Q000378:metabolism; D006435:Renal Dialysis
chemical_list: D015938:Complement Membrane Attack Complex; D004187:Disaccharides; D005290:Ferric Compounds; D006397:Hematinics; D058085:Iron Compounds; D037601:Mannose-Binding Lectin; D011414:Properdin; C557707:iron isomaltoside 1000; C522335:ferric carboxymaltose; D008320:Maltose; D015922:Complement C1q; D015933:Complement C3d; D007505:Iron-Dextran Complex; D000077605:Ferric Oxide, Saccharated; D005937:Glucaric Acid; D052203:Ferrosoferric Oxide