Nephrology
`
`American Journal of
`
` Editorial
`
` Am J Nephrol 2017;45:60–62
` DOI: 10.1159/000451069
`
` Published online: November 29, 2016
`
` Complement Activation-Related Pseudo-Allergy:
`A Fresh Look at Hypersensitivity Reactions to
`Intravenous Iron
`
` Iain C. Macdougall Katherine Vernon
`
` Department of Renal Medicine, King’s College Hospital, London , UK
`
` Intravenous (IV) iron has been available as a therapeu-
`tic agent for well over 50 years, with much of its use pre-
`ceding the modern-day regulatory control of drugs by
`agencies such as the FDA, European Medicines Agency
`and others. In nephrological practice, there was an expo-
`nential interest in IV iron coinciding with the introduc-
`tion of recombinant human erythropoietin in the late
`1980s, when it was realized that, firstly, there was a need
`for supplemental iron to support increased erythropoie-
`sis, 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 ad-
`ministering 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 oxyhydrox-
`ide, 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
`
`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). Im-
`feron was a high molecular weight (HMW) iron dextran
`preparation, and it is now clear that the incidence of se-
`vere immediate hypersensitivity reactions to HMW IV
`iron compounds (also including Dexferrum) was unac-
`ceptably high; both products have subsequently been
`withdrawn from the market.
` The cause of these anaphylactic-type reactions was be-
`lieved to be IgE-mediated, and classified as a type I hyper-
`sensitivity 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 bio-
`logical rationale for this assumption. Other mechanisms
`were also considered, such as immune complex forma-
`tion and complement activation, but no evidence was
`found to implicate these biological pathways [3] .
` The assumption that immediate hypersensitivity reac-
`tions were antibody-mediated persisted with other IV
`iron preparations, such as iron sucrose and iron sodium
`
` © 2016 S. Karger AG, Basel
`
`
`E-Mail karger@karger.com
` www.karger.com/ajn
`
` Prof. Iain C. Macdougall
` Consultant Nephrologist and Professor of Clinical Nephrology
` Renal Unit, King’s College Hospital
` London SE5 9RS (UK)
` E-Mail iain.macdougall   @   nhs.net
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1059 - Page 1
`
`

`

`gluconate, as well as more modern-day IV irons, feru-
`moxytol, ferric carboxymaltose and iron isomaltoside
`1000. The evidence for this, however, has been at best
`slender and at worst non-existent. For example, in con-
`trast to the known presence of dextran antibodies in man,
`there has never been any description of circulating anti-
`bodies against sucrose, and this seems biologically im-
`plausible.
` This has generated a fresh look at what might be caus-
`ing hypersensitivity reactions to IV iron. A new hypoth-
`esis states that some of the reactions may be related to the
`transient presence of free (‘labile’) iron in circulation,
`caused by iron leaching out of the iron-carbohydrate
`complex too rapidly to be mopped up by transferrin. This
`was proposed as a possible explanation for why less stable
`iron-carbohydrate complexes, such as iron sodium glu-
`conate, might cause immediate reactions, particularly if
`too high a dose was administered too rapidly. Indeed, the
`administration dose of iron sodium gluconate is lower
`than for all the other IV iron preparations on the market.
` However, more recently, a new concept of what might
`be causing many (if not the majority) of the hypersensi-
`tivity reactions to IV iron has arisen – the concept of com-
`plement activation-related pseudo-allergy (CARPA). As
`the name implies, complement plays a major role in the
`proposed mechanism of these reactions.
` Complement is an ancient part of the innate immune
`system performing a critical role in the defense against
`infection, clearance of apoptotic cells and immune com-
`plexes, and link with the adaptive immune system. How-
`ever, it may also mediate tissue injury through the gen-
`eration of the anaphylatoxins, C3a and C5a, and the mem-
`brane attack complex (C5b-9). It is now recognized that a
`number of modern-day therapeutic molecules may acti-
`vate complement via a non IgE-mediated mechanism
`with the C3a and C5a anaphylatoxins binding to mast
`cells (as well as basophil leucocytes and macrophages),
`triggering the release of a number of vasoactive mediators
`that cause the clinical features associated with hypersen-
`sitivity reactions. This is the process known as CARPA,
`and it is now apparent that this is the basis for hypersen-
`sitivity reactions to a number of drugs such as monoclonal
`antibodies (e.g., rituximab),
`liposome-encapsulated
`products (e.g., Doxil or AmBisome) and micellarized an-
`ti-cancer drugs (e.g., paclitaxel). For example, marked
`complement activation was seen in cancer patients in-
`fused with Doxil, and was correlated with the severity and
`frequency of hypersensitivity reactions. Furthermore, the
`rate of drug infusion was critical both in the risk of hyper-
`sensitivity reactions and complement activation [4] .
`
` Is it possible that IV iron infusions could be triggering
`the same biological process? 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. Nev-
`ertheless, 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 reac-
`tions seen with IV iron, using a number of methods, in-
`cluding complement activation by 5 different IV iron
`preparations in vitro using functional complement as-
`says, as well as studying complement activation in a group
`of hemodialysis patients receiving IV ferric carboxymalt-
`ose.
` In their in vitro assays, iron dextran and ferric car-
`boxymaltose (but not iron sucrose) caused complement
`activation. In an ex vivo assay, IV iron, particularly iron
`dextran, significantly increased complement activation in
`the blood of healthy volunteers and hemodialysis pa-
`tients. Their data, therefore, suggested that IV iron com-
`pounds may have complement-activating potential, and
`that hypersensitivity reactions to IV iron could potential-
`ly be CARPA-mediated.
` Clearly, extrapolating these laboratory results into the
`clinical setting is aspirational, and there was also no con-
`sistency regarding the results seen with the various IV
`iron preparations between the different experimental
`models. So, the models are not sensitive enough to be able
`to differentiate between the various IV iron preparations
`regarding their propensity to develop hypersensitivity re-
`actions.
` The design of the experiments by Hempel et al. [5] did
`not allow the authors to determine whether the comple-
`ment activation seen was due to the iron itself or the car-
`bohydrate shell. The expanding body of literature on
`nanoparticles [6] , however, suggests that it is more likely
`to be related to the carbohydrate shell. It would, therefore,
`be interesting for the authors to repeat their experiments
`with an isolated carbohydrate shell preparation (i.e., in
`the absence of iron) to advance this hypothesis.
` Furthermore, due to the standard-of-care in their re-
`nal unit, the only IV iron preparation tested in their di-
`alysis patients was ferric carboxymaltose. Due to the di-
`alysis procedure itself, there is already a background in-
`crease in complement activation. It would have been
`interesting to test other IV iron preparations in dialysis
`patients, as well as ferric carboxymaltose administered to
`a non-dialysis patient population, both using the licensed
`6-minute slow bolus injection of 500 mg, and perhaps
`also infusing the same dose over 1 h to look at comple-
`
` CARPA and Hypersensitivity to IV Iron
`
`Am J Nephrol 2017;45:60–62
`DOI: 10.1159/000451069
`
`61
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`ment activation in their model. These and other experi-
`ments could be considered in the future.
` Clearly, given the rarity of hypersensitivity reactions,
`the ability of IV iron to activate complement is not the
`only factor that drives hypersensitivity. Other factors that
`are known to play a part in the development of hypersen-
`sitivity include patient characteristics, such as genetics,
`underlying atopy, old age, rate of drug administration,
`auto-immune disease, mastocytosis and conditions of
`pre-existent complement activation.
` 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 impli-
`cated in the pathogenesis of IV iron hypersensitivity. It
`is time for nephrologists to bury the hatchet of IgE-in-
`
`duced 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. As discussed by Szebeni et al. [7] , this
`has implications for the management of iron reactions,
`focusing less on drugs such as steroids and anti-hista-
`mines, and more on low reactogenic administration
`protocols.
`
` Disclosure Statement
`
` Prof. Iain C. Macdougall has received consultancy fees, re-
`search support and lecture honoraria from a number of IV iron
`manufacturers, including AMAG, Vifor Pharma and Pharmacos-
`mos. Dr. Katherine Vernon has nothing to declare.
`
` References
`
` 1 Heath CW, Strauss MB, Castle WB: Quantita-
`tive aspects of iron deficiency in hypochromic
`anemia: (the parenteral administration of
`iron). J Clin Invest 1932; 11: 1293–1312.
` 2 Hamstra RD, Block MH, Schocket AL: Intra-
`venous iron dextran in clinical medicine.
`JAMA 1980; 243: 1726–1731.
` 3 Fleming LW, Stewart WK, Parratt D: Dextran
`antibodies, complement conversion and cir-
`culating immune complexes after intravenous
`iron dextran therapy in dialysed patients.
`Nephrol Dial Transplant 1992; 7: 35–39.
`
` 4 Chanan-Khan A, Szebeni J, Savay S, Liebes L,
`Rafique NM, Alving CR, Muggia FM: Com-
`plement activation following first exposure to
`pegylated liposomal doxorubicin (Doxil):
`possible role in hypersensitivity reactions.
`Ann Oncol 2003; 14: 1430–1437.
` 5 Hempel CJ, Poppelaarsa F, Gaya da Costa M,
`Franssen CF, de Vlaam TP, Daha MR, Berger
`SP, Seelen MA, Gaillard CA: Distinct in vitro
`complement activation by various intrave-
`nous iron preparations. Am J Nephrol 2016;
` 45: 49–59.
`
` 6 Szebeni J: Complement activation-related
`pseudoallergy: a stress reaction in blood trig-
`gered by nanomedicines and biologicals. Mol
`Immunol 2014; 61: 163–173.
` 7 Szebeni J, Fishbane S, Hedenus M, Howaldt S,
`Locatelli F, Patni S, Rampton D, Weiss G,
`Folkersen J: Hypersensitivity to intravenous
`iron: classification, terminology, mechanisms
`and management. Br J Pharmacol 2015; 172:
` 5025–5036.
`
`62
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`Am J Nephrol 2017;45:60–62
`DOI: 10.1159/000451069
`
` Macdougall/Vernon
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1059 - Page 3
`
`