Intravenous iron: do we adequately understand the short- and long-term risks in clinical practice?
Corresponding Author
Deborah Rund
Hebrew University-Hadassah Medical Organization, Ein Kerem, Jerusalem, Israel
Correspondence: Deborah Rund, Hebrew University-Hadassah Medical Organization, Ein Kerem, Jerusalem 91120, Israel.
E-mail: [email protected]
Search for more papers by this authorCorresponding Author
Deborah Rund
Hebrew University-Hadassah Medical Organization, Ein Kerem, Jerusalem, Israel
Correspondence: Deborah Rund, Hebrew University-Hadassah Medical Organization, Ein Kerem, Jerusalem 91120, Israel.
E-mail: [email protected]
Search for more papers by this authorSummary
Intravenous (IV) iron as a therapeutic agent is often administered but not always fully understood. The benefits of IV iron are well proven in many fields, particularly in nephrology. IV iron is beneficial not only for true iron deficiency but also for iron-restricted anaemia (functional iron deficiency). Yet, the literature on intravenous iron has many inconsistencies regarding its adverse effects. Over the last several years, newer forms of iron have been developed, leading to the more regular use of iron and in larger doses. This review will summarize some of the older and newer literature regarding the differences among iron products, including the mechanisms and frequency of their adverse events (AEs). The pathway and frequency of an underrecognized adverse event (hypophosphataemia) will be discussed. Recent insights on infection risk and iron handling by macrophages are examined. Potential but presently unproven risks of iron overload due to IV iron are discussed. The impact of these on the risk:benefit ratio and dosing of intravenous iron are considered in different clinical settings, including pregnancy and cancer. IV iron is an essential component of the therapy of anaemia and understanding these issues will enable more informed treatment decisions and knowledgeable use of these drugs.
Conflicts of interest
None.
References
- 1Lopez A, Cacoub P, Macdougall IC, Peyrin-Biroulet L. Iron deficiency anaemia. Lancet. 2016; 387(10021): 907–16.
- 2Goetsch AT, Moore CV, Minnich V. Observations on the effect of massive doses of iron given intravenously to patients with hypochromic anemia. Blood. 1946; 1: 129–42.
- 3Danielson BG. Structure, chemistry, and pharmacokinetics of intravenous iron agents. J Am Soc Nephrol. 2004; 15(Suppl 2): S93–S98.
- 4Fletes R, Lazarus JM, Gage J, Chertow GM. Suspected iron dextran-related adverse drug events in hemodialysis patients. Am J Kidney Dis. 2001; 37(4): 743–9.
- 5Chertow GM, Mason PD, Vaage-Nilsen O, Ahlmén J. Update on adverse drug events associated with parenteral iron. Nephrol Dial Transplant. 2006; 21(2): 378–82.
- 6Nikravesh N, Borchard G, Hofmann H, Philipp E, Flühmann B, Wick P. Factors influencing safety and efficacy of intravenous iron-carbohydrate nanomedicines: from production to clinical practice. Nanomedicine. 2020; 26:102178. https://doi.org/10.1016/j.nano.2020.102178.
- 7Fütterer S, Andrusenko I, Kolb U, Hofmeister W, Langguth P. Structural characterization of iron oxide/hydroxide nanoparticles in nine different parenteral drugs for the treatment of iron deficiency anaemia by electron diffraction (ED) and X-ray powder diffraction (XRPD). J Pharm Biomed Anal. 2013; 86: 151–60.
- 8Neiser S, Rentsch D, Dippon U, Kappler A, Weidler PG, Göttlicher J, et al. Physico-chemical properties of the new generation IV iron preparations ferumoxytol, iron isomaltoside 1000 and ferric carboxymaltose. Biometals. 2015; 28(4): 615–35.
- 9Jahn MR, Andreasen HB, Fütterer S, Nawroth T, Schünemann V, Kolb U, et al. A comparative study of the physicochemical properties of iron isomaltoside 1000 (Monofer), a new intravenous iron preparation and its clinical implications. Eur J Pharm Biopharm. 2011; 78(3): 480–91. https://doi.org/10.1016/j.ejpb.2011.03.016.
- 10 EMA-CHMP. New recommendations to manage risk of allergic reactions with intravenous iron-containing medicines. 2013; Vol. EMA/579491/2013, pp 1–3: http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/IV_irn_31/WC500151308
- 11Macdougall IC, Comin-Colet J, Breymann C, Spahn DR, Koutroubakis IE. Iron sucrose: a wealth of experience in treating iron deficiency. Adv Ther. 2020; 37(5): 1960–2002. https://doi.org/10.1007/s12325-020-01323-z. Epub 2020 Apr 15.
- 12Camaschella C, Nai A, Silvestri L. Iron metabolism and iron disorders revisited in the hepcidin era. Haematologica. 2020; 105(2): 260–72. https://doi.org/10.3324/haematol.2019.232124.
- 13Macdougall IC, Hutton RD, Cavill I, Coles GA, Williams JD. Poor response to treatment of renal anaemia with erythropoietin corrected by iron given intravenously. BMJ. 1989; 299(6692): 157–8. https://doi.org/10.1136/bmj.299.6692.157.
- 14Achebe MM, Gafter-Gvili A. How I treat anemia in pregnancy: iron, cobalamin, and folate. Blood. 2017; 129(8): 940–9. https://doi.org/10.1182/blood-2016-08-672246.
- 15Nielsen OH, Ainsworth M, Coskun M, Weiss G. Management of iron-deficiency anemia in inflammatory bowel disease: a systematic review. Medicine (Baltimore). 2015; 94(23): e963. https://doi.org/10.1097/MD.0000000000000963.
- 16Gowanlock Z, Lezhanska A, Conroy M, Crowther M, Tiboni M, Mbuagbaw L, et al. Iron deficiency following bariatric surgery: a retrospective cohort study. Blood Adv. 2020; 4(15): 3639–47. https://doi.org/10.1182/bloodadvances.2020001880.
- 17Moretti D, Goede JS, Zeder C, Jiskra M, Chatzinakou V, Tjalsma H, et al. Oral iron supplements increase hepcidin and decrease iron absorption from daily or twice-daily doses in iron-depleted young women. Blood. 2015; 126(17): 1981–9. https://doi.org/10.1182/blood-2015-05-642223.
- 18Stoffel NU, Cercamondi CI, Brittenham G, Zeder C, Geurts-Moespot AJ, Swinkels DW, et al. Iron absorption from oral iron supplements given on consecutive versus alternate days and as single morning doses versus twice-daily split dosing in iron-depleted women: two open-label, randomised controlled trials. Lancet Haematol. 2017; 4(11): e524–e533. https://doi.org/10.1016/S2352-3026(17)30182-5.
- 19Peeling P, Dawson B, Goodman C, Landers G, Wiegerinck ET, Swinkels DW, et al. Effects of exercise on hepcidin response and iron metabolism during recovery. Int J Sport Nutr Exerc Metab. 2009; 19(6): 583–97. https://doi.org/10.1123/ijsnem.19.6.583.
- 20McCormick R, Moretti D, McKay AKA, Laarakkers CM, Vanswelm R, Trinder D, et al. The impact of morning versus afternoon exercise on iron absorption in athletes. Med Sci Sports Exerc. 2019; 51(10): 2147–55. https://doi.org/10.1249/MSS.0000000000002026.
- 21Adkinson NF, Strauss WE, Macdougall IC, Bernard KE, Auerbach M, Kaper RF, et al. Comparative safety of intravenous ferumoxytol versus ferric carboxymaltose in iron deficiency anemia: a randomized trial. Am J Hematol. 2018; 93(5): 683–90.
- 22Avni T, Bieber A, Grossman A, Green H, Leibovici L, Gafter-Gvili A. The safety of intravenous iron preparations: systematic review and meta-analysis. Mayo Clin Proc. 2015; 90(1): 12–23. https://doi.org/10.1016/j.mayocp.2014.10.007.
- 23Hazell L, Shakir SA. Under-reporting of adverse drug reactions: a systematic review. Drug Saf. 2006; 29(5): 385–96. https://doi.org/10.2165/00002018-200629050-00003.
- 24Wysowski DK, Swartz L, Borders-Hemphill BV, Goulding MR, Dormitzer C. Use of parenteral iron products and serious anaphylactic-type reactions. Am J Hematol. 2010; 85(9): 650–4. https://doi.org/10.1002/ajh.21794.
- 25Rampton D, Folkersen J, Fishbane S, Hedenus M, Howaldt S, Locatelli F, et al. Hypersensitivity reactions to intravenous iron: guidance for risk minimization and management. Haematologica. 2014; 99(11): 1671–6. https://doi.org/10.3324/haematol.2014.111492.
- 26 Joint Task Force on Practice Parameters; American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol. 2010; 105(4): 259–73. https://doi.org/10.1016/j.anai.2010.08.002
- 27Szebeni J, Fishbane S, Hedenus M, Howaldt S, Locatelli F, Patni S, et al. Hypersensitivity to intravenous iron: classification, terminology, mechanisms and management. Br J Pharmacol. 2015; 172(21): 5025–36. https://doi.org/10.1111/bph.13268.
- 28Novey HS, Pahl M, Haydik I, Vaziri ND. Immunologic studies of anaphylaxis to iron dextran in patients on renal dialysis. Ann Allergy. 1994; 72(3): 224–8.
- 29Neiser S, Koskenkorva TS, Schwarz K, Wilhelm M, Burckhardt S. Assessment of dextran antigenicity of intravenous iron preparations with Enzyme-Linked Immunosorbent Assay (ELISA). Int J Mol Sci. 2016; 17(7): 1185. https://doi.org/10.3390/ijms17071185.
- 30DeLoughery TG, Auerbach M. Is low-molecular weight iron dextran really the most risky iron? Unconvincing data from an unconvincing study. Am J Hematol. 2016; 91(5): 451–2. https://doi.org/10.1002/ajh.24326.
- 31Santosh S, Podaralla P, Miller B. Anaphylaxis with elevated serum tryptase after administration of intravenous ferumoxytol. NDT Plus. 2010; 3(4): 341–2. https://doi.org/10.1093/ndtplus/sfq084.
- 32Hempel JC, Poppelaars F, Gaya da Costa M, Franssen CF, de Vlaam TP, Daha MR, et al. Distinct in vitro complement activation by various intravenous iron preparations. Am J Nephrol. 2017; 45(1): 49–59. https://doi.org/10.1159/000451060.
- 33Verhoef JJF, de Groot AM, van Moorsel M, Ritsema J, Beztsinna N, Maas C, et al. Iron nanomedicines induce Toll-like receptor activation, cytokine production and complement activation. Biomaterials. 2017; 119: 68–77. https://doi.org/10.1016/j.biomaterials.2016.11.025.
- 34Xu Y, Guo N, Dou D, Ran X, Liu C. Metabolomics analysis of anaphylactoid reaction reveals its mechanism in a rat model. Asian Pac J Allergy Immunol. 2017; 35(4): 224–32. https://doi.org/10.12932/AP0845.
- 35Redwood AJ, Pavlos RK, White KD, Phillips EJ. HLAs: Key regulators of T-cell-mediated drug hypersensitivity. HLA. 2018; 91(1): 3–16. https://doi.org/10.1111/tan.13183.
- 36Potaczek DP, Harb H, Michel S, Alhamwe BA, Renz H, Tost J. Epigenetics and allergy: from basic mechanisms to clinical applications. Epigenomics. 2017; 9(4): 539–71. https://doi.org/10.2217/epi-2016-0162.
- 37Chertow GM, Mason PD, Vaage-Nilsen O, Ahlmén J. On the relative safety of parenteral iron formulations. Nephrol Dial Transplant. 2004; 19(6): 1571–5. https://doi.org/10.1093/ndt/gfh185.
- 38Okam MM, Mandell E, Hevelone N, Wentz R, Ross A, Abel GA. Comparative rates of adverse events with different formulations of intravenous iron. Am J Hematol. 2012; 87(11): E123–E124. https://doi.org/10.1002/ajh.23322.
- 39Wang C, Graham DJ, Kane RC, Xie D, Wernecke M, Levenson M, et al. Comparative risk of anaphylactic reactions associated with intravenous iron products. JAMA. 2015; 314(19): 2062–8. https://doi.org/10.1001/jama.2015.15572.
- 40Bhandari S, Kalra PA, Kothari J, Ambühl PM, Christensen JH, Essaian AM, et al. A randomized, open-label trial of iron isomaltoside 1000 (Monofer®) compared with iron sucrose (Venofer®) as maintenance therapy in haemodialysis patients. Nephrol Dial Transplant. 2015; 30(9): 1577–89. https://doi.org/10.1093/ndt/gfv096.
- 41Derman R, Roman E, Modiano MR, Achebe MM, Thomsen LL, Auerbach M. A randomized trial of iron isomaltoside versus iron sucrose in patients with iron deficiency anemia. Am J Hematol. 2017; 92(3): 286–91. https://doi.org/10.1002/ajh.24633.
- 42Louzada ML, Hsia CC, Al-Ani F, Ralley F, Xenocostas A, Martin J, et al. Randomized double-blind safety comparison of intravenous iron dextran versus iron sucrose in an adult non-hemodialysis outpatient population: a feasibility study. BMC Hematol. 2016; 16: 7. https://doi.org/10.1186/s12878-016-0046-8.
- 43Sivakumar C, Jubb VM, Lamplugh A, Bhandari S. Safety of intravenous iron - cosmofer and monofer therapy in peritoneal dialysis and non-dialysis-dependent chronic kidney disease patients. Perit Dial Int. 2019; 39(2): 192–5. https://doi.org/10.3747/pdi.2018.00125.
- 44Ehlken B, Nathell L, Gohlke A, Bocuk D, Toussi M, Wohlfeil S. Evaluation of the reported rates of severe hypersensitivity reactions associated with Ferric Carboxymaltose and Iron (III) Isomaltoside 1000 in Europe Based on Data from EudraVigilance and VigiBase™ between 2014 and 2017. Drug Saf. 2019; 42(3): 463–71. https://doi.org/10.1007/s40264-018-0769-5.
- 45Litton E, Xiao J, Ho KM. Safety and efficacy of intravenous iron therapy in reducing requirement for allogeneic blood transfusion: systematic review and meta-analysis of randomised clinical trials. BMJ. 2013; 347: f4822. https://doi.org/10.1136/bmj.f4822.
- 46Clevenger B, Gurusamy K, Klein AA, Murphy GJ, Anker SD, Richards T. Systematic review and meta-analysis of iron therapy in anaemic adults without chronic kidney disease: updated and abridged Cochrane review. Eur J Heart Fail. 2016; 18(7): 774–85. https://doi.org/10.1002/ejhf.514.
- 47Lim W, Afif W, Knowles S, Lim G, Lin Y, Mothersill C, et al. Canadian expert consensus: management of hypersensitivity reactions to intravenous iron in adults. Vox Sang. 2019; 114(4): 363–73. https://doi.org/10.1111/vox.12773.
- 48Okada M, Imamura K, Iida M, Fuchigami T, Omae T. Hypophosphatemia induced by intravenous administration of Saccharated iron oxide. Klin Wochenschr. 1983; 61(2): 99–102. https://doi.org/10.1007/BF01496662.
- 49Sato K, Shiraki M. Saccharated ferric oxide-induced osteomalacia in Japan: iron-induced osteopathy due to nephropathy. Endocr J. 1998; 45(4): 431–9. https://doi.org/10.1507/endocrj.45.431.
- 50Schouten BJ, Hunt PJ, Livesey JH, Frampton CM, Soule SG. FGF23 elevation and hypophosphatemia after intravenous iron polymaltose: a prospective study. J Clin Endocrinol Metab. 2009; 94(7): 2332–7. https://doi.org/10.1210/jc.2008-2396.
- 51van Vuren AJ, Gaillard CAJM, Eisenga MF, van Wijk R, van Beers EJ. The EPO-FGF23 signaling pathway in erythroid progenitor cells: opening a new area of research. Front Physiol. 2019; 10: 304. https://doi.org/10.3389/fphys.2019.00304.
- 52Shimada T, Muto T, Urakawa I, Yoneya T, Yamazaki Y, Okawa K, et al. Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo. Endocrinology. 2002; 143(8): 3179–82. https://doi.org/10.1210/endo.143.8.8795.
- 53Wheeler JA, Clinkenbeard EL. Regulation of Fibroblast Growth Factor 23 by Iron, EPO, and HIF. Curr Mol Biol Rep. 2019; 5(1): 8–17. https://doi.org/10.1007/s40610-019-0110-9.
- 54Wolf M, Koch TA, Bregman DB. Effects of iron deficiency anemia and its treatment on fibroblast growth factor 23 and phosphate homeostasis in women. J Bone Miner Res. 2013; 28(8): 1793–803. https://doi.org/10.1002/jbmr.1923.
- 55Wolf M, Chertow GM, Macdougall IC, Kaper R, Krop J, Strauss W. Randomized trial of intravenous iron-induced hypophosphatemia. JCI Insight. 2018; 3(23):e124486. https://doi.org/10.1172/jci.insight.124486.
- 56Roberts MA, Huang L, Lee D, MacGinley R, Troster SM, Kent AB, et al. Effects of intravenous iron on fibroblast growth factor 23 (FGF23) in haemodialysis patients: a randomized controlled trial. BMC Nephrol. 2016; 17(1): 177. https://doi.org/10.1186/s12882-016-0391-7.
- 57Edmonston D, Wolf M. FGF23 at the crossroads of phosphate, iron economy and erythropoiesis. Nat Rev Nephrol. 2020; 16(1): 7–19. https://doi.org/10.1038/s41581-019-0189-5.
- 58Glaspy JA, Lim-Watson MZ, Libre MA, Karkare SS, Hadker N, Bajic-Lucas A, et al. Hypophosphatemia associated with intravenous iron therapies for iron deficiency anemia: a systematic literature review. Ther Clin Risk Manag. 2020; 16: 245–59. https://doi.org/10.2147/TCRM.S243462.
- 59Cassat JE, Skaar EP. Iron in infection and immunity. Cell Host Microbe. 2013; 13(5): 509–19. https://doi.org/10.1016/j.chom.2013.04.010.
- 60Philpott CC, Ryu MS, Frey A, Patel S. Cytosolic iron chaperones: Proteins delivering iron cofactors in the cytosol of mammalian cells. J Biol Chem. 2017; 292(31): 12764–71. https://doi.org/10.1074/jbc.R117.791962.
- 61Ganz T, Aronoff GR, Gaillard CAJM, Goodnough LT, Macdougall IC, Mayer G, et al. Iron administration, infection, and anemia management in CKD: untangling the effects of intravenous iron therapy on immunity and infection risk. Kidney Med. 2020; 2(3): 341–53. https://doi.org/10.1016/j.xkme.2020.01.006.
- 62Scheiber-Mojdehkar B, Lutzky B, Schaufler R, Sturm B, Goldenberg H. Non-transferrin-bound iron in the serum of hemodialysis patients who receive ferric saccharate: no correlation to peroxide generation. J Am Soc Nephrol. 2004; 15(6): 1648–55. https://doi.org/10.1097/01.asn.0000130149.18412.56.
- 63Stefanova D, Raychev A, Arezes J, Ruchala P, Gabayan V, Skurnik M, et al. Endogenous hepcidin and its agonist mediate resistance to selected infections by clearing non-transferrin-bound iron. Blood. 2017; 130(3): 245–57. https://doi.org/10.1182/blood-2017-03-772715.
- 64Pasricha SR, Armitage AE, Prentice AM, Drakesmith H. Reducing anaemia in low income countries: control of infection is essential. BMJ. 2018; 362: k3165. https://doi.org/10.1136/bmj.k3165.
- 65Jaeggi T, Kortman GA, Moretti D, Chassard C, Holding P, Dostal A, et al. Iron fortification adversely affects the gut microbiome, increases pathogen abundance and induces intestinal inflammation in Kenyan infants. Gut. 2015; 64(5): 731–42. https://doi.org/10.1136/gutjnl-2014-307720.
- 66Khosravi A, Mazmanian SK. Disruption of the gut microbiome as a risk factor for microbial infections. Curr Opin Microbiol. 2013; 16(2): 221–7. https://doi.org/10.1016/j.mib.2013.03.009.
- 67Galloway-Peña JR, Smith DP, Sahasrabhojane P, Wadsworth WD, Fellman BM, Ajami NJ, et al. Characterization of oral and gut microbiome temporal variability in hospitalized cancer patients. Genome Med. 2017; 9(1): 21. https://doi.org/10.1186/s13073-017-0409-1.
- 68La Carpia F, Wojczyk BS, Annavajhala MK, Rebbaa A, Culp-Hill R, D'Alessandro A, et al. Transfusional iron overload and intravenous iron infusions modify the mouse gut microbiota similarly to dietary iron. NPJ Biofilms Microbiomes. 2019; 5: 26. https://doi.org/10.1038/s41522-019-0097-2.
- 69Lee T, Clavel T, Smirnov K, Schmidt A, Lagkouvardos I, Walker A, et al. Oral versus intravenous iron replacement therapy distinctly alters the gut microbiota and metabolome in patients with IBD. Gut. 2017; 66(5): 863–71. https://doi.org/10.1136/gutjnl-2015-309940.
- 70Agarwal R, Kusek JW, Pappas MK. A randomized trial of intravenous and oral iron in chronic kidney disease. Kidney Int. 2015; 88(4): 905–14. https://doi.org/10.1038/ki.2015.163.
- 71Yen CL, Lin YS, Lu YA, Lee HF, Lee CC, Tung YC, et al. Intravenous iron supplementation does not increase infectious disease risk in hemodialysis patients: a nationwide cohort-based case-crossover study. BMC Nephrol. 2019; 20(1): 327. https://doi.org/10.1186/s12882-019-1495-7.
- 72Macdougall IC, White C, Anker SD, Bhandari S, Farrington K, Kalra PA, et al.; PIVOTAL Investigators and Committees. Intravenous iron in patients undergoing maintenance hemodialysis. N Engl J Med. 2019; 380(5): 447–58. https://doi.org/10.1056/NEJMoa1810742. Erratum. In: N Engl J Med, 2019 Jan 14.
- 73Shah A, Palmer AJR, Fisher SA, Rahman SM, Brunskill S, Doree C, et al. What is the effect of perioperative intravenous iron therapy in patients undergoing non-elective surgery? A systematic review with meta-analysis and trial sequential analysis. Perioper Med (Lond). 2018; 7: 30. https://doi.org/10.1186/s13741-018-0109-4.
- 74Shin HW, Park JJ, Kim HJ, You HS, Choi SU, Lee MJ. Efficacy of perioperative intravenous iron therapy for transfusion in orthopedic surgery: a systematic review and meta-analysis. PLoS One. 2019; 14(5):e0215427. https://doi.org/10.1371/journal.pone.0215427.
- 75Shah A, Fisher SA, Wong H, Roy NB, McKechnie S, Doree C, et al. Safety and efficacy of iron therapy on reducing red blood cell transfusion requirements and treating anaemia in critically ill adults: a systematic review with meta-analysis and trial sequential analysis. J Crit Care. 2019; 49: 162–71.
- 76Shah A, Sugavanam A, Reid J, Palmer AJ, Dickson E, Brunskill S, et al. Risk of infection associated with intravenous iron preparations: protocol for updating a systematic review. BMJ Open. 2019; 9(6):e024618. https://doi.org/10.1136/bmjopen-2018-024618.
- 77Del Vecchio L, Longhi S, Locatelli F. Safety concerns about intravenous iron therapy in patients with chronic kidney disease. Clin Kidney J. 2016; 9(2): 260–7. https://doi.org/10.1093/ckj/sfv142.
- 78Bailie GR, Larkina M, Goodkin DA, Li Y, Pisoni RL, Bieber B, et al. Data from the Dialysis Outcomes and Practice Patterns Study validate an association between high intravenous iron doses and mortality. Kidney Int. 2015; 87(1): 162–8. https://doi.org/10.1038/ki.2014.275.
- 79Sarkar J, Potdar AA, Saidel GM. Whole-body iron transport and metabolism: mechanistic, multi-scale model to improve treatment of anemia in chronic kidney disease. PLoS Comput Biol. 2018; 14(4):e1006060. https://doi.org/10.1371/journal.pcbi.1006060. Published 2018 Apr 16.
- 80Hershko C, Graham G, Bates GW, Rachmilewitz EA. Non-specific serum iron in thalassaemia: an abnormal serum iron fraction of potential toxicity. Br J Haematol. 1978; 40(2): 255–63.
- 81Hershko C. Iron loading and its clinical implications. Am J Hematol. 2007; 82(12 Suppl): 1147–8. https://doi.org/10.1002/ajh.21070.
- 82Brissot P, Ropert M, Le Lan C, Loréal O. Non-transferrin bound iron: a key role in iron overload and iron toxicity. Biochim Biophys Acta. 2012; 1820(3): 403–10. https://doi.org/10.1016/j.bbagen.2011.07.014.
- 83Détivaud L, Island ML, Jouanolle AM, Ropert M, Bardou-Jacquet E, Le Lan C, et al. Ferroportin diseases: functional studies, a link between genetic and clinical phenotype. Hum Mutat. 2013; 34(11): 1529–36. https://doi.org/10.1002/humu.22396.
- 84Ganz T, Nemeth E. Hepcidin and iron homeostasis. Biochim Biophys Acta. 2012; 1823(9): 1434–43. https://doi.org/10.1016/j.bbamcr.2012.01.014.
- 85Nemeth E. Anti-hepcidin therapy for iron-restricted anemias. Blood. 2013; 122(17): 2929–31. https://doi.org/10.1182/blood-2013-08-522466.
- 86Goodnough LT, Nemeth E, Ganz T. Detection, evaluation, and management of iron-restricted erythropoiesis. Blood. 2010; 116(23): 4754–61. https://doi.org/10.1182/blood-2010-05-286260.
- 87Thomas DW, Hinchliffe RF, Briggs C, Macdougall IC, Littlewood T, Cavill I,; et al. Guideline for the laboratory diagnosis of functional iron deficiency. Br J Haematol. 2013; 161(5): 639–48. https://doi.org/10.1111/bjh.12311.
- 88Wood JK, Milner PF, Pathak UN. The metabolism of iron-dextran given as a total-dose infusion to iron deficient Jamaican subjects. Br J Haematol. 1968; 14(2): 119–29. https://doi.org/10.1111/j.1365-2141.1968.tb01481.x.
- 89Winn NC, Volk KM, Hasty AH. Regulation of tissue iron homeostasis: the macrophage "ferrostat". JCI Insight. 2020; 5(2):e132964.
- 90Soares MP, Hamza I. Macrophages and iron metabolism. Immunity. 2016; 44(3): 492–504. https://doi.org/10.1016/j.immuni.2016.02.016.
- 91Chen Y, Xiang J, Qian F, Diwakar BT, Ruan B, Hao S, et al. Epo receptor signaling in macrophages alters the splenic niche to promote erythroid differentiation. Blood. 2020; 136(2): 235–46. https://doi.org/10.1182/blood.2019003480.
- 92Rostoker G, Vaziri ND, Fishbane S. Iatrogenic iron overload in dialysis patients at the beginning of the 21st century. Drugs. 2016; 76(7): 741–57. https://doi.org/10.1007/s40265-016-0569-0.
- 93Casu C, Nemeth E, Rivella S. Hepcidin agonists as therapeutic tools. Blood. 2018; 131(16): 1790–4. https://doi.org/10.1182/blood-2017-11-737411.
- 94Cooke KS, Hinkle B, Salimi-Moosavi H, Foltz I, King C, Rathanaswami P, et al. A fully human anti-hepcidin antibody modulates iron metabolism in both mice and nonhuman primates. Blood. 2013; 122(17): 3054–61.
- 95Kim A, Fung E, Parikh SG, Gabayan V, Nemeth E, Ganz T. Isocitrate treatment of acute anemia of inflammation in a mouse model. Blood Cells Mol Dis. 2016; 56(1): 31–6. https://doi.org/10.1016/j.bcmd.2015.09.007.
- 96Leitch HA, Gattermann N. Hematologic improvement with iron chelation therapy in myelodysplastic syndromes: clinical data, potential mechanisms, and outstanding questions. Crit Rev Oncol Hematol. 2019; 141: 54–72. https://doi.org/10.1016/j.critrevonc.2019.06.002.
- 97Macdougall IC, White C, Anker SD, Bhandari S, Farrington K, Kalra PA, et al.; on behalf of the PIVOTAL Trial investigators. Randomized Trial Comparing Proactive, High-Dose versus Reactive, Low-Dose Intravenous Iron Supplementation in Hemodialysis (PIVOTAL): Study Design and Baseline Data. Am J Nephrol. 2018; 48(4): 260–8. https://doi.org/10.1159/000493551.
- 98Kuo KL, Hung SC, Tseng WC, Tsai MT, Liu JS, Lin MH, et al.; Taiwan Society of Nephrology Renal Registry Data System. Association of anemia and iron parameters with mortality among patients undergoing prevalent hemodialysis in Taiwan: the AIM - HD study. J Am Heart Assoc. 2018; 7(15):e009206. https://doi.org/10.1161/JAHA.118.009206.
- 99Beshara S, Sörensen J, Lubberink M, Tolmachev V, Långström B, Antoni G, et al. Pharmacokinetics and red cell utilization of 52Fe/59Fe-labelled iron polymaltose in anaemic patients using positron emission tomography. Br J Haematol. 2003; 120(5): 853–9. https://doi.org/10.1046/j.1365-2141.2003.03590.x.
- 100Auerbach M, Chaudhry M, Goldman H, Ballard H. Value of methylprednisolone in prevention of the arthralgia-myalgia syndrome associated with the total dose infusion of iron dextran: a double blind randomized trial. J Lab Clin Med. 1998; 131(3): 257–60. https://doi.org/10.1016/s0022-2143(98)90098-1.
- 101Auerbach M, Pappadakis JA, Bahrain H, Auerbach SA, Ballard H, Dahl NV. Safety and efficacy of rapidly administered (one hour) one gram of low molecular weight iron dextran (INFeD) for the treatment of iron deficient anemia. Am J Hematol. 2011; 86(10): 860–2. https://doi.org/10.1002/ajh.22153.
- 102Auerbach M, Strauss W, Auerbach S, Rineer S, Bahrain H. Safety and efficacy of total dose infusion of 1020 mg of ferumoxytol administered over 15 min. Am J Hematol. 2013; 88(11): 944–7. https://doi.org/10.1002/ajh.23534.
- 103Auerbach M, Macdougall I. The available intravenous iron formulations: history, efficacy, and toxicology. Hemodial Int. 2017; 21(Suppl 1): S83–S92. https://doi.org/10.1111/hdi.12560.
- 104Wong L, Smith S, Gilstrop M, Derman R, Auerbach S, London N, et al. Safety and efficacy of rapid (1,000 mg in 1 hr) intravenous iron dextran for treatment of maternal iron deficient anemia of pregnancy. Am J Hematol. 2016; 91(6): 590–3. https://doi.org/10.1002/ajh.24361.
- 105Fisher AL, Nemeth E. Iron homeostasis during pregnancy. Am J Clin Nutr. 2017; 106(Suppl 6): 1567S–1574S. https://doi.org/10.3945/ajcn.117.155812.
- 106Auerbach M. Commentary: Iron deficiency of pregnancy - a new approach involving intravenous iron. Reprod Health. 2018; 15(Suppl 1): 96. https://doi.org/10.1186/s12978-018-0536-1.
- 107Pavord S, Daru J, Prasannan N, Robinson S, Stanworth S, Girling J, et al. UK guidelines on the management of iron deficiency in pregnancy. Br J Haematol. 2020; 188(6): 819–30. https://doi.org/10.1111/bjh.16221.
- 108Govindappagari S, Burwick RM. Treatment of iron deficiency anemia in pregnancy with intravenous versus oral iron: systematic review and meta-analysis. Am J Perinatol. 2019; 36(4): 366–76. https://doi.org/10.1055/s-0038-1668555.
- 109Qassim A, Grivell RM, Henry A, Kidson-Gerber G, Shand A, Grzeskowiak LE. Intravenous or oral iron for treating iron deficiency anaemia during pregnancy: systematic review and meta-analysis. Med J Aust. 2019; 211(8): 367–73. https://doi.org/10.5694/mja2.50308.
- 110Sangkhae V, Fisher AL, Wong S, Koenig MD, Tussing-Humphreys L, Chu A, et al. Effects of maternal iron status on placental and fetal iron homeostasis. J Clin Invest. 2020; 130(2): 625–40. https://doi.org/10.1172/JCI127341.
- 111Rodgers GM 3rd, Becker PS, Blinder M, Cella D, Chanan-Khan A, Cleeland C, et al. Cancer- and chemotherapy-induced anemia. J Natl Compr Cancer Netw. 2012; 10(5): 628–53. https://doi.org/10.6004/jnccn.2012.0064
- 112Katodritou E, Zervas K, Terpos E, Brugnara C. Use of erythropoiesis stimulating agents and intravenous iron for cancer and treatment-related anaemia: the need for predictors and indicators of effectiveness has not abated. Br J Haematol. 2008; 142(1): 3–10. https://doi.org/10.1111/j.1365-2141.2008.07163.x.
- 113Steinmetz HT. The role of intravenous iron in the treatment of anemia in cancer patients. Ther Adv Hematol. 2012; 3(3): 177–91. https://doi.org/10.1177/2040620712440071.
- 114Bennett CL, Silver SM, Djulbegovic B, Samaras AT, Blau CA, Gleason KJ, et al. Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA. 2008; 299(8): 914–24. https://doi.org/10.1001/jama.299.8.914.
- 115Glaspy J, Crawford J, Vansteenkiste J, Henry D, Rao S, Bowers P, et al. Erythropoiesis-stimulating agents in oncology: a study-level meta-analysis of survival and other safety outcomes. Br J Cancer. 2010; 102(2): 301–15. https://doi.org/10.1038/sj.bjc.6605498.
- 116Bohlius J, Bohlke K, Castelli R, Djulbegovic B, Lustberg MB, Martino M, et al. Management of cancer-associated anemia with erythropoiesis-stimulating agents: ASCO/ASH clinical practice guideline update. Blood Adv. 2019; 3(8): 1197–210. https://doi.org/10.1182/bloodadvances.2018030387.
- 117Troadec MB, Loréal O, Brissot P. The interaction of iron and the genome: for better and for worse. Mutat Res. 2017; 774: 25–32. https://doi.org/10.1016/j.mrrev.2017.09.002.
- 118Kew MC. Hepatic iron overload and hepatocellular carcinoma. Cancer Lett. 2009; 286(1): 38–43. https://doi.org/10.1016/j.canlet.2008.11.001.
- 119Pfeifhofer-Obermair C, Tymoszuk P, Petzer V, Weiss G, Nairz M. Iron in the tumor microenvironment-connecting the dots. Front Oncol. 2018; 8:549. https://doi.org/10.3389/fonc.2018.00549.