Other studies have shown contrasting results regarding risk of infections associated with i.v. iron [31–33]. In another meta-analysis that included 103 RCT, Avni et al. [34▪] concluded that there was no increased risk of infections with the use of i.v. irons. Ishida et al. [35▪] published a retrospective observational cohort study using data from the US Renal Data System examining 22 820 adult Medicare beneficiaries receiving in-centre haemodialysis, who had been hospitalized for bacterial infection in 2010; 2463 (10.8%) had received i.v. iron in the 14 days preceding their hospitalization. Patients treated with i.v. iron did not have a higher 30-day mortality (odds ratio 0.86) or readmission rate for infection within 30 days of discharge, compared with patients not receiving i.v. iron.
Another concern is that i.v. iron might cause endothelial damage and promote atherosclerosis by generating oxidative stress [34▪] with potential consequences of long-term cardiovascular toxicity. Intravenous iron has been shown to induce oxidative stress  as labile iron is able to generate highly reactive hydroxyl radicals by reacting with hydrogen peroxide in the Fenton reaction . This is supported by a small study by Agarwal et al.  showing that iron sucrose induces oxidative stress associated with transient proteinuria and tubular damage in CKD patients. The direct toxic effect of iron on renal tubular cells appears greatest with iron sucrose and less with iron dextran and iron isomaltoside .
Intravenous irons differ in their capability to induce medically significant hypophosphatemia . This has been reported most often with ferric carboxymaltose  arguing against a class effect; the mechanism is substance specific via an increase in fibroblast growth factor 23 [43,44]. This area requires further study to clarify the significance of these variable effects of i.v. iron preparations.
Owing to the relatively high risk of anaphylactic reactions observed with the historic i.v. irons, there has been some reluctance in the use of i.v. irons, and recent studies have suggested continued risk. However, investigating the frequencies of ADRs, especially anaphylactic reactions, is difficult as clinicians define the term differently and it is well recognized that milder reactions, which are usually self-limiting, may be misclassified as anaphylactic reactions. Using fatalities or SMQ terms as outcome measures might help in this matter as well as the algorithms provided by the KDIGO expert group (Macdougall et al. ), Rampton et al. , and Szebeni et al. . Nonetheless, there is no doubt that the HMW iron dextrans are associated with increased risks, and therefore, these i.v. irons should be avoided [9–14].
The second and third-generation i.v. irons are considered equally efficacious in treating iron deficiency in equivalent doses but they differ in their stability , ability to induce oxidative stress [36–38], their effect on immune function [25,26], and dosing and administration options . Iron isomaltoside seems to have a lower frequency of serious and severe hypersensitivity reactions, when using a novel approach of prospectively reported standardized medical terms pooled from different randomized trials. This is a promising approach for future research into the risk of serious hypersensitivity. In conclusion, with the exception of HMW iron dextran, serious or life-threatening reactions are very rare with the use of i.v. irons, and they can be used safely, albeit not overlooking the need for caution, in the treatment of IDA, including that frequently seen in CKD.
Papers of particular interest, published within the annual period of review, have been highlighted as:
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15▪▪. Wang C, Graham DJ, Kane RC, et al. Comparative risk of anaphylactic reactions associated with intravenous iron
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The study compared the RR of anaphylaxis in 688 183 iron-naïve Medicare recipients treated with i.v. iron dextran, ferric gluconate, iron sucrose, or ferumoxytol between 2003 and 2013. Using questionable definitions of anaphylaxis, they found that this occurred at a rate of 68/100 000 doses for iron dextran and 24/100 000 with the other three irons.
16▪▪. DeLoughery TG, Auerbach M. Is low-molecular weight iron dextran really the most risky iron? Unconvincing data from an unconvincing study. Am J Hematol 2016; 91:451–452.
A critical review of the study performed by Wang et al. [15▪▪] that highlights several controversial methodological issues.
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21. Macdougall IC, Bircher AJ, Eckardt KU, et al. Iron management in chronic kidney disease
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23. CDER Medical Review of Ferric carboxymaltose, Application Number: 203565Orig1s000. 21-7-2013. [Accessed 6 June 2016].
24. Fishbane S. Review of issues relating to iron and infection. Am J Kidney Dis 1999; 34 (4 Suppl 2):S47–S52.
25. Fell LH, Zawada AM, Rogacev KS, et al. Distinct immunologic effects of different intravenous iron
preparations on monocytes. Nephrol Dial Transplant 2014; 29:809–822.
26. Fell LH, Seiler-Mussler S, Sellier AB, et al. Impact of individual intravenous iron
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28▪▪. Agarwal R, Kusek JW, Pappas MK. A randomized trial of intravenous and oral iron in chronic kidney disease
. Kidney Int 2015; 88:905–914.
An RCT conducted in 136 NDD-CKD patients with IDA treated with either oral iron or i.v. iron sucrose. The primary outcome measure was rate of loss of glomerular filtration rate over time. The study was halted early by the safety monitoring committee because SAEs (infections and major cardiovascular events) occurred more frequently with i.v. iron sucrose than with oral iron and because of futile results relating to the primary outcome.
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31. Anker SD, Comin CJ, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med 2009; 361:2436–2448.
32. Macdougall IC, Bock AH, Carrera F, et al. FIND-CKD: a randomized trial of intravenous ferric carboxymaltose versus oral iron in patients with chronic kidney disease
and iron deficiency anaemia
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33. Hoen B, Paul-Dauphin A, Kessler M. Intravenous iron
administration does not significantly increase the risk of bacteremia in chronic hemodialysis patients. Clin Nephrol 2002; 57:457–461.
34▪. Avni T, Bieber A, Grossman A, et al. The safety of intravenous iron
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A meta-analysis of 103 RCTs, including 10 390 patients, who received i.v. iron or a comparator, placebo, or no iron between 1965 and 2013. It concluded that there was no increased risk of infections or other SAE with the use of i.v. irons compared with these other therapies.
35▪. Ishida JH, Marafino BJ, McCulloch CE, et al. Receipt of intravenous iron
and clinical outcomes among hemodialysis patients hospitalized for infection. Clin J Am Soc Nephrol 2015; 10:1799–1805.
A large retrospective observational cohort study, including data from 22 820 patients, who were Medicare beneficiaries receiving in-centre haemodialysis and who had been hospitalized for bacterial infection in 2010; 2463 (10.8%) had received i.v. iron in the 14 days preceding their hospitalization. The 30-day mortality and readmission rates for infection were similar in those patients receiving i.v. iron compared with patients not receiving i.v. iron.
36. Zager RA, Johnson AC, Hanson SY, Wasse H. Parenteral iron formulations: a comparative toxicologic analysis and mechanisms of cell injury. Am J Kidney Dis 2002; 40:90–103.
37. Bresgen N, Eckl PM. Oxidative stress and the homeodynamics of iron metabolism. Biomolecules 2015; 5:808–847.
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39. Zager RA, Johnson AC, Hanson SY. Parenteral iron nephrotoxicity: potential mechanisms and consequences. Kidney Int 2004; 66:144–156.
40▪. Kalra PA, Bhandari S, Saxena S, et al. A randomized trial of iron isomaltoside 1000 versus oral iron in nondialysis-dependent chronic kidney disease
patients with anaemia. Nephrol Dial Transplant 2015; 31:646–655.
An RCT conducted in 351 iron-deficient NDD-CKD patients receiving either iron isomaltoside or oral iron. The short-term safety profile of iron isomaltoside was comparable with oral iron in patients with NDD-CKD and renal-related anaemia, but more patients stopped oral therapy because of side-effects.
41. Kalra PA, Bhandari S. Efficacy and safety of iron isomaltoside (Monofer) in the management of patients with iron deficiency anemia. Int J Nephrol Renovasc Dis 2016; 9:53–64.
42. Van Wyck DB, Mangione A, Morrison J, et al. Large-dose intravenous ferric carboxymaltose injection for iron deficiency anemia in heavy uterine bleeding: a randomized, controlled trial. Transfusion 2009; 49:2719–2728.
43. Wolf 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; 28:1793–1803.
44. Dahlerup J, Jacobsen BA, van der Woude J, et al. High-dose fast infusion of parenteral iron isomaltoside is efficacious in inflammatory bowel disease patients with iron deficiency anaemia
without profound changes in phosphate or fibroblast growth factor 23. Scand J Gastroenterol 2016; 21:1–7.
45▪. Bhandari S, Kalra PA, Kothari J, 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; 30:1577–1589.
An RCT conducted in 351 haemodialysis patients receiving either iron isomaltoside or iron sucrose. The short-term safety profile of both iron preparations was very similar, and irons were well tolerated.
46. Jahn MR, Andreasen HB, Futterer S, 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; 78:480–491.
47. Auerbach M, Macdougall IC. Safety of intravenous iron
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