Labile iron in parenteral iron formulations: a quantitative and comparative study
Sir,
The recent paper by Van Wyck et al. [1] examined in vitro transfer of iron from iron products to transferrin. The discussion appears to have missed several relevant points. First, the wide concentration range examined appears not to be clinically relevant for all products. As mentioned in the Methods section, ferric gluconate has a far lower peak concentration (1900 mcg/dl after 125 mg) than iron dextrans (30803396 mcg/dl after 100 mg) or iron sucrose (3000 mcg/dl after 100 mg). Similarly, the peak concentration for 62.5 mg of ferric gluconate is significantly lower than the peak concentration after 50 mg of iron dextran or iron sucrose, yet these lower doses when given once every week or two to haemodialysis patients, are most likely to match ongoing iron losses [2]. When these concentrations are analysed in the authors' Figure 1 (see attached Figure 1) it becomes apparent that one would predict little clinical difference between these products even though 25% more ferric gluconate is being administered. In figure 2 of their paper the authors excluded from their analysis the 865 mcg/dl results, yet this is very close to the peak concentration obtained after 62.5 mg of ferric gluconate (965 mcg/dl), and would likely be close to the peak serum concentration of 25 mg of iron sucrose or iron dextran.

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Fig. 1. Relationship between the change in Tf-bound iron (Delta Tf-Bound Iron) and concentration of added iron for each of four iron formulations. The two iron dextrans examined include iron dextran-I (INFeD®) and iron dextran-D (Dexferrum®). Each data point represents the mean of six replicate experiments. (1) reproduced with permission from the ERAEDTA
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Additionally, the discussion does not mention or discuss the wide variation in serum half-life of the iron products (
1 h for ferric gluconate,
6 h for iron sucrose and 4860 h for iron dextran). A long serum half-life would influence the time for continued iron donation, the peak drug concentration achieved, and have serious implications for administration of higher than approved doses of these products. In spite of the risk of anaphylaxis, iron dextran is still used in the US for total dose infusions (
1000 mg given over 23 h) for convenience reasons. Van Wyck et al. have stated that 500 mg of iron sucrose can be administered safely over 4 h. While others and I have found 250500 mg of ferric gluconate infused over 1 h well tolerated in haemodialysis patients, we recommended only the 250 mg dose [3]. Based on the present study results alone, perhaps higher dose infusions should not be recommended at all, or if necessary the agent with the shortest half-life and lowest peak concentration should be used.
On a more clinically pertinent note, the authors state that the Scandinavian Hemoglobin Normalization Trial results support the safety of iron sucrose because the high haemoglobin arm received
80 mg per week of i.v. iron and did not have a higher mortality than the lower haemoglobin group. An alternative interpretation is that the higher dose of iron sucrose led to unrecognized excess mortality that negated the benefits of anaemia correction. The authors also state that there has never been harm related to labile iron. However, there have never been studies designed to evaluate this. There are human data showing in vivo injury likely due to labile iron, including the association of accelerated atherosclerosis with i.v. iron dose [4], reduced forearm blood flow due to endothelial dysfunction after i.v. iron [5], and oxidation of lipids [6] and proteins [7] after standard doses of i.v. iron, and polymorphonuclear cell dysfunction after 300 mg of iron in peritoneal dialysis patients [8].
Perhaps the best conclusion that can be made from these in vitro results is that clinical studies and in vivo studies can better address the safety of i.v. iron.
Conflict of interest statement. I am a consultant to, and a member of the speakers Bureau of Abbott Renal Care, Amgen, and Watson Pharma.
Daniel W. Coyne
Associate Professor of Medicine,
Renal Diseases
Washington University School of Medicine
St Louis, MO
USA
Email: dcoyne{at}im.wustl.edu
References
- Van Wyck D, Anderson J, Johnson K. Labile iron in parenteral iron formulations: a quantitative and comparative study. Nephrol Dial Transplant 2004; 19: 561565[Abstract/Free Full Text]
- National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Anemia of Chronic Renal Disease, 2000. Am J Kidney Dis 2001; 37: S182S238[Medline]
- Folkert VW, Michael B, Agarwal R et al. Chronic use of sodium ferric gluconate complex in hemodialysis patients: safety of higher-dose (> or = 250 mg) administration. Am J Kidney Dis 2003; 41: 651657[CrossRef][ISI][Medline]
- Drueke T, Witko-Sarsat V, Massy Z et al. Iron therapy, advanced oxidation protein products, and carotid artery intima-media thickness in end-stage renal disease. Circulation 2002; 106: 22122217[Abstract/Free Full Text]
- Rooyakkers TM, Stroes ES, Kooistra MP et al. Ferric saccharate induces oxygen radical stress and endothelial dysfunction in vivo. Eur J Clin Invest 2002; 32 [Suppl 1]: 916[Medline]
- Roob JM, Khoschsorur G, Tiran A et al. Vitamin E attenuates oxidative stress induced by intravenous iron in patients on hemodialysis. J Am Soc Nephrol 2000; 11: 539549[Abstract/Free Full Text]
- Tovbin D, Mazor D, Vorobiov M, Chaimovitz C, Meyerstein N. Induction of protein oxidation by intravenous iron in hemodialysis patients: role of inflammation. Am J Kidney Dis 2002; 40: 10051012[CrossRef][ISI][Medline]
- Deicher R, Ziai F, Cohen G, Mullner M, Horl WH. High-dose parenteral iron sucrose depresses neutrophil intracellular killing capacity. Kidney Int 2003; 64: 728736[CrossRef][ISI][Medline]