Division of Nephrology, Henry Ford Hospital, Detroit, Michigan, USA
Sir,
Soluble iron salts are considered too toxic for parenteral administration since iron is a transition element capable of generating free radicals. Of the two common valences, Fe(II) is the most reactive form leading to the production of highly reactive hydroxyl radicals (OH) by the Fenton reaction, or alkoxyl and peroxyl radicals from the breakdown of lipid peroxides [1]. Therefore, only polynuclear ferric hydroxide carbohydrate complexes such as irondextran, polymaltose, gluconate, saccharate and chondroitin sulfate are used for intravenous or intramuscular use. The very low intravenous acute toxicity of polynuclear iron complexes (LD50>2002500 mg Fe/kg), compared to soluble iron salts (1020 mg Fe/kg), has been attributed to their low ionic iron content, since most of the iron is present as Fe(III) that is bound strongly to the carbohydrate moiety [2]. The ionic iron content of an irondextran preparation (Imferon®) was approximated to be 1/300th of the total iron present [3]. Furthermore, Cox and co-workers have found that 12% of iron present in fresh ampoules of Imferon® is ferrous iron, present as an extremely weak ferrousdextran complex [4]. Presumably, depolymerization of irondextran complex releases free dextran molecules (mol.wt 6000 Da,
33 glucose units) and ionic iron. Furthermore, change in pH when the polynuclear iron complexes come in contact with plasma may further induce depolymerization and formation of ferric hydroxide [5]. Consistent with these in vitro results, a recent clinical study found that eight of the 10 haemodialysis patients given 100 mg Fe(III) hydroxidesucrose complex intravenously had bleomycin detectable free iron in the circulation [6]. That redox active iron is released by colloidal iron compounds in the circulation, is further evidenced by the rise in plasma total peroxide and malondialdehyde concentrations within 10 min following infusion of 100 mg iron sucrose complex [7].
Acute adverse reactions to intravenous iron dextran occur at a frequency of six to seven episodes per 1000 haemodialysis patients treated [8]. In extreme cases, refractory hypotension, respiratory failure and death may ensue. A postulated allergic reaction to the dextran moiety is unlikely to be the cause of these anaphylactoid reactions since patients exhibiting such reactions to iron dextran do not have anti-dextran antibodies either by precipitation or by complement fixation tests [5]. These reactions are likely due to release of free iron in the circulation. In the anesthetized cat, infusion of irondextran complex (Imferon®) produces a hypotensive response that exhibits a rough correlation with its ferrous iron content and can be abolished by reducing the speed of infusion, while ferric iron produces a smaller transient depressor response followed by a more sustained presser response [4,5]. In addition to these acute effects, free radical generation and lipid peroxidation catalysed by free iron may play a role in the pathogenesis of a variety of chronic diseases such as inflammation, ischaemia, atherosclerosis, cancer, heart disease and stroke. Recent evidence suggests an increase in cardiovascular and infectious mortality in the US maintenance dialysis patients receiving higher doses of irondextran intravenously [9].
Parenteral iron has been recommended for the treatment of iron deficiency in the majority of maintenance haemodialysis patients receiving erythropoietin [10,11]. With the notable exception of heparin and citrate administered in the pre-dialyser arterial blood line to prevent clotting of the dialyser, most drugs including iron are infused into the post-dialyser or venous blood line of the extracorporeal haemodialysis circuit [1215]. If infused into the arterial blood line, significant removal of drugs by dialysis and ultrafiltration could occur in the first pass through the dialyser, since most drugs are either small molecules (<500 Da), or in the lowest ranges of middle molecular weight. However, the removal of polynuclear ferric hydroxidecarbohydrate complexes such as irondextran, polymaltose, gluconate, saccharate and chondroitin sulfate by dialysis is clinically insignificant since these are large molecules (50 000300 000 Da) [16,17]. Other studies have shown removal of small amounts of iron when irondextran solutions are dealysed in vitro. Using a low-flux cuprophane coil membrane, 0.20.25% of radiolabelled iron was removed by a 4-h in vitro dialysis [18], and about 8% of iron, as measured by atomic absorption, was cleared from Infed® using a variety of high-flux, hollow fibre dialysers [16]. Though the authors of these reports believed that irondextran was being removed by dialysis, the methods used for measuring iron in the dialysate would not distinguish between free and bound iron. The pore size of currently used dialysis membranes, including high efficiency membranes, prevents significant removal of molecules >20 000 Da, including albumin (Mr 68 000) (19). Even with high-flux polysulfone haemofiltres permeability in the higher molecular weight range (above 40 000 Da) is low (sieving coefficient <0.05) before secondary membrane formation, and becomes negligible after the secondary membrane formation is complete, within 20 min after the start of the treatment [20]. Since polynuclear irondextran complexes are 100280 000 Da, dialysis should only remove either free iron or iron bound to free dextran molecules (mol.wt between 5000 and 7500 Da). In fact, these reports suggest that of the total amount of iron present in polynuclear iron dextran preparations, a significant amount (0.58%) is either present free or loosely bound to dextran. Free ionic iron or the iron loosely bound to low molecular weight dextran molecules is amenable to removal by diffusive or convective transport during haemodialysis, and the efficiency of removal of these toxic iron species can be maximized if the colloidal iron preparations are infused into the arterial blood line rather than the venous blood line as is currently practiced. Since the dialysate is free of iron there is an infinite concentration gradient for diffusion of free iron from the blood to the dialysate compartment. Any free ionic iron or iron loosely complexed to free carbohydrate molecules along with any preservatives or stabilizing agents present in the pharmaceutical composition would be removed while traversing the dialyser, prior to entering the patient. This method may also minimize infusion of free dextran present in the iron dextran preparation, thereby reducing the formation of anti-dextran antibodies. Iron complexes can be delivered into the arterial blood line by infusion into the arterial chamber or the arterial line, either as a slow bolus injection or as a continuous infusion. Since heparin is administered in a similar way, it may be possible to administer an iron heparin mixture if the two are pharmacologically compatible. It has been shown that iron polymaltose and iron dextran are physically compatible with heparin, and serum iron parameters are similar when the iron and heparin are given together or separately [21,22].
We have recently demonstrated that soluble ferric pyrophosphate (mol.wt 745 Da), infused via the dialysate is safe and effective in maintaining iron balance in maintenance haemodialysis patients [23]. Further studies are needed to examine slow continuous intravenous infusion of ferric pyrophosphate directly into the blood stream, at a rate that mimics administration of iron via the dialysate. Similar to the colloidal iron compounds, it may be feasible to infuse ferric pyrophosphate into the arterial blood line since pyrophosphate is effective in transferring iron rapidly to transferrin and transferrin bound iron will not be removed during passage through the dialyser. On the other hand any free ferric pyrophosphate molecules or free ionic iron will be removed by convective or diffusive transport in the first pass through the dialyser, thereby preventing any potential adverse reactions.
Administration of iron into the arterial instead of the venous blood line is simple and does not require any significant modifications to the modern dialysis machines. Further studies are needed to compare oxidant stress and circulating free iron, using the two techniques and to examine any potential adverse effects on the dialyser membrane when iron is infused into the arterial blood line.
Acknowledgments
The author is grateful to Dr Anatole Besarab for a careful review of this manuscript.
References
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