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MAKING SENSE: A SCIENTIFIC APPROACH TO IV THERAPY |
Department of Medicine and Surgery, University of Arizona College of Medicine, Tucson, Arizona
Correspondence to Dr. David B. Van Wyck, Kidney Health Institute, LLC, 6720 North Nanini Drive, Tucson, AZ 85704-6128. Phone: 520-906-8262; Fax: 520-498-5027; E-mail: dvanwyck{at}sprynet.com
As Dr. Danielson discussed in the article "Structure, Chemistry, and Pharmacokinetics of Intravenous Iron Agents" in this supplement, the pharmacokinetics and internal iron disposition of all intravenous (IV) iron agents are characterized by initial clearance from the plasma space into fixed phagocytic cells of the reticuloendothelial system (RES) followed by intracellular liberation of iron from the iron-carbohydrate complex, release of iron from RES cells to circulating transferrin (Tf), and, finally, donation of Tf-bound iron to erythroid precursors in marrow. In the iron-avid patient, utilization of IV iron by this stepwise mechanism is rapid and relatively complete. All IV iron agents, however, show evidence of a second, limited pathway in which iron passes directly from the iron-carbohydrate compound to Tf. Evidence that iron-carbohydrate agents can directly release biologically active iron and bypass the presumed safety of RES uptake has prompted a series of questions with potentially important implications for IV iron administration in patients
Do IV Iron Agents Release Free Iron?
Concern that parenteral iron-carbohydrate compounds release free iron is neither new nor confined to a single iron agent. In the mid-1960s, examination of iron dextran Imferon by polarography and high-voltage electrophoresis suggested that 0.3% of the total iron in the compound consists of ionic iron in the ferrous (Fe+2) state, probably weakly bound to dextran (1). These investigators were the first to predict that a small fraction of weakly bound or labile iron could provoke iron-mediated hypotension if large doses were injected rapidly.
Subsequent efforts to identify free, ionic iron in iron-carbohydrate agents have proved unsuccessful. No dialyzable iron has been found in iron dextran (2,3), ferric gluconate (4), or iron sucrose (5). The product package insert for ferric gluconate reports that <1% of iron in ferric gluconate is dialyzable in vitro (6). Neither iron sucrose nor iron dextran release detectable iron to dialysate using high-flux or high-efficiency dialyzers (7).
Evidence for a Labile, Bioactive Iron Fraction
Although there is no convincing evidence of unbound, dialyzable, or free iron in any IV iron agent, all agents show evidence of a labile, biologically active iron fraction. In vitro and in vivo manifestations of a labile iron fraction in iron-carbohydrate compounds include iron assay interference (agents falsely elevate serum iron results), oversaturation of Tf (true increase in iron available for Tf binding exceeds unbound iron-binding capacity), non–Tf-bound iron (NTBI), direct iron donation to Tf, altered intracellular iron homeostasis, cytotoxicity, neutrophil impairment, bacterial growth enhancement, oxidant stress, or catalytic iron (Table 1
).
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prompt several conclusions. Each manifestation of labile iron is shared by all IV iron agents tested, but not all agents have been tested for each manifestation. Not all attempts to demonstrate labile iron effects have shown positive results, and some positive results more likely are due to tissue iron excess, total iron dose, or underlying disease than to the tested IV iron agent itself. Serum iron assays falsely detect a portion of iron in iron-carbohydrate compounds as if it were Tf bound. The degree of interference varies by agent class, by agents within the same class, and by assay method. The consequent false elevation of serum iron has confounded assessment of Tf oversaturation after IV iron administration in patients. Of course, assay interference does not exclude a true increase in serum Tf-bound iron. Iron agents convincingly donate iron directly to Tf, and the resulting increase in Tf-bound iron is both theoretically (8) and demonstrably (9) sufficient to saturate Tf fully after rapid IV iron injection.
The relationship among Tf saturation, NTBI, and biologically active iron defies simplicity. Tf oversaturation is not a prerequisite for the appearance of either NTBI or labile iron. Indeed, although both NTBI and biologically active labile iron appear transiently after IV iron administration, each may also arise in patients who do not undergo IV iron therapy, without iron overload, or early after oral iron administration. Neither NTBI nor labile iron has been characterized chemically: NTBI reflects the results of assays for that portion of serum iron that is not bound to Tf, and labile iron is identified only by the biologic activity that it manifests in vitro or in vivo. Although labile iron may contribute to NTBI, not all NTBI shows evidence of biologic activity, and in some assays, NTBI and labile iron seem to be distinct entities.
It is also apparent that labile iron released from iron-carbohydrate compounds in the extracellular space shows evidence of transport into non-RES cells. Exposure of hepatic parenchymal cells to IV iron agents in tissue culture produces an abrupt increase in the intracellular labile iron pool. The increase in intracellular iron activates key regulatory responses to restore iron homeostasis.
Cytotoxicity to cells in tissue culture has been demonstrated after exposure to IV iron agents. However, the concentration of iron agent needed to demonstrate cell toxicity in vitro is far higher than can be achieved in patients after IV iron administration.
Relationship between Labile Iron and the Chemistry of IV Iron Agents
Results of comparative studies of labile iron activity associated with IV iron agents consistently show an inverse relationship between labile iron and molecular weight of the iron-carbohydrate compound. Whether the examined manifestation is interference with serum iron assay, rate of iron degradation, direct donation of iron to Tf, generation of oxidant stress, or alteration of intracellular iron homeostasis, the magnitude of the labile iron effect is greatest in iron-carbohydrate compounds of lowest molecular weight and least in those of the highest weight.
Recent imaging and direct measurement of the core radius of iron-carbohydrate compounds provide a potential explanation (43). If, as proposed, labile iron reflects the ionic iron that is first released from IV iron agents, then the point of release likely would be the surface of the iron-oxyhydroxide core. The focus of attention, therefore, should be the total surface area available for iron release.
Because all agents share the same core chemistry, the rate of iron release per unit surface area likely would be similar among agents (differing, perhaps, only by the strength of the carbohydrate ligand-core iron bond). However, for the same total amount of core iron, surface area available for iron release increases dramatically as core radius decreases. In short, a collection of many small spheres exposes a greater total surface area than does a collection of an equal mass of fewer, larger spheres.
That the relationship between surface area and core radius is not linear explains why small core radius differences between agents of small molecular weight are as significant as large core radius differences between agents of high molecular weight. This is simple mathematics. Because surface area is a function of the product of 4
and the square of the radius, Surface area = 4r2, and volume is a function of the cube of the radius, Volume = 4/3r3, then the ratio of surface area to volume is a function of the product of the constant 3 and reciprocal of the radius: Surface Area:Volume Ratio = 3r–1.
Thus, as the radius increases, surface area to volume ratio decreases first abruptly, then more gradually (Figure 1). Because large iron-oxyhydroxide cores such as those in iron dextran tend to assume an ellipsoidal (football or cigar-like) rather than spherical shape, the effective core radius is more difficult to estimate, but the same general relationships apply.
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Given the reassuring evidence of safety of IV iron in clinical practice, do any of the broad range of findings on labile iron in vitro and in vivo have implications for IV iron administration in patients? This question returns attention to previous speculation that the presence in an iron-carbohydrate compound of a small biologically active iron fraction could provoke a free-iron–like reaction in patients if sufficient agent were administered too rapidly. The labile iron fraction is indeed small but larger than originally estimated. Moreover, the size of the fraction is not uniform among agents. As expected, the labile iron fraction follows the sequence SFGC>IS>ID INFeD>ID Dexferrum, varying inversely with core radius and overall molecular weight (Figure 2).
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in "Safety of Intravenous Iron in Clinical Practice: Implications of Anemia Management Protocols" in this supplement.
If labile iron can cause a free-iron–like reaction and free-iron–like reactions are dose limiting, then, by extension, the size of the labile iron fraction may be dose limiting, and, if so, then the maximum tolerated dose and rate of administration would be inversely related to labile iron fraction and would follow the sequence ID>IS>SFGC. This proposed effect of labile iron explains the relationship between dose size, rate of infusion, and rate of adverse drug events observed in Table 1 in "Safety of Intravenous Iron in Clinical Practice: Implications of Anemia Management Protocols," fits the observed differences between IV iron agents in maximum tolerated single dose and rate of infusion, predicts that agents of larger overall molecular weight likely will be associated with greater safety at high doses and rapid injection rates, explains why patients who weigh <50 kg are more likely to experience adverse reactions than larger patients given the same dose (44), confirms the observation that Tf saturation is more likely to occur in patients with low total iron-binding capacity (and therefore lower unbound iron binding capacity) (17), and suggests that labile iron provides the pathogenetic basis for dose-limiting and infusion rate–limiting acute IV iron toxicity (10–42)(43).
References
This article has been cited by other articles:
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  G. Guz, G. L. Glorieux, R. De Smet, M.-A. F. Waterloos, R. C. Vanholder, and A. W. Dhondt Impact of iron sucrose therapy on leucocyte surface molecules and reactive oxygen species in haemodialysis patients Nephrol. Dial. Transplant., October 1, 2006; 21(10): 2834 - 2840. [Abstract] [Full Text] [PDF]
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