A review, tutorial article investigating the safety of IV iron therapy. The author examines the use of IV iron therapy in patients with anemia of end-stage renal disease (ESRD) undergoing recombinant human erythropoietin (rHuEPO) therapy.

Feldman HI, Santanna J, Guo WS, et al.

Hoen B, Paul-Dauphin A, Kessler M

Fishbane S, Kowalski EA

Reviewed by: Roland Schaefer

Background: An adequate iron supply is needed to optimize rHuEPO treatment of the anemia of ESRD. IV iron therapy rather than oral iron is the optimal method for ensuring an adequate iron supply in hemodialysis patients. There are many reports of poor compliance with oral iron due togastrointestinal side effects, as well as and poor intestinal absorption. While IV iron optimizes rHuEPO therapy, some clinicians fear a number of theoretical short- and long-term complications that could outweigh the benefit of this therapy.

The author examines each of the perceived risks of IV iron therapy in turn. These are anaphylactic and free iron reactions, increased risk of infection; increased oxidative stress and cardiac morbidity and mortality.

Concerns About the Short-Term Safety of IV Iron: Anaphylactic reactions have been reported since iron dextran first became available in the 1950s, however, these reactions are due to dextran rather than to the iron. Fishbane et al. (1996) report a 0.7% incidence of serious anaphylactic reactions to IV iron dextran in ESRD patients, and a 5.2% incidence of adverse events in hemodialysis patients. An earlier study by Hamstra et al. (1980) reported a 0.6% incidence of serious anaphylactic reactions to IV iron dextran. However, iron sucrose has superseded this earlier iron preparation and is considered safe in this regard.

With regards to free iron reactions, the author considers free iron, or non-transferrin bound iron, to be an artefact. It has not been demonstrated that free circulating iron can exist at the levels that have been suggested.

Concerns About the Long-Term Safety of IV Iron: The author reviews three studies examining the association between raised ferritin levels and infection in ESRD patients. Seifert et al. (1987) report higher rates of bacterial infection in patients with serum ferritin levels between 1,001-2,000 ?g/L in comparison to those with serum ferritin levels between 10-330 ?g/L (that is, 0.18 vs.0.58 infections per patient-therapy-year, p < 0.01). Tielemans et al. report an increased rate of infection and bacteremia when serum ferritin levels > 500 ?g/L (p < 0.00025), while Boelaert et al. (1990) report an increased rate of bacteremia when serum ferritin levels > 1,000 ?g/L, but serum ferritin levels < 500 and 500-1,000 ?g/L had the same level of risk.

However, two studies conducted by Hoen et al. examined the risk factors for bacterial infections in hemodialysis patients, in 1995 their multivariate analysis demonstrated that independent risk factors for bacterial infection were: a previous history of bacterial infection (odds ratio: 3.9), presence of a central venous catheter (odds ratio: 31.0) and a serum level > 500 ?g/L (odds ratio: 1.8). A later study in 1998 reported that patients with bacteremia and those without showed no difference in ferritin levels (346 ? 502 vs. 353 ? 434 ?g/L, p=0.44). They identified the following risk factors: vascular catheter access, a history of bacteremia, immunosuppressive therapy and an 1 g/dL increase in Hb.

These studies suggest that anemia rather than excess iron, is responsible for increased risk of infection. There is no evidence that IV iron therapy causes an increase in infection. There are concerns that free iron may lead to oxidative stress. This has been demonstrated in vitro but not in vivo with IV iron. With regards to oral iron compounds, unbound reactive iron may occur and have fatal consequences especially in children.

The author maintains that if free iron existed it is likely that it would increase the risk of coronary heart disease through the oxidation of lipids. A study by Salonen et al. (1992) reports a two-fold increase in acute myocardial infarction in men with serum ferritin > 200 ?g/L. However, a study by Gartside et al. (1995) reported no correlation between iron levels and cardiovascular disease. A prospective study by Dennis et al. (1997) failed to show a relationship between ferritin level and cardiovascular death. The author concludes that although some epidemiological studies have shown an association between ferritin levels and cardiovascular disease, such associations are post-hoc and in this way raised ferritin levels may actually be a consequence rather than a causeof cardiovascular disease.

• Adequate iron supply is necessary in order to optimize the response to rHuEPO therapy in ESRD patients, in this way dextran-free IV iron preparations such a iron sucrose are considered ideal.
• Fears concerning the excess of iron in the body are unfounded.
• There is no evidence that IV iron sucrose causes free iron reactions.
• There is no evidence of an increase in infection due to IV iron sucrose therapy.
• Although some epidemiological studies have shown an association between ferritin levels and cardiovascular disease, such associations are post-hoc and in this way raised ferritin levels may actually be a consequence rather than a cause of cardiovascular disease.