Impairment of Transendothelial Leukocyte Migration by Iron Complexes

Abstract

Abstract. Although iron sucrose and iron gluconate are generally well tolerated in patients who are treated for renal anemia, recent clinical studies and cell culture experiments suggested significant toxicity and long-term side effects arising from the use of these iron complexes. Because of the possible role of iron in infection or cardiovascular disease, it was theorized that parenteral iron compounds influence endothelial and PMN interaction in vitro. A well-established double-chamber method was used to assess the effect of different concentrations of iron sucrose and iron gluconate (1, 25, 50, and 100 g/ml) on the transendothelial migration of PMN. Preincubation of PMN and endothelial cells as well as preincubation of PMN alone with 25, 50, or 100 g/ml iron resulted in a significant decrease in PMN migration. In contrast, after incubation of the endothelial cells alone with iron, no reduction in the transendothelial migration of PMN was observed. Preincubation of PMN and/or endothelial cells with 1 g/ml iron did not lead to any decrease in the rate of migrated PMN. The only significant change in experiments with 1 g/ml was an increase in PMN migration after preincubation of endothelial cells and PMN with iron gluconate. A four-way ANOVA showed a significant effect of the iron concentration (P Ͻ 0.000001), of type of iron complex (P Ͻ 0.005), of the preincubation of endothelial cell (P Ͻ 0.001), and of the preincubation of PMN with iron (P Ͻ 0.000001) on PMN diapedesis. It is concluded that iron sucrose and iron gluconate cause a significant inhibition of transendothelial migration of PMN.Renal anemia therapy requires an intravenous iron substitution in addition to the erythropoietin therapy in the majority of patients (1). Iron substitution not only reduces the erythropoietin dosage needed but also is necessary to maintain the target hemoglobin above 11 g/dl (2,3). There are several iron preparations for intravenous use available, all of which have potential side effects, such as allergic reactions, cell injury, or endothelial dysfunction (4 -7). Moreover, iron therapy may be associated with infectious complications and with loss of the ability of patient serum to resist the bacterial growth (8 -10). PMN play a vital role in the nonspecific immune reaction against bacterial infections executing functions such as chemotaxis, transendothelial migration, phagocytosis, and intracellular killing by proteolytic enzymes or toxic oxygen radicals. Although the effects of iron on chemotaxis of PMN, phagocytosis, and intracellular killing in PMN were studied previously, the effect of iron complexes on PMN-endothelial cell interaction is unknown. Therefore, we examined the effect of incubation of PMN and/or endothelial cells with two widely used iron complexes, iron(III)-hydroxide-sucrose complex (iron sucrose) and iron(III)-sodium-gluconate in sucrose (iron gluconate), on the PMN migration through the endothelium in an in vitro setting.

Intravenous Iron Sucrose Changes the Intraperitoneal Homeostasis

“…The effect of iron sucrose on blood leukocytes and endothelial cells observed previously by others in in vitro experiments [20] may also explain the reduced intraperitoneal flux of blood leukocytes.…”

Clinical Aspects of Iron Use in the Anemia of Kidney Disease

“…Both iron sucrose and ferric gluconate inhibit migration of PMNL through endothelial cells in doses equivalent to concentrations measured in the plasma of dialysis patients who were treated with these intravenous iron products. Greater impairment in PMNL migration was found when endothelial cells were incubated in vitro for iron sucrose as compared with ferric gluconate (80). Parenteral iron therapy exacerbates experimental sepsis (81).…”

How to Supplement Iron in Patients with Renal Anemia

“…In addition, in many in vitro studies, iron has been shown to impair the immune response against pathogens. For example, incubation with iron-induced apoptosis, reduced phagocytic function and impaired transendothelial migration of polymorphonuclear leukocytes [36,37] . In keeping with these in vitro observations, iron overload resulted in the worsening of infections in various animal models in vivo [38][39][40] .…”