Neutrophil impairment associated with iron therapy in hemodialysis patients with functional iron deficiency

Hemodialysis patients treated with recombinant human erythropoietin (rhEPO) need adequate iron supplementation to avoid rhEPO hyporesponsiveness due to iron deficiency. Low serum ferritin reflects absolute iron deficiency, whereas normal or high ferritin values in combination with low transferrin saturation (< 20%) indicate functional iron deficiency. In this study, healthy subjects (group I) were compared with intravenous (i.v.) rhEPO-treated and i.v. iron-saccharate-treated regular hemodialysis patients that were subdivided into three groups as follows: patients with serum ferritin > 100 and < 350 micrograms/L (group II), patients with ferritin < 60 micrograms/L (group III), and patients with ferritin > 650 micrograms/L but transferrin saturation < 20% (group IV). Polymorphonuclear leukocyte (PMNL) parameters (phagocytosis, intracellular killing of bacteria, oxidative metabolism, glucose uptake, intracellular calcium) for each group were compared with those of multitransfused, iron-overloaded primary hematologic patients (group V) and those of patients suffering from hereditary hemochromatosis (group VI). Compared with PMNL obtained from healthy subjects (group I), group II hemodialysis patients showed mild inhibition of phagocytosis but significant inhibition of intracellular killing of bacteria. Oxidative burst of PMNL from group II patients was also significantly reduced after stimulation in vitro. These dysfunctions were not affected by absolute iron deficiency (comparable data in group III patients). However, impairment of PMNL was markedly aggravated in group IV patients. Intracellular calcium concentration under basal conditions and after stimulation was not different. These data suggest that iron is responsible for the PMNL dysfunctions observed in group IV patients. The PMNL defect of group IV patients was comparable to group V and group VI patients with normal renal function, suggesting again a direct inhibitory effect of iron. It is concluded that hemodialysis patients with high ferritin but low serum iron and low transferrin saturation ("functional iron deficiency") display a significant impairment of fundamental PMNL functions during i.v. iron and rhEPO therapy. This may result in increased risk of infectious complications. Therefore, overtreatment of hemodialysis patients with i.v. iron should be avoided.