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

Abstract

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.

Plasma iron controls neutrophil production and function

“…We hypothesize that therapeutic hepcidin suppression could be leveraged to control neutrophil numbers and functionality during infection with pathogens insensitive to hepcidin-mediated hypoferremia ( 56 ) or during autoimmunity where raised hepcidin might contribute to neutrophil dysfunction and proinflammatory NETosis. However, given results from iron-loaded hemochromatosis and dialysis patients, it will be important to avoid extreme iron loading of neutrophils as this may also lead to dysfunction ( 16 , 57 , 58 ).…”

Iron excess affects release of neutrophil extracellular traps and reactive oxygen species but does not influence other functions of neutrophils

“…37 Our results show that mice suffering from hereditary and diet-induced iron overload did not demonstrate any alterations in phagocytosis. According to Patruta et al, 38 iron overload in humans resulting from regular hemodialysis leads to a reduction of the phagocytic ability of cells. These observations are in line with Alexiewicz et al, 39 who also reported reduced phagocytosis in hemodialysis patients; however, they linked this observation to elevated resting levels of cytosolic calcium.…”

Secondary Immunodeficiency Related to Kidney Disease (SIDKD)—Definition, Unmet Need, and Mechanisms

“…For example, there is a concern that iron administration for renal anemia could decrease host defense. Indeed, iron can decrease the phagocytic capacity of neutrophils and macrophages 168 , 169 . Iron can also impair the proliferation of T cells, lower IL-2 and IFN- γ production, and reduce the antibody response of B cells 170 – 172 .…”