Abstract
Iron deficiency anemia (IDA) is a major problem in chronic kidney disease (CKD), causing increased mortality. Ferritin stores iron, representing iron status. Hepcidin binds to ferroportin, thereby inhibiting iron absorption/efflux. Inflammation in CKD increases ferritin and hepcidin independent of iron status, which reduce iron availability. While intravenous iron therapy (IIT) is superior to oral iron therapy (OIT) in CKD patients with inflammation, OIT is as effective as IIT in those without. Inflammation reduces predictive values of ferritin and hepcidin for iron status and responsiveness to iron therapy. Upper limit of ferritin to predict iron overload is higher in CKD patients with inflammation than in those without. However, magnetic resonance imaging studies show lower cutoff levels of serum ferritin to predict iron overload in dialysis patients with apparent inflammation than upper limit of ferritin proposed by international guidelines. Compared to CKD patients with inflammation, optimal ferritin levels for IDA are lower in those without, requiring reduced iron dose and leading to decreased mortality. The management of IDA should differ between CKD patients with and without inflammation and include minimization of inflammation. Further studies are needed to determine the impact of inflammation on ferritin, hepcidin and therapeutic strategy for IDA in CKD.
Highlights
Iron deficiency (ID) occurs in two major forms; absolute ID as defined by a decrease in the body iron stores and functional ID (FID), a disorder in which the total body iron stores are normal or increased but the iron supply to the bone marrow is inadequate [1]
The aim of this review is to provide an overview of clinical and experimental studies regarding a role of ferritin, hepcidin and inflammation in the regulation of ID anemia (IDA), efficacy of oral iron therapy (OIT) and intravenous iron therapy (IIT), predictive values of ferritin and hepcidin for the response to iron therapy, upper limit of ferritin levels to predict iron overload, optimal ferritin levels during iron therapy, complications and outcome in chronic kidney disease (CKD) patients
Inflammation highly associated with CKD increases ferritin and hepcidin, which block iron absorption and efflux, leading to reduced iron availability for erythropoiesis and subsequent hyporesponsiveness to iron therapy and erythropoiesis-stimulating agents (ESA)
Summary
Iron deficiency (ID) occurs in two major forms; absolute ID as defined by a decrease in the body iron stores and functional ID (FID), a disorder in which the total body iron stores are normal or increased but the iron supply to the bone marrow is inadequate [1]. Optimal levels of serum ferritin during iron therapy for IDA remain to be determined in CKD patients. Inflammation as defined by the innate immune response to stimuli such as pathogens, cellular injury and metabolic stress [13] is part of the complex biologic response to tissue injury, infection, ischemia and autoimmune diseases It is characterized by the acute-phase response including elevated inflammation markers such as C-reactive protein (CRP, >0.3 mg/dL) [14] and pro-inflammatory cytokines which promote CRP synthesis [15]. Inflammation-mediated increase in hepcidin leads to iron trapping within the macrophages and hepatocytes, resulting in FID [19]. Inflammation has an impact on the expression of ferritin and hepcidin as well as therapeutic strategy for the management of IDA in CKD patients. This review especially focuses on the impact of inflammation on these issues in CKD patients
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