Impact of Inflammation on Ferritin, Hepcidin and the Management of Iron Deficiency Anemia in Chronic Kidney Disease

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.

Keywords: C-reactive protein; chronic kidney disease; ferritin; hepcidin; inflammation; iron deficiency anemia.

Figure 1

Regulation of systemic iron homeostasis. Divalent metal transporter 1 (DMT1) at the apical membrane of enterocytes takes up Fe²⁺ from the lumen after duodenal cytochrome b (DCYTB) reduces dietary Fe³⁺ to Fe²⁺. Ferroportin (FPN) at the basolateral membrane exports Fe²⁺ into the circulation. FPN cooperates with hephaestin that oxidizes Fe²⁺ to Fe³⁺. In hepatocytes and macrophages, Fe²⁺ is oxidized by a ferroxidase, ceruloplasmin (CP). Diferric (Fe³⁺₂) transferrin (holo-Tf) supplies iron to all cells and tissues through binding to Tf receptor 1 (TfR1) and endocytosis. Erythrocytes are phagocytized by macrophages. Hemoglobin-derived heme in enterocytes and macrophages is catabolized by heme oxygenase-1 (HO-1). After sensing iron, hepatocytes produce and release hepcidin. In iron deficiency (A), low hepcidin facilitates iron export by FPN into the circulation. In iron overload (B), high hepcidin binds to FPN and inhibits iron export from enterocytes, hepatocytes and macrophages by triggering internalization and degradation of FPN, leading to reduction of iron storage. Dashed line indicates less iron supply. x: inhibition. Figures adapted from [12].

Figure 1

Regulation of systemic iron homeostasis. Divalent metal transporter 1 (DMT1) at the apical membrane of enterocytes takes up Fe²⁺ from the lumen after duodenal cytochrome b (DCYTB) reduces dietary Fe³⁺ to Fe²⁺. Ferroportin (FPN) at the basolateral membrane exports Fe²⁺ into the circulation. FPN cooperates with hephaestin that oxidizes Fe²⁺ to Fe³⁺. In hepatocytes and macrophages, Fe²⁺ is oxidized by a ferroxidase, ceruloplasmin (CP). Diferric (Fe³⁺₂) transferrin (holo-Tf) supplies iron to all cells and tissues through binding to Tf receptor 1 (TfR1) and endocytosis. Erythrocytes are phagocytized by macrophages. Hemoglobin-derived heme in enterocytes and macrophages is catabolized by heme oxygenase-1 (HO-1). After sensing iron, hepatocytes produce and release hepcidin. In iron deficiency (A), low hepcidin facilitates iron export by FPN into the circulation. In iron overload (B), high hepcidin binds to FPN and inhibits iron export from enterocytes, hepatocytes and macrophages by triggering internalization and degradation of FPN, leading to reduction of iron storage. Dashed line indicates less iron supply. x: inhibition. Figures adapted from [12].

Figure 2

Regulation of hepcidin by iron status and inflammation. Under high iron conditions, increased holo-Tf induces bone morphogenetic protein (BMP)-6 in non-parenchymal cells in the liver, disrupts hereditary hemochromatosis protein (HFE)-transferrin receptor (TfR)1 interaction to promote HFE-TfR2 interaction and its association with membrane-anchored hemojuvelin (mHJV), forming a complex of HFE/TfR2/BMP-6/BMPR/HJV/neogenin, which is dispensable for hepcidin transcription via BMP/small mothers against decapentaplegic (SMAD) signaling. In iron overload, furin, which cleaves mHJV, is downregulated, thereby increasing hepcidin. Low iron conditions increase matriptase (MT)-2 and furin, which cleaves mHJV, reduces BMP-6 production and facilitates the HFE-TfR1 interaction, leading to inhibition of BMP/SMAD-dependent hepcidin transcription. Pro-inflammatory cytokines such as interleukin (IL)-1β and IL-6 stimulate hepcidin expression via the Janus kinase (JAK)/signal transducers and activators of transcription (STAT)3 signaling. Inflammation induces other cytokine, activin B, which stimulates BMP/SMAD signaling, synergically with IL-6 and STAT3 signaling, leading to hepcidin expression. Endoplasmic reticulum (ER) stress associated with inflammation increases hepcidin via SMAD1/5/8 and cyclic-AMP-responsive-element-binding protein (CREB)H that binds and activates hepcidin promoter activity. Inflammation increases hepcidin by inhibiting MT-2 via decreased STAT5 and peroxisome proliferator-activated receptor γ coactivator (PGC)-1α which antagonizes lipopolysaccharide-induced hepcidin transcription via the interaction with hepatocyte nuclear factor 4α. Inflammation-induced IL-1β enhances hepcidin transcription by inducing CCAT enhancer-binding protein (C/EBP)δ. Hepcidin translation is mediated indirectly through erythropoietin (EPO)/EPOR-induced erythropoiesis and possibly growth differentiation factor (GDF)15. gp130: glycoprotein 130. Dashed line: cleavage, →: activation, ├: inhibition.