Iron and Chronic Kidney Disease: Still a Challenge

Abstract

Anemia is a clinical feature of chronic kidney disease (CKD). Most common causes are iron and erythropoietin deficiency. The last two decades have yielded significant advances in understanding iron balance's physiology, including iron trafficking and the crosstalk between iron, oxygen, and erythropoiesis. This knowledge sheds new light on the regulation and disturbance of iron homeostasis in CKD and holds the promise for developing new diagnostic and therapeutic tools to improve the management of iron disorders. Hepcidin-ferroportin axis has a central role in regulating body iron balance and coordinating communication between tissues and cells that acquire, store, and utilize iron. Recent research has revealed a bidirectional relationship between fibroblast growth factor 23 (FGF23) and iron status, anemia, and inflammation, as well as the role of erythroferrone (ERFE) in iron homeostasis. However, ERFE concentrations and actions are not well-characterized in CKD patients. Studies on ERFE in CKD are limited with slightly conflicting results. Despite general interest in iron metabolism in kidney diseases, studies on the less prevalent renal replacement therapy mode, such as peritoneal dialysis or hemodiafiltration, are scarce. Slightly more was published on hemodialysis. There are several novel options on the horizon; however, clinical data are limited. One should be aware of the potential risks and benefits of the novel, sophisticated therapies. An inhibition of hepcidin on the different pathways might be also a viable adjunctive therapeutic option in other clinical situations.

Keywords: HIF-1α; anemia; chronic kidney disease; erythroferrone; hepcidin; iron.

Figure 1

Regulation of EPO transcription. HIF 2α, hypoxia-inducible factor 2α; HIF β, hypoxia-inducible factor β; PDHs, O₂ and iron-dependent HIF prolyl-4-hydroxylases; UQ, ubiquitin; CBP, CREB-binding protein; EPO, erythropoietin.

Figure 2

Regulation of hepcidin synthesis by erythroferrone. Increased circulating levels of ERFE sequestrate BMP receptor ligands to decrease SMAD1/5/8 phosphorylation; lower levels of phosphorylated SMAD1/5/8 result in less SMAD1/5/8–SMAD4 complex formation, diminishing its nuclear concentration and decreasing hepcidin transcription. ERFE, erythroferrone; BMP, bone morphogenetic protein; SMAD, suppressor of mothers against decapentaplegic proteins; HJV, hemojuvelin; BRE, BMP-responsive elements in the hepcidin promoter; P, phosphate.

Figure 3

Duodenal iron absorption. The iron transporter DMT1 takes up ferrous iron, reduced from ferric iron by DCYTB, on the enterocyte's luminal. Iron can be used inside the cell, exported to circulation by FPN after ferrous iron is oxidized to ferric iron by HEPH or stored in FN. Heme, after entering the enterocyte through an unknown mechanism, is converted to iron by HMOX. HIF 2α stimulates the expression of DMT1 and FPN—apical and basolateral transporters. DCYTB, duodenal cytochrome B reductase; DTM1, divalent metal transporter 1; FPN, ferroportin; HEPH, hephaestin; HMOX, heme oxygenase; FN, ferritin; Tf, transferrin; Holo-Tf, holotransferrin.

Figure 4

Iron recycling in macrophages. Macrophages recover iron from phagocytized erythrocytes and heme from heme–HPX or HP–hemoglobin complexes after degradation by HMOX. Iron not used in the macrophage is stored in FN or exported to the circulation by FPN with CP's cooperation. Heme–HPX, heme–hemopexin; HP-Hb, haptoglobin–hemoglobin; HMOX, heme oxygenase; FPN, ferroportin; CP, ceruloplasmin; FN, ferritin; Tf, transferrin; Holo-Tf, holotransferrin; PCBP1, poly(rC)-binding protein 1.

Figure 5

The regulation of hepcidin expression by iron and inflammation. Increased systemic iron stimulates the production of the ligand BMP6, which binds to the BMPRI (ALK2/ALK3) and BMPRII receptors, and the co-receptor HJV to stimulate phosphorylation of the SMAD1/5/8 signaling molecules; phosphorylated SMAD1/5/8 binds to SMAD4 and translocates to the nucleus to bind BRE in the hepcidin promoter. In iron overload diferric transferrin displaces HFE from TFR1 to enable iron uptake and stabilizes TFR2 potentiating SMAD signaling (the role of the other HFE and TFR2 proteins is still unclear). Inflammation also stimulates hepcidin production; inflammation increases IL-6 binding to IL-6R and stimulating phosphorylation of JAKs and STAT3; phosphorylated STAT3 homodimers translocate to nucleus and bind to SRE in hepcidin promoter. The proposed mechanism of interaction between inflammatory and BMP signaling includes activin B, which is induced by inflammation, and binds to BMPRs to stimulate SMAD1/5/8 phosphorylation. The interaction between SMAD and STAT can also take place at the level of hepcidin promoter. BMP, bone morphogenetic protein; BMPR, bone morphogenetic protein receptor; SMAD, suppressor of mothers against decapentaplegic proteins; JAK, Janus kinase; STAT3, signal transducer and activator of transcription; HJV, hemojuvelin; HFE, hemochromatosis protein; IL-6, interleukin 6; IL-6R, interleukin 6 receptor; TfR, transferrin receptor; BRE, BMP-responsive elements in the hepcidin promoter; SRE, STAT-responsive elements in the hepcidin promoter; P, phosphate.

Figure 6

Iron metabolism dysregulation in chronic kidney disease. The central role in iron metabolism regulation plays an increased level of hepcidin, decreasing FPN on cell membranes and thus diminishing duodenal iron absorption and acquirement from stores in RES. Hepcidin expression and production are stimulated by iron treatment, inflammation, uremic milieu, and fibroblast growth factor 23 (FGF23), and, at the same time, its removal is impaired due to decreased glomerular filtration rate (GFR). Both erythropoietin and erythroferrone play suppressive effect on hepcidin production. FPN, ferroportin; RES, reticuloendothelial system; HIF-2, hypoxia-inducible factor 2; DCYTB, duodenal cytochrome B reductase; DTM1, divalent metal transporter 1; FGF23, fibroblast growth factor 23; EPO, erythropoietin; ESA, erythropoiesis-stimulating agent.