Figure 2.

Mechanisms of ESA hyporesponsiveness. Overview of pathogenic mechanisms by which inflammatory cytokines suppress iron uptake and mobilization and erythropoiesis, thereby worsening anemia in patients with CKD. IL-6 stimulates liver production of hepcidin, which downregulates ferroportin (FPN) on all cells and thereby restricts iron availability resulting in functional iron deficiency. In the duodenum, DCYTB reduces ferric iron (Fe³⁺) to its ferrous form (Fe²⁺), which is then transported into the cytosol of enterocytes by DMT1. DCYTB and DMT1 are mostly HIF-2-regulated. Absorbed iron is released into the circulation by FPN, the only known cellular iron exporter, the expression of which is regulated by HIF-2 and hepcidin. FPN exports Fe²⁺, which is oxidized to Fe³⁺ by enterocyte hephaestin or, in the case of hepatocytes and RES cells, by plasma ceruloplasmin before transport in a complex with TF to the bone marrow and other organs. TF-Fe³⁺ complexes bind specific cell surface TF receptors and then enter cells via endocytosis of TF-receptors to which they are bound. TF is HIF-regulated, and hypoxia and HIF-PHIs increase TF plasma levels and total iron-binding capacity. Increased hepcidin synthesis in the liver due to inflammation results in decreased FPN cell surface expression, as hepcidin promotes FPN degradation and lowers its cell surface expression. As a result, less iron is released from enterocytes, hepatocytes, and RES cells. In CKD, plasma hepcidin levels are increased at baseline due to diminished renal clearance. Functional iron deficiency is exacerbated further by inflammation. Tumor necrosis factor α (TNF-α) decreases EPO synthesis in the kidney, further exacerbating relative EPO-deficiency in patients with CKD anemia, and, together with IL-1β and interferon γ (IFNγ), suppresses erythroid maturation and proliferation. Although not shown, TNF-α also increases hemophagocytosis of RBCs by macrophages, thereby decreasing RBC life span and exacerbating iron sequestration in RES cells. BM, bone marrow; DCYTB, duodenal cytochrome b; DMT1, divalent metal transporter 1; RES, reticuloendothelial system; TF, transferrin.