611 Decreased EPO production by injured fibroblast like epithelial cells is not the only mechanism by which endogenous EPO produc tion is decreased in kidney disease The kidney functions as a “critmet[.]
32 Management of Anemia in Children Receiving Chronic Dialysis a 611 Normaxic conditions Prolyl hydroxylase domain proteins 2-Oxoglutarate Acetate Iron Ub Hydroxylation and acetylation HIF-α OH HIF-α Ub OH HIF-α OAc OH Ub Von Hippel-Lindau protein (VHL) binds VHL Ubiquitination HIF-α OAc VHL OH Proteosome action OH Ub OAc VHL Ub Ub OH OH HIF-α degradation OAc VHL Cell cytoplasm Oxygen b OH Hypoxic conditions Prolyl hydroxylase domain proteins 2-Oxoglutarate Acetate Iron Translocation to the nucleus, no hydroxylation or acetylation HIF-α Proliferation HIF-α Coactivators HIF-α binds with HIF−β and coactivators HIF-α HIF-α Transcription of hypoxiaresponsive genes HIF-β Hypoxia response element Target genes HIF-β Cell cytoplasm Low oxygen Cell nucleus Coactivators Fig 32.2 Role of hypoxia-inducible factor α (HIF-α) under normoxic and hypoxic conditions (Modified from Ref 10) Decreased EPO production by injured fibroblast- like epithelial cells is not the only mechanism by which endogenous EPO production is decreased in kidney disease The kidney functions as a “critmeter” in that it senses oxygen tension and then regulates red cell mass by secreting EPO [7] Diminished oxygen consumption by diseased renal tissue leads to dysregulation of EPO production by increasing tissue oxygen pressure, which in turn leads to decreased HIF stability [7] The result is decreased EPO transcription occurring independently of damage to EPO-producing cells The action of EPO is mediated through its binding to the EPO receptor, which is found on the cell membrane of erythroid precursors in the bone marrow Once the EPO receptor is activated, a critical cascade of signal transduction results in increased survival of the red blood cell precursors [1, 13] Once bound to its receptor, EPO rapidly disappears from the circulation, indicating likely internalization [1, 13] The degree of EPO receptor binding depends on the carbohydrate content of EPO, with decreased binding affinity with increasing glycosylation of the EPO molecule; this likely accounts for the prolonged in vivo half-life of hyper-glycosylated EPO analogues as will be discussed later in this chapter [9, 14, 15] I ron Is Required for the Synthesis of Hemoglobin Iron is required for many physiologic functions including oxygen transport and cell growth and M A Atkinson and B A Warady 612 Fe Hepcidin FpCh Fe Hepcidin FpCh Macrophage Fe Enterocyte absorption [3] Transferrin is the glycoprotein iron transporter that binds tightly but reversibly to iron in plasma, preventing the oxidative stress that freely circulating iron would induce Iron that has been transported into the circulation bound to transferrin is released to erythroblasts via the interaction of transferrin with the transferrin receptor and receptor-mediated endocytosis [3] epcidin Regulates the Ferroportin- H Based Movement of Iron Fe Decreased Fe recycling Decreased dietary uptake Fig 32.3 Mechanism of action of hepcidin via direct binding to and downregulation of ferroportin (Contributed by Cindy N. Roy, PhD, Baltimore, MD; [Modified from Ref 19]) Fe iron, FpCh ferroportin channel survival The typical adult human body contains about 3.5 g of iron, and most of that (2.1 g) is incorporated into hemoglobin [16] Effective erythropoiesis depends not only on erythropoietin production, but also on the availability of iron, and incorporation of iron into erythroblasts is a rate-limiting step in the maturation of red blood cells in the bone marrow Once iron is absorbed, there is no specific mechanism for its excretion from the body, and so most iron utilized in erythropoiesis is recycled from iron already present in hemoglobin Iron is essential for hemoglobin synthesis [3] Hemoglobin consists of four heme groups, each of which requires the incorporation of one Fe2+ ion for oxygen binding [17] Each mature red blood cell contains approximately 300 million hemoglobin molecules, and two-thirds of total body iron is located in the erythroid compartment [17] To produce billions of erythrocytes daily, approximately 25 mg of iron must be made available to the bone marrow [3] The majority of this iron is supplied by macrophages which recycle iron from senescent red blood cells, while only 1–2 mg of iron daily comes from intestinal The iron-regulatory protein hepcidin, a 25-amino acid antimicrobial peptide encoded by the HAMP gene and produced by hepatocytes, has emerged as the key regulator of iron homeostasis [18] Hepcidin regulates both intestinal iron absorption and body iron distribution through its posttranslational suppression of cell-membrane expression of ferroportin, which is the sole cellular iron exporter Small intestinal ferroportin expression is upregulated in iron deficiency by HIF-2 [12] Hepcidin binding to ferroportin causes internalization and lysosomal degradation of ferroportin, which results in downregulation of dietary iron absorption via intestinal enterocytes, and inhibits the release of stored iron from reticuloendothelial cells [19] (Fig. 32.3) In this way, hepcidin prevents the utilization of absorbed or stored iron for erythropoiesis by the bone marrow, a process which in the short term may serve as a host-defense mechanism intended to sequester iron from invading pathogens or malignant cells [20] A number of pathways have been shown to regulate HAMP gene expression via mechanisms involving iron status, erythropoiesis, and inflammation Iron loading has been shown to increase the production of hepcidin, and hepcidin expression is modulated based on circulating levels of transferrin-bound iron via a BMP-SMAD signaling pathway [6, 17] Erythropoietin-stimulated erythroblasts produce erythroferrone, a hormone which acts directly on hepatocytes to suppress HAMP mRNA and decrease hepcidin production, with a resultant increased iron acquisition from absorption and storage sites [3, 6, 17] The reduc- 32 Management of Anemia in Children Receiving Chronic Dialysis tion in erythroblast number resulting from EPO deficiency diminishes the production of erythroferrone and prevents it from checking hepcidin production [6] Hepcidin expression is induced by inflammation in general and in particular by the inflammatory cytokine IL-6 It is cleared from the circulation by glomerular filtration, leading to increased levels in the setting of decreased renal function [21] Hepcidin has been found to be elevated in both adults and children with CKD and on dialysis, and levels are positively correlated with serum ferritin levels [22, 23] Hepcidin is also cleared from the circulation by hemodialysis [23] A study in the CKiD cohort found that in children with mild-to-moderate CKD, higher hepcidin levels were associated with lower hemoglobin and an increased risk for incident anemia [21] Epidemiology of Anemia in Children on Dialysis 613 Table 32.1 Definitions of anemia in children with kidney disease Age group (years) 1–2 3–5 6–8 9–11 12–14 15–19 Age group (years) 0.5–5 5–12 12–15 >15 and adult Age group (years)