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Molecular Mechanisms of Hepcidin Regulation: Implications for the Anemia of CKD

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Anemia is prevalent in patients with chronic kidney disease (CKD) and is associated with lower quality of life and higher risk of adverse outcomes, including cardiovascular disease and death. Anemia management in patients with CKD currently revolves around the use of erythropoiesis-stimulating agents and supplemental iron. However, many patients do not respond adequately and/or require high doses of these medications. Furthermore, recent clinical trials have shown that targeting higher hemoglobin levels with conventional therapies leads to increased cardiovascular morbidity and mortality, particularly when higher doses of erythropoiesis-stimulating agents are used and in patients who are poorly responsive to therapy. One explanation for the poor response to conventional therapies in some patients is that these treatments do not fully address the underlying cause of the anemia. In many patients with CKD, as with patients with other chronic inflammatory diseases, poor absorption of dietary iron and the inability to use the body's iron stores contribute to the anemia. Recent research suggests that these abnormalities in iron balance may be caused by increased levels of the key iron regulatory hormone hepcidin. This article reviews the pathogenesis of anemia in CKD, the role and regulation of hepcidin in systemic iron homeostasis and the anemia of CKD, and the potential diagnostic and therapeutic implications of these findings.

Section snippets

Background

Iron is required for hemoglobin synthesis in the production of red blood cells. Iron also is a constituent of several proteins that carry out essential housekeeping functions and thus is critical for cell growth and survival. However, excess iron can generate free radicals that damage lipid membranes, proteins, and nucleic acids, leading to cell death. As a result, iron levels must be regulated tightly both on a cellular level and systemically. Hepcidin now is recognized to be a key mediator of

Case Vignette

A 55-year-old woman with hemodialysis-dependent end-stage renal disease (ESRD) secondary to diabetic nephropathy had persistent anemia despite escalating erythropoiesis-stimulating agent (ESA) dosing. Serum hemoglobin level was 7.5 g/dL (reference range, 12-16 g/dL), and hematocrit was 23.4% (reference range, 36%-46%). Serum iron level was 22 μg/dL (reference range, 30-160 μg/dL), total iron-binding capacity was 188 μg/dL (reference range, 230-404 μg/dL), and serum transferrin saturation was

Anemia of CKD

Anemia is prevalent in patients with CKD and contributes to lower quality of life.1 Anemia in patients with CKD also is associated with numerous adverse outcomes, including hospitalization, cardiovascular disease, cognitive impairment, and mortality.1 Inadequate production of erythropoietin commonly is believed to be the most important factor in the pathogenesis of anemia in these patients, and many patients are treated with ESAs. However, approximately 10%-20% of patients are poorly responsive

Hepcidin Regulation by the BMP6-HJV-SMAD Signaling Pathway

Mutations in the HJV gene are the most common cause of the more severe juvenile-onset form of hereditary hemochromatosis and result in a phenotype similar to mutations in the gene encoding hepcidin itself.24, 33 A link between the bone morphogenetic protein (BMP) signaling pathway and iron metabolism was discovered when HJV was shown to be a BMP coreceptor43 and BMP signals were shown to regulate hepcidin expression (Fig 2).43, 44

BMPs are members of the TGF-β (transforming growth factor β)

Summary

Hepcidin excess increasingly is being identified as a contributing factor to anemia in patients with CKD/ESRD by impairing iron absorption from the diet and iron mobilization from body stores. A multitude of factors can modulate hepcidin levels in the CKD/ESRD population: iron administration, ESA administration, body iron burden, inflammation, renal clearance, and dialysis. More studies are needed to better understand the diagnostic utility of hepcidin in patients with CKD/ESRD as a measure of

Acknowledgements

Support: Dr Babitt is supported in part by National Institutes of Health (NIH) grant K08 DK-075846, the Satellite Dialysis Young Investigator Grant of the National Kidney Foundation, and a Claflin Distinguished Scholar Award from the Massachusetts General Hospital. Dr Lin is supported in part by NIH grants RO1 DK-069533 and RO1 DK-071837.

Financial Disclosure: Drs Babitt and Lin have ownership interest in a startup company, Ferrumax Pharmaceuticals, that has licensed technology from the

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    Originally published online as doi:10.1053/j.ajkd.2009.12.030 on March 2, 2010.

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