In TranslationMolecular Mechanisms of Hepcidin Regulation: Implications for the Anemia of CKD
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.