Regulation of Hepcidin-25 by Short- and Long-Acting rhEPO May Be Dependent on Ferritin and Predict the Response to rhEPO in Hemodialysis Patients

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Abstract

Background/Aims: We examined whether regulation of hepcidin-25 by short- or long-acting recombinant human erythropoietin (rhEPO) is dependent on ferritin and predicts the response to rhEPO in hemodialysis (HD) patients. Methods: Two studies with rhEPO were performed in 9 HD patients with a 2-year interval. Serum hepcidin-25 was measured at 0-18 h after intravenous epoetin-β (EPO) or methoxy polyethylene glycol-epoetin-β (PEG-EPO) administration and on days 3-7 after PEG-EPO. Hemoglobin (Hb), serum ferritin, transferrin, C-reactive protein (CRP), and interleukin (IL)-6 were analyzed before hepcidin measurement and 6 months after rhEPO. Based on the serum ferritin levels before hepcidin measurement, the patients in the two studies with EPO or PEG-EPO were combined into low (11; serum ferritin of <15.0 ng/ml) and high ferritin groups (7; serum ferritin of ≥15.0 ng/ml). The response of hepcidin-25 to rhEPO and the effect of rhEPO on anemia were compared between the groups. Results: The serum hepcidin-25 levels rose at 6-9 h and returned to the baseline at 18 h after EPO. They rose at 6-9 h, returned to the baseline at 18 h, and decreased on day 5-7 after PEG-EPO. Serum hepcidin-25 levels were low (<5.0 ng/ml) in the low ferritin group, but rose at 6-9 h after rhEPO in the high ferritin group. Serum transferrin levels were similar, and CRP and IL-6 were normal in both groups. Hb tended to increase in the low ferritin group, but it significantly decreased in the high ferritin group after rhEPO. Conclusion: Regulation of hepcidin-25 by rhEPO may be dependent on ferritin, affecting the response to rhEPO in HD patients.

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Hepcidin and iron regulation, 10 years later.

Tomas Ganz (2011)

Under evolutionary pressure to counter the toxicity of iron and to maintain adequate iron supply for hemoglobin synthesis and essential metabolic functions, humans and other vertebrates have effective mechanisms to conserve iron and to regulate its concentration, storage, and distribution in tissues. The iron-regulatory hormone hepcidin, first described 10 years ago, and its receptor and iron channel ferroportin control the dietary absorption, storage, and tissue distribution of iron. Hepcidin causes ferroportin internalization and degradation, thereby decreasing iron transfer into blood plasma from the duodenum, from macrophages involved in recycling senescent erythrocytes, and from iron-storing hepatocytes. Hepcidin is feedback regulated by iron concentrations in plasma and the liver and by erythropoietic demand for iron. Genetic malfunctions affecting the hepcidin-ferroportin axis are a main cause of iron overload disorders but can also cause iron-restricted anemias. Modulation of hepcidin and ferroportin expression during infection and inflammation couples iron metabolism to host defense and decreases iron availability to invading pathogens. This response also restricts the iron supply to erythropoietic precursors and may cause or contribute to the anemia associated with infections and inflammatory disorders.

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Suppression of hepcidin during anemia requires erythropoietic activity.

Victroia Gabayan, Victoria Pak, Tomas Ganz … (2006)

Hepcidin, the principal iron regulatory hormone, regulates the absorption of iron from the diet and the mobilization of iron from stores. Previous studies indicated that hepcidin is suppressed during anemia, a response that would appropriately increase the absorption of iron and its release from stores. Indeed, in the mouse model, hepcidin-1 was suppressed after phlebotomy or erythropoietin administration but the suppression was reversed by inhibitors of erythropoiesis. The suppression of hepcidin necessary to match iron supply to erythropoietic demand thus requires increased erythropoiesis and is not directly mediated by anemia, tissue hypoxia, or erythropoietin.

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Detection of serum hepcidin in renal failure and inflammation by using ProteinChip System.

Rumi Wakatabe, Hisanori Umehara, M Higuchi … (2006)

Hepcidin, a key regulator of iron metabolism, is expressed in the liver, distributed in blood, and excreted in urine. However, to date, no reliable and practical method for measuring the bioactive form of hepcidin in serum has been developed. Here, we used surface-enhanced laser desorption ionization time of flight mass spectrometry (SELDI-TOF MS) to analyze the distinctive serum proteomic patterns of patients receiving hemodialysis. In the range of 1000 to 15,000 m/z, we found 3 peptides at 2192, 2789, and 2851 m/z that showed a significant correlation with the serum ferritin levels. The molecular sizes of peptides at 2192 and 2789 m/z matched with the reported sizes of hepcidin-20 and -25, respectively, and the serum peptide at 2789 m/z was identified as hepcidin-25 by collision-induced dissociation tandem MS. By using SELDI-TOF MS, we developed a semiquantitative assay for hepcidin-25. In this assay, the level of serum hepcidin-25 correlated well with levels of serum ferritin and serum interleukin-6. Hepcidin-25 was found to accumulate in the serum of patients receiving hemodialysis; this could contribute to the pathogenesis of renal anemia by decreasing the available iron for hematopoiesis. Thus, SELDI-TOF MS would be a clinically useful tool to detect and semiquantify bioactive hepcidin in serum.

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Author and article information

Journal

Journal ID (publisher-id): NNE

Journal ID (pmc): NNE

Journal ID (doi): 10.1159/issn.1664-5529

Title: Nephron Extra

Publisher: S. Karger AG

ISSN (Electronic): 1664-5529

Publication date Subscription-year: 2014

Publication date Collection: January – April 2014

Publication date (Electronic): 16 April 2014

Volume: 4

Issue: 1

Pages: 55-63

Affiliations

^aDivision of Nephrology, Department of Internal Medicine, and ^bDepartment of Pediatrics, Public Central Hospital of Matto Ishikawa, and ^cDivision of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Ishikawa, and ^dBiomarker Society, Kawasaki, Japan

Author notes

*Norishi Ueda, MD, PhD, Department of Pediatrics, Public Central Hospital of Matto Ishikawa, 3-8 Kuramitsu, Hakusan, Ishikawa 924-8588 (Japan), E-Mail nueda@mattohp.com

Article

Publisher ID: 362212 Pmcid ID: PMC4024510 Other ID: Nephron Extra 2014;4:55-63

DOI: 10.1159/000362212

PMC ID: PMC4024510

PubMed ID: 24847351

License:

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