We developed and validated the first serum enzyme-linked immunosorbent assay for hepcidin, the principal iron-regulatory hormone that has been very difficult to measure. In healthy volunteers, the 5% to 95% range of hepcidin concentrations was 29 to 254 ng/mL in men (n ‫؍‬ 65) and 17 to 286 ng/mL in women (n ‫؍‬ 49), with median concentrations 112 versus 65 (P < .001). The lower limit of detection was 5 ng/mL. Serum hepcidin concentrations in 24 healthy subjects correlated well with their urinary hepcidin (r ‫؍‬ 0.82). Serum hepcidin appropriately correlated with serum ferritin (r ‫؍‬ 0.63), reflecting the regulation of both proteins by iron stores. Healthy volunteers showed a diurnal increase of serum hepcidin at noon and 8 pm compared with 8 am, and a transient rise of serum hepcidin in response to iron ingestion. Expected alterations in hepcidin levels were observed in a variety of clinical conditions associated with iron disturbances. Serum hepcidin concentrations were undetectable or low in patients with iron deficiency anemia (ferritin < 10 ng/mL), iron-depleted HFE hemochromatosis, and juvenile hemochromatosis. Serum hepcidin concentrations were high in patients with inflammation (C-reactive protein > 10 mg/ dL), multiple myeloma, or chronic kidney disease. The new serum hepcidin enzymelinked immunosorbent assay yields accurate and reproducible measurements that appropriately reflect physiologic, pathologic, and genetic influences, and is informative about the etiology of iron disorders. IntroductionHepcidin is the principal iron-regulatory hormone that mediates the homeostasis of extracellular iron concentrations. 1,2 Although the peptide is initially synthesized as an 84-amino acid preprohepcidin, it is processed in hepatocytes by a signal peptidase and the prohormone convertase furin 3 to its bioactive form, a 25-amino acid peptide circulating in plasma 4,5 and excreted in urine. 5 Hepcidin acts by regulating iron influx into plasma from tissues engaged in iron storage or transport: duodenal enterocytes that absorb dietary iron, hepatocytes that store iron, and macrophages that recycle iron from senescent erythrocytes. At the molecular level, hepcidin binds to the sole known cellular iron efflux channel, ferroportin, and induces its internalization and lysosomal degradation 6 by mechanisms similar to those that inactivate other more conventional membrane receptors. N-terminally truncated breakdown products of hepcidin are detectable in plasma 7 and urine 5,8 but show impaired ability to internalize ferroportin. 9 Hepcidin synthesis is physiologically increased by elevated plasma iron concentration, 10,11 decreased by erythropoietic activity, 12 and pathologically increased by inflammation. 10,13 Hepcidin excess plays the major role in anemia of inflammation [14][15][16] and iron-resistant iron-deficiency anemia. [17][18][19][20] At the opposite extreme, hepcidin deficiency is the cause of iron overload in most hereditary hemochromatoses 21 and contributes to iron overload in ␤-thalassemia and other ir...

Background and objectives: Hepcidin is a key regulator of iron homeostasis, but its study in the setting of chronic kidney disease (CKD) has been hampered by the lack of validated serum assays.Design, setting, participants, & measurements: This study reports the first measurements of bioactive serum hepcidin using a novel competitive ELISA in 48 pediatric (PCKD2-4) and 32 adult (ACKD2-4) patients with stages 2 to 4 CKD along with 26 pediatric patients with stage 5 CKD (PCKD5D) on peritoneal dialysis.Results: When compared with their respective controls (pediatric median ‫؍‬ 25.3 ng/ml, adult ‫؍‬ 72.9 ng/ml), hepcidin was significantly increased in PCKD2-4 (127.3 ng/ml), ACKD2-4 (269.9 ng/ml), and PCKD5D (652.4 ng/ml). Multivariate regression analysis was used to assess the relationship between hepcidin and indicators of anemia, iron status, inflammation, and renal function. In PCKD2-4 (R 2 ‫؍‬ 0.57), only ferritin correlated with hepcidin. In ACKD2-4 (R 2 ‫؍‬ 0.78), ferritin and soluble transferrin receptor were associated with hepcidin, whereas GFR was inversely correlated. In PCKD5D (R 2 ‫؍‬ 0.52), percent iron saturation and ferritin were predictors of hepcidin. In a multivariate analysis that incorporated all three groups (R 2 ‫؍‬ 0.6), hepcidin was predicted by ferritin, C-reactive protein, and whether the patient had stage 5D versus stages 2 to 4 CKD.Conclusions: These findings suggest that increased hepcidin across the spectrum of CKD may contribute to abnormal iron regulation and erythropoiesis and may be a novel biomarker of iron status and erythropoietin resistance.

GSK1278863 induced an effective EPO response and stimulated non-EPO mechanisms for erythropoiesis in anemic non-dialysis-dependent and dialysis-dependent patients with CKD.

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Testosterone administration is associated with suppression of serum hepcidin. Greater increases in hematocrit in older men during testosterone therapy are related to greater suppression of hepcidin.