Hepcidin seems to have no direct effect on the iron status of erythrocytes, and expression of hepcidin is induced by a certain intensity of inflammatory stimulation. Long-acting rHuEPO stimulates erythropoiesis in the bone marrow, which utilizes iron, restores the Hb level, and then reduces the serum hepcidin level.
Measurements of serum hepcidin levels have not been reliable, because its protein structure is not specifically detected by enzyme immunoassay [10
]. However, SELDI-TOF MS has made it possible to measure serum hepcidin levels [4
]. There have been several reports regarding serum hepcidin levels in chronic kidney disease (CKD) [11
]. Increased serum hepcidin levels were originally demonstrated in hemodialysis patients by the SELDI-TOF-MS method [4
]. Although the absolute values of hepcidin have not been established, many reports have confirmed elevation of serum hepcidin levels in hemodialysis patients. The serum hepcidin levels of predialysis CKD patients tend to increase as their glomerular filtration rates are declined [14
], and they have been found to be altered by erythropoietin or intravenous iron administration. Several factors, including endogenous and exogenous erythropoietin, decreased erythropoiesis in the bone marrow, iron deficiency as a result of dietary restriction and overloading due to negative erythropoiesis, chronic stress conditions in CKD, and so forth, tend to modify hepcidin production and function. Thus, it is not easy to discriminate the pathophysiological condition of hepcidin status in CKD [16
In this study, serum hepcidin levels were measured to clarify the role of hepcidin in PD patients, who had been receiving an injection of erythropoietin every month. The serum hepcidin level of PD patients may be affected by several factors, including continuous artificial fluid retention, chronic peritoneal irritation by the dialysate, and occult infection or inflammation in the peritoneum. There have been no reports regarding the serum hepcidin levels of PD patients measured by the SELDI-TOF-MS method. Malyszick L reported the serum hepcidin levels of PD patients measured as prohepcidin by enzyme assay. The hepcidin levels in that study were found to be correlated with residual kidney function, but the investigators measured prohepcidin and hepcidin by enzyme assays [17
]. In the present study, the mean serum hepcidin level of the PD patients was 80.7 ± 59.4
ng/mL, which was higher than the previously reported level measured by the SELDI-TOF-MS method in hemodialysis patients.
Hepcidin is thought to be the major regulator of dietary iron absorption and cellular iron release, and it exerts its regulatory function by counteracting the function of ferroportin, the major cellular iron exporter in the various cells membrane [19
]. Hepcidin induces the internalization and degradation of ferroportin [20
], resulting in increasing intracellular iron stores, decreased dietary iron absorption, and decreased circulating iron levels. Hepcidin controls the entry of iron into the plasma mediated by ferroportin, and there is a crosstalk between plasma iron saturation or iron stores and plasma hepcidin level in physiological state. Iron stores and circulating transferrin bound iron provide distinct signals that affect hepcidin synthesis in hepatocytes [21
], resulting in the positive correlation between serum iron biomarkers and hepcidin levels.
In addition, several physiologic and pathologic processes regulate hepcidin synthesis. Hepcidin levels are likely to be regulated by several independent mechanisms, as previously reviewed [23
]. Conditions in which demand for circulating iron is increased induce a decrease in hepatocellular hepcidin synthesis, and a decrease in the serum hepcidin level results in the release of stored iron and an increase in dietary iron absorption. Such conditions include iron deficiency, hypoxia, and condition in which erythropoietic activity is increased. Particularly, high erythropoietic activity demands sufficient iron supply suppresses hepcidin synthesis. Thus, there is negative correlation between Hb concentration and hepcidin levels as shown in .
In this study, the similar relation among hepcidin levels, Hb concentration, and iron parameters except for RET-He could be observed. PD patients' serum hepcidin levels were significantly positively correlated with their serum ferritin and TSAT levels, but no correlations were found between their serum hepcidin levels and RET-He levels, suggesting that hepcidin has no effect on the iron dynamics of reticulocytes. Stimulation of erythropoiesis by ESA therapy increases the demand for instantly available iron, which often proves insufficient even in patients whose whole body iron store is not significantly depleted [24
]. Absolute iron deficiency in HD patients has been defined on the basis of TSAT and serum ferritin levels, whereas functional iron deficiency results when there is a need for a greater amount of iron to support erythropoiesis than can be supplied. Thus, the conventional methods of estimating iron stores, such as serum ferritin and TSAT measurements, are inadequate to evaluate functional iron deficiency. A strong correlation between serum ferritin and TSAT levels and serum hepcidin levels has been confirmed, but there is no information about the relation between hepcidin and reticulocyte hemoglobin. No correlation was found between the serum hepcidin levels and reticulocyte hemoglobin levels in this study, suggesting that hepcidin does not directly regulate iron metabolism in newly produced erythrocytes.
The primary mediator of inflammation seems to be IL-6, which causes the signal transducer and activator of transcription-3 to bind to the hepcidin promoter, increasing its activity [26
]. Previous studies have shown markedly increased serum hepcidin levels in humans with chronic infections and severe inflammatory diseases, suggesting that elevated serum hepcidin levels play a key role in the anemia of inflammation and reticuloendothelial blockade [27
]. Correlations between serum hepcidin levels and serum levels of inflammatory markers, including IL-6, IL-1, and high sensitive CRP, have been found in several studies [4
]. However, several studies have not necessarily shown the relationship between serum hepcidin levels and the levels of these inflammatory markers [11
]. Since low levels of CRP and IL-6, biomarkers of inflammation, were not correlated with the serum hepcidin levels, there is likely to be a threshold for stimulation of hepcidin induction by inflammation.