Association of Prohepcidin and Hepcidin-25 with Erythropoietin Response and Ferritin in Hemodialysis Patients

Abstract

Hepcidin is a key regulator of iron metabolism. In this study, we examined whether measurement of hepcidin is useful in assessing recombinant human erythropoietin (rHuEPO) responsiveness in regular hemodialysis (HD) patients in a cross-sectional fashion. We examined the association between serum prohepcidin, a prohormone of hepcidin, and rHuEPO dosage and the rHuEPO/hemoglobin (Hb) ratio in 75 HD patients. We also semiquantatively measured the peak intensity of serum hepcidin-25, the major form of mature hepcidin, in 24 HD patients by using surface-enhanced laser desorption ionization time of flight time mass spectrometry, and compared those between rHuEPO-hyporesponsive (rHuEPO 192 ± 10 [126–252] IU/kg/week, n = 15) and responsive patients (rHuEPO 40 ± 9 [0–81] U/kg/week, n = 9). A significant but weak relationship was found between serum prohepcidin and rHuEPO dosage (r = 0.24, p < 0.05) and rHuEPO/Hb ratio (r = 0.22, p = 0.06). However, prohepcidin did not become an indicator of hematopoietic parameters by multiple regression analysis. Serum hepcidin-25 intensity was significantly and positively correlated with ferritin (r = 0.51, p < 0.01) but not with log-transformed C-reactive protein. There was no difference in the intensities of serum hepcidin-25 between rHuEPO-hyporesponsive and responsive patients (64 ± 10 vs. 52 ± 16 AU, p = NS). It follows from these findings that the assessment of serum hepcidin using currently available assays was not valid in predicting rHuEPO responsiveness in chronic HD patients.

Hyporesponsiveness to Erythropoietin Therapy in Hemodialyzed Patients: Potential Role of Prohepcidin, Hepcidin, and Inflammation

“…In the recent paper of Bradbury et al, [23] CRP appeared to be an independent predictor of greater erythropoietin requirements. In our study, hyporesponsive patients had significantly higher hsCRP than responders as in the study of Kato et al [24] We also found lower serum cholesterol, LDL, and albumin, as well as higher hsCRP and proinflammatory cytokines, suggesting MIA syndrome, a finding not confirmed by Kato et al [24] They observed no difference in hepcidin-25 (measured using SELDI-TOF), whereas in our study, a tendency to higher hepcidin levels (measured by RIA) were found. Similarly, in the study of Shinzato et al, [25] no significant difference in serum prohepcidin was found between HD patients with rHuEPO-resistant anemia and HD patients without anemia and iron deficiency.…”

HFE Mutations Modulate the Effect of Iron on Serum Hepcidin-25 in Chronic Hemodialysis Patients

“…Interestingly, hepcidin levels were correlated with ferritin in these subjects (1,4). Theoretically, increased hepcidin levels may reduce intestinal iron absorption and iron recycling from monocytes (24), decreasing serum iron available for the erythropoiesis (28) and the therapeutic effect of ESAs and i.v.…”

“…I ncreased serum levels of hepcidin, the novel iron hormone inhibiting iron absorption from enterocytes and iron recycling from macrophages, have recently been reported in patients with end-stage renal disease (ESRD), and hypothesized to contribute to the alterations of iron metabolism and anemia of ESRD (1)(2)(3)(4)(5).…”

“…In previous studies, elevated levels of serum prohepcidin, an immature form of hepcidin measured by ELISA, were found in patients with ESRD (2). However, pro-hepcidin levels have not been found to correlate with mature biologically active hepcidin and with iron stores (1,27). …”

Role of hepcidin in recombinant human erythropoietin therapy resistance among chronic hemodialysis patients

“…In addition to its effect on iron metabolism; hepcidin may contribute to rhEPO resistance through a direct inhibitory effect on erythroid progenitor proliferation and survival [5]. Other studies revealed contradictory results; Kato et al [19] found hepcidin levels were not different between rhEPO-responsive and rhEPO resistant dialysis patients, whereas Ford et al [20] found no relationship of hepcidin with rhEPO dose. Over expression of hepcidin in animals impairs the response to even supra physiological doses of rhEPO [21].…”