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

Luca Valenti^*, Domenico Girelli, Giovanni Francesco Valenti, Annalisa Castagna, Giovanna Como, Natascia Campostrini, Raffaela Rametta^*, Paola Dongiovanni^*, Piergiorgio Messa, and Silvia Fargion^*

^* Center for Metabolic and Liver Diseases, Department of Internal Medicine, Università degli Studi di Milano, Fondazione Ospedale Maggiore Policlinico MaRE IRCCS, Milano, Italy; Department of Clinical and Experimental Medicine, University of Verona, Policlinico GB Rossi, Verona, Italy; and Department of Nephrology, Fondazione Ospedale Maggiore Policlinico MaRE IRCCS, Milano, Italy

Correspondence: Luca Valenti or Silvia Fargion, Department of Internal Medicine, UO Medicina Interna 1B, University of Milano, Ospedale Policlinico Mangiagalli e Regina Elena Fondazione IRCCS, Via F Sforza 35, 20122 Milano, Italy. Phone: 39 2 55036286; Fax: 39 2 50320296; E-mail: luca.valenti{at}unimi.it or silvia.fargion{at}unimi.it

Background and objectives: Increased serum hepcidin has been reported in patients receiving chronic hemodialysis, and hypothesized to contribute to the alterations of iron metabolism of end-stage renal disease. However, no quantitative assessment is available to date; the clinical determinants are still under definition; and the role of genetic factors, namely HFE mutations, has not yet been evaluated. The aim of this study was to quantitatively assess serum hepcidin-25 in hemodialysis patients versus controls, and analyze the relationship between hepcidin, iron indices, HFE genotype, and erythropoietic parameters.

Design, setting, participants & measurements: Sixty-five hemodialysis patients and 57 healthy controls were considered. Hepcidin-25 was evaluated by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry, HFE genotype by restriction analysis.

Results: Serum hepcidin-25 was higher in hemodialysis patients compared with controls. In patients, hepcidin-25 correlated positively with ferritin and C reactive protein, and negatively with serum iron after adjustment for confounders. Hepcidin/ferritin ratio was lower in patients with (n = 25) than in those without (n = 40) HFE mutations. At multivariate analysis, hepcidin-25 was independently associated with ferritin and HFE status. In a subgroup of 22 "stable" patients, i.e., with Hb levels on target, normal CRP levels, and absence of complications for at least 1 yr, hepcidin-25 was negatively correlated with Hb levels independently of confounders.

Conclusions: Serum hepcidin-25 is increased in hemodialysis patients, regulated by iron stores and inflammation, and relatively reduced in subjects carrying frequent HFE mutations. Hepcidin-25 may contribute to the pathogenesis of anemia by decreasing iron availability.