HFE mutations modulate the effect of iron on serum hepcidin-25 in chronic hemodialysis patients.
OBJECTIVE
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.


METHODS
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.
Valenti
Luca
L
Center for Metabolic and Liver Diseases, Department of Internal Medicine, Universitá degli Studi di Milano,Fondazione Ospedale Maggiore Policlinico MaRE IRCCS, Via F Sforza 35, 20122 Milano, Italy. luca.valenti@unimi.it
Girelli
Domenico
D
Valenti
Giovanni Francesco
GF
Castagna
Annalisa
A
Como
Giovanna
G
Campostrini
Natascia
N
Rametta
Raffaela
R
Dongiovanni
Paola
P
Messa
Piergiorgio
P
Fargion
Silvia
S
D000328:Adult; D000368:Aged; D000740:Anemia / Q000097:blood / Q000209:etiology* / Q000235:genetics; D023181:Antimicrobial Cationic Peptides / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D016022:Case-Control Studies; D004920:Erythropoiesis; D005260:Female; D005293:Ferritins / Q000097:blood; D005838:Genotype; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000235:genetics; D007501:Iron / Q000097:blood*; D007676:Kidney Failure, Chronic / Q000097:blood / Q000150:complications / Q000235:genetics / Q000628:therapy*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D006435:Renal Dialysis; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D055815:Young Adult
D023181:Antimicrobial Cationic Peptides; D015415:Biomarkers; C578702:HAMP protein, human; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D002097:C-Reactive Protein; D005293:Ferritins; D007501:Iron