<i>HFE</i> Genotype Influences Erythropoiesis Support Requirement in Hemodialysis Patients: A Prospective Study

Abstract

Background/Aims: HFE protein controls iron absorption and cycling, and HFE mutations influence iron status. The aim was to evaluate the effect of the HFE genotype on the need for iron and erythropoietin in Italian hemodialysis patients. Methods: Ninety-six prevalent patients were evaluated at the time of enrolment and prospectively followed for 3 years. Patients were given r-HuEPO and Fe³⁺-gluconate according to guidelines. The HFE genotype was determined by restriction analysis. Results: Three patients (3%) carried the C282Y mutation, 4 (4%) were homozygous and 18 (19%) heterozygous for the H63D mutation, and 71 (74%) were negative for both. At enrolment, subjects positive for HFE mutations had higher iron stores (ferritin 617 ± 663 vs. 423 ± 386 ng/ml, p = 0.05), were receiving less iron (82.5 ± 66 vs. 110 ± 154 mg/month, p = 0.05) and a lower r-HuEPO dosage (98 ± 83 vs. 142 ± 138 U/kg/week, p = 0.03). Consistently during the study period, patients positive for HFE mutations received a lower amount of r-HuEPO (94.5 ± 63 vs. 186 ± 344 U/kg/week, p = 0.01) and iron (97 ± 63 vs. 121 ± 68 mg/month, p = 0.07). Upon Cox regression analysis, after adjustment for confounding variables, the presence of HFE mutations was associated with a reduced risk of death (HR 0.6, 95% CI 0.34–1.03, p = 0.06). Conclusion:HFE mutations reduce the amount of r-HuEPO and iron necessary to support erythropoiesis in hemodialysis.

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

“…This hypothesis is supported by recent data by our group indicating that frequent HFE mutations, affecting about 30% of Caucasians and believed to cause a relative deficit in hepcidin release (30,34), are associated with higher iron availability, more efficient erythropoiesis, and possibly a better prognosis (31). In the general population, the C282Y HFE mutation is detected in about 3 to 10%, whereas the H63D in about 22 to 28% of subjects.…”

“…iron, as commonly observed in CHD patients (3). Supporting this hypothesis, we recently reported that frequent mutations in the HFE gene, which decrease hepcidin response to iron stores (29,30), are associated with increased sensitivity to ESAs and iron in CHD patients, and may be associated with a better clinical outcome (31). However, in a study considering a series of 24 patients, hepcidin-25 was not significantly associated with r-HuEpo responsiveness (1).…”

“…Exclusion criteria were active major infectious diseases (pneumonia, sepsis), neoplasia, congestive heart failure (NYHA stage III and IV), unstable ischemic heart disease, hepatic failure, and the ␤-thalassemic trait. Part of this series has previously been described elsewhere in detail (12,31).…”

Modulation of Iron Metabolism and Hepcidin Release by HFE Mutations in Chronic Hemodialysis Patients: Pathophysiological and Therapeutic Implications

“…Finally, chronic iron supplementation is a strong inducer of hepcidin also in CHD patients, thereby paradoxically hampering the optimal utilization of large doses of administered iron. Indeed, overall evidence indicate that serum ferritin and C reactive protein levels, reflecting iron stores and inflammation, are the major determinants of hepcidin levels in CHD and ESRD (Tomosugi, Kawabata et al 2006;Kato, Tsuji et al 2008;Valenti, Girelli et al 2009 (Valenti, Valenti et al 2008). Moreover, we recently reported that frequent mutations in the HFE gene, which decrease hepcidin response to iron stores (Piperno, Girelli et al 2007;Vujic Spasic, Kiss et al 2008), are associated with increased sensitivity to ESAs and iron in CHD patients, and may be associated with a better clinical outcome (Valenti, Valenti et al 2008).…”

“…Indeed, overall evidence indicate that serum ferritin and C reactive protein levels, reflecting iron stores and inflammation, are the major determinants of hepcidin levels in CHD and ESRD (Tomosugi, Kawabata et al 2006;Kato, Tsuji et al 2008;Valenti, Girelli et al 2009 (Valenti, Valenti et al 2008). Moreover, we recently reported that frequent mutations in the HFE gene, which decrease hepcidin response to iron stores (Piperno, Girelli et al 2007;Vujic Spasic, Kiss et al 2008), are associated with increased sensitivity to ESAs and iron in CHD patients, and may be associated with a better clinical outcome (Valenti, Valenti et al 2008). However, in a preliminary report hepcidin-25 was not significantly associated with Epo responsiveness (Kato, Tsuji et al 2008), and in another recent study an association between greater iron doses, increased darbepoietin resistance index, and low hepcidin levels, possibly downregulated by ESAs and anemia, was detected (Bratescu, Barsan et al 2010), thus suggesting that other mechanisms besides increased hepcidin are involved in the pathogenesis of anemia in CHD.…”