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

Canavesi, Elena; Valenti, L.

doi:10.5772/22735

Cited by 2 publications

(10 citation statements)

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“…We previously reported that in CHD patients common HFE mutations that alter hepatic iron sensing [13] were associated with lower hepcidin levels relatively to iron stores [6,14], achievement of target Hb levels for lower doses of iron, and with reduced mortality due to sepsis and cardiovascular disease, previously linked to more intense iron supplementation [15-18]. These initial results are in line with the hypothesis that inhibition of hepcidin in CHD may improve anemia control, and even survival in CHD patients [2,3,19,20]. …”

Section: Introductionmentioning

confidence: 75%

“…In CHD patients, it is usually difficult to control anemia because of a complex derangement of iron metabolism, which is due to chronic inflammation, blood losses, and concomitant Epo administration [2]. Increased serum levels of hepcidin, the hepatic hormone regulating iron metabolism, have been suggested to contribute to the functional iron deficiency that limit erythropoiesis in CHD [2,3,31].…”

Section: Discussionmentioning

confidence: 99%

“…Treatment is based on erythropoiesis stimulating agents in association with intravenous (i.v.) iron formulations, but is of often difficult to achieve and maintain the desired hemoglobin (Hb) levels without incurring in side effects [2,3]. …”

Section: Introductionmentioning

confidence: 99%

“…ESRD is characterized by major alterations in iron metabolism including low transferrin saturation (TS), resulting in reduced iron availability for the erythroblasts, and hyperferritinemia [2,4]. Upregulation of serum levels of hepcidin, the hepatic hormone regulating systemic iron metabolism, has been proposed to explain the alterations of iron metabolism of CHD patients and the resistance to anemia treatment [5,6].…”

Section: Introductionmentioning

confidence: 99%

“…Upregulation of serum levels of hepcidin, the hepatic hormone regulating systemic iron metabolism, has been proposed to explain the alterations of iron metabolism of CHD patients and the resistance to anemia treatment [5,6]. Increased serum levels of hepcidin have indeed been reported in ESRD and CHD [2,5,7-11]. In response to increased iron stores, hepcidin inhibits intestinal iron absorption and iron recycling from monocytes by binding and inactivating the iron exporter Ferroportin-1.…”

Section: Introductionmentioning

confidence: 99%

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The A736V TMPRSS6 polymorphism influences hepcidin and iron metabolism in chronic hemodialysis patients: TMPRSS6 and hepcidin in hemodialysis

et al. 2013

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BackgroundAim of this study was to evaluate whether the A736V TMPRSS6 polymorphism, a major genetic determinant of iron metabolism in healthy subjects, influences serum levels of hepcidin, the hormone regulating iron metabolism, and erythropoiesis in chronic hemodialysis (CHD).MethodsTo this end, we considered 199 CHD patients from Northern Italy (157 with hepcidin evaluation), and 188 healthy controls without iron deficiency, matched for age and gender. Genetic polymorphisms were evaluated by allele specific polymerase chain reaction assays, and hepcidin quantified by mass spectrometry.ResultsSerum hepcidin levels were not different between the whole CHD population and controls (median 7.1, interquartile range (IQR) 0.55-17.1 vs. 7.4, 4.5-17.9 nM, respectively), but were higher in the CHD subgroup after exclusion of subjects with relative iron deficiency (p = 0.04). In CHD patients, the A736V TMPRSS6 polymorphism influenced serum hepcidin levels in individuals positive for mutations in the HFE gene of hereditary hemochromatosis (p < 0.0001). In particular, the TMPRSS6 736 V variant was associated with higher hepcidin levels (p = 0.017). At multivariate analysis, HFE and A736V TMPRSS6 genotypes predicted serum hepcidin independently of ferritin and C reactive protein (p = 0.048). In patients without acute inflammation and overt iron deficiency (C reactive protein <1 mg/dl and ferritin >30 ng/ml; n = 86), hepcidin was associated with lower mean corpuscular volume (p = 0.002), suggesting that it contributed to iron-restricted erythropoiesis. In line with previous results, in patients without acute inflammation and severe iron deficiency the “high hepcidin” 736 V TMPRSS6 variant was associated with higher erythropoietin maintenance dose (p = 0.016), independently of subclinical inflammation (p = 0.02).ConclusionsThe A736V TMPRSS6 genotype influences hepcidin levels, erythropoiesis, and anemia management in CHD patients. Evaluation of the effect of TMPRSS6 genotype on clinical outcomes in prospective studies in CHD may be useful to predict the outcomes of hepcidin manipulation, and to guide treatment personalization by optimizing anemia management.

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Section: Introductionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The A736V TMPRSS6 polymorphism influences hepcidin and iron metabolism in chronic hemodialysis patients: TMPRSS6 and hepcidin in hemodialysis

et al. 2013

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HFE mutations and iron in hemodialysis patients

Valenti

Pelusi

2017

Hemodialysis International

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In chronic hemodialysis patients, a disruption in iron metabolism ranging from absolute to functional deficiency, with compartmentalization of this metal into macrophages, is often observed. Chronic inflammation indeed often causes an upregulation of the iron hormone hepcidin, thereby reducing iron absorption and availability to the erythron. We systematically reviewed the literature on the role of genetic risk factors on iron metabolism in hemodialysis. In this setting, mutations in the HFE gene of hereditary hemochromatosis may confer an adaptive benefit by decreasing hepcidin release, thus improving iron availability to erythropoiesis, anemia control, and the response to erythropoiesis stimulating agents and iron itself, and reducing the side effects of these therapies. The HFE protein together with Transferrin receptor-2 may also have a direct role on erythroid differentiation and iron uptake in erythroid cells. In addition, other genetic determinants of iron status, such as variants in Matriptase-2 (TMPRSS6), have been shown to influence iron metabolism in chronic hemodialysis patients, most likely acting through hepcidin regulation. Although data must be confirmed in larger prospective studies, this favorable shift in iron metabolism balance possibly results in reduced mortality, in particular because of cardiovascular and infective diseases. Further genetic studies may offer a valuable tool to test these hypotheses and guide personalized clinical management and the research of new therapies.

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

Cited by 2 publications

References 151 publications

The A736V TMPRSS6 polymorphism influences hepcidin and iron metabolism in chronic hemodialysis patients: TMPRSS6 and hepcidin in hemodialysis

The A736V TMPRSS6 polymorphism influences hepcidin and iron metabolism in chronic hemodialysis patients: TMPRSS6 and hepcidin in hemodialysis

HFE mutations and iron in hemodialysis patients

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