Hepcidin and HFE protein: Iron metabolism as a target for the anemia of chronic kidney disease

Abstract

The anemia of chronic kidney disease and hemodialysis is characterized by chronic inflammation and release of cytokines, resulting in the upregulation of the iron hormone hepcidin, also increased by iron therapy and reduced glomerular filtration, with consequent reduction in iron absorption, recycling, and availability to the erythron. This response proves advantageous in the short-term to restrain iron availability to pathogens, but ultimately leads to severe anemia, and impairs the response to erythropoietin (Epo) and iron. Homozygosity for the common C282Y and H63D HFE polymorphisms influence iron metabolism by hampering hepcidin release by hepatocytes in response to increased iron stores, thereby resulting in inadequate inhibition of the activity of Ferroportin-1, inappropriately high iron absorption and recycling, and iron overload. However, in hemodialysis patients, carriage of HFE mutations may confer an adaptive benefit by decreasing hepcidin release in response to iron infusion and inflammation, thereby improving iron availability to erythropoiesis, anemia control, the response to Epo, and possibly survival. Therefore, anti-hepcidin therapies may improve anemia management in hemodialysis. However, HFE mutations directly favor hemoglobinization independently of hepcidin, and reduce macrophages activation in response to inflammation, whereas hepcidin might also play a beneficial anti-inflammatory and anti-microbic action during sepsis, so that direct inhibition of HFE-mediated regulation of iron metabolism may represent a valuable alternative therapeutic target. Genetic studies may offer a valuable tool to test these hypotheses and guide the research of new therapies.

HFE mutations and iron in hemodialysis patients

“…In fact, individuals who readily incorporate iron into hemoglobin require lower doses of iron and ESA, have less side effects, and may have a better prognosis . Therefore, identification of the genetic determinants of iron regulation in CHD may reveal novel biomarkers for risk stratification and personalized clinical management and potential new therapeutic targets …”

“…[8][9][10] Therefore, identification of the genetic determinants of iron regulation in CHD may reveal novel biomarkers for risk stratification and personalized clinical management and potential new therapeutic targets. 11…”

Effects of Daprodustat, a Novel Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor on Anemia Management in Japanese Hemodialysis Subjects

“…ability [1] . Erythropoiesis-stimulating agents (ESAs) are used worldwide to treat anemia due to CKD [2] .…”

“…Interestingly, secondary analyses of both the Correction of Hemogloblin and Outcomes in Renal Insufficiency trial [7] and the Trial to Reduce Cardiovascular Events with Aranesp Therapy [8] support the hypothesis that a higher dose of ESA, rather than the hemoglobin level reached, was associated with increased risk for cardiovascular events. In addition, ESAs require adequate iron supplementation [9] , and intravenous (IV) iron supplementation may be associated with infection risk and iron overload in a dose-related manner [1,9] .…”

Iron therapy in chronic kidney disease: Recent changes, benefits and risks

“…ACCEPTED MANUSCRIPT 14 markers of oxidative stress are significantly increased in CKD patients [64,65] and are involved in the progression of renal disease [66].…”