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.