Potential hazards of recent trends in liberal iron use for renal anemia

A randomized controlled trial,the Proactive IV Iron Therapy in Haemodialysis Patients (PIVOTAL), has recently shown that a high-dose (‘proactive’) intravenous iron regimen was superior to a low-dose (‘reactive’) regimen for hemodialysis patient outcomes and overall safety. However, even in the low-dose group, a substantial amount of iron was administered to maintain serum ferritin >200 ng/mL. This type of comparison may have strongly affected the safety results. Iron has two opposite effects on erythropoiesis: it activates erythroid differentiation directly by supplying iron but inhibits it indirectly by stimulating hepcidin and enhancing oxidative stress. Hepcidin plays an essential role not only in iron homeostasis and the anemia of chronic kidney disease, but also in its complications such as atherosclerosis and infection. Its main stimulation by iron—and to a lesser degree by inflammation—should urge clinicians to avoid prescribing excessive amounts of iron. Furthermore, as serum ferritin is closely correlated with serum hepcidin and iron storage, it would seem preferable to rely mainly on serum ferritin to adjust iron administration, defining an upper limit for risk reduction. Based on our estimations, the optimal range of serum ferritin is ∼50–150 ng/mL, which is precisely within the boundaries of iron management in Japan. Considering the contrasting ranges of target ferritin levels between end-stage renal disease patients in Japan and the rest of the world, the optimal range proposed by us will probably be considered as unacceptable by nephrologists abroad. Only well-balanced, randomized controlled trials with both erythropoiesis-stimulating agents and iron will allow us to settle this controversy.