Iatrogenic iron overload and its potential consequences in patients on hemodialysis

Iron overload was considered rare in hemodialysis patients until recently, but its clinical frequency is now increasingly recognized. The liver is the main site of iron storage and the liver iron concentration (LIC) is closely correlated with total iron stores in patients with secondary hemosiderosis and genetic hemochromatosis. Magnetic resonance imaging (MRI) is now the gold standard method for estimating and monitoring LIC. Studies of LIC in hemodialysis patients by magnetic susceptometry thirteen years ago and recently by quantitative MRI have demonstrated a relation between the risk of iron overload and the use of intravenous (IV) iron products prescribed at doses determined by the iron biomarker cutoffs contained in current anemia management guidelines. These findings have challenged the validity of both iron biomarker cutoffs and current clinical guidelines, especially with respect to recommended IV iron doses. Moreover, three recent long-term observational studies suggested that excessive IV iron doses might be associated with an increased risk of cardiovascular events and death in hemodialysis patients. It has been hypothesized that iatrogenic iron overload in the era of erythropoiesis-stimulating agents might silently increase complications in dialysis patients without creating obvious, clinical signs and symptoms. High hepcidin-25 levels were recently linked to fatal and nonfatal cardiovascular events in dialysis patients. It has been postulated that the main pathophysiological pathway leading to these events might involve the pleiotropic master hormone hepcidin, which regulates iron metabolism, leading to activation of macrophages in atherosclerotic plaques and then to clinical cardiovascular events. Thus, the potential iron overload toxicity linked to chronic administration of IV iron therapy is now becoming one of the most controversial topics in the management of anemia in hemodialysis patients.