Iatrogenic Iron Overload in Dialysis Patients at the Beginning of the 21st Century

Abstract

Iron overload used to be considered rare in hemodialysis patients but its clinical frequency is now increasingly realized. 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 hemosideroses and genetic hemochromatosis. Magnetic resonance imaging is now the gold standard method for LIC estimation and monitoring in non-renal patients. Studies of LIC in hemodialysis patients by quantitative magnetic resonance imaging and magnetic susceptometry have demonstrated a strong 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. Three long-term observational studies have recently suggested that excessive IV iron doses may be associated with an increased risk of cardiovascular events and death in hemodialysis patients. We postulate that iatrogenic iron overload in the era of erythropoiesis-stimulating agents may silently increase complications in dialysis patients without creating frank clinical signs and symptoms. High hepcidin-25 levels were recently linked to fatal and nonfatal cardiovascular events in dialysis patients. It is therefore tempting to postulate that the main pathophysiological pathway leading to these events may involve the pleiotropic master hormone hepcidin (synergized by fibroblast growth factor 23), which regulates iron metabolism. Oxidative stress as a result of IV iron infusions and iron overload, by releasing labile non-transferrin-bound iron, might represent a 'second hit' on the vascular bed. Finally, iron deposition in the myocardium of patients with severe iron overload might also play a role in the pathogenesis of sudden death in some patients.

Fig. 1

Results of a cross-sectional quantitative magnetic resonance imaging (MRI) study of 119 hemodialysis patients (according to [3] and [8])

Fig. 2

Correlation between the infused iron dose and hepatic iron stores in 11 hemodialysis patients studied by quantitative magnetic resonance imaging (according to [8])

Fig. 3

Time course of hepatic iron stores studied by magnetic resonance imaging in hemodialysis patients (according to [8]). a Initial and final hepatic iron concentrations on magnetic resonance imaging (MRI) in 11 patients receiving iron therapy (median time is given in abcissa). b Initial and final hepatic iron concentrations on MRI in 33 patients with hepatic iron overload, after iron withdrawal (n = 19) or a major iron dose reduction (n = 14) (median time is given in abcissa)