Considerations and Challenges in Defining Optimal Iron Utilization in Hemodialysis

Abstract

Trials raising concerns about erythropoiesis-stimulating agents, revisions to their labeling, and changes to practice guidelines and dialysis payment systems have provided strong stimuli to decrease erythropoiesis-stimulating agent use and increase intravenous iron administration in recent years. These factors have been associated with a rise in iron utilization, particularly among hemodialysis patients, and an unprecedented increase in serum ferritin concentrations. The mean serum ferritin concentration among United States dialysis patients in 2013 exceeded 800 ng/ml, with 18% of patients exceeding 1200 ng/ml. Although these changes are broad based, the wisdom of these practices is uncertain. Herein, we examine influences on and trends in intravenous iron utilization and assess the clinical trial, epidemiologic, and experimental evidence relevant to its safety and efficacy in the setting of maintenance dialysis. These data suggest a potential for harm from increasing use of parenteral iron in dialysisdependent patients. In the absence of well powered, randomized clinical trials, available evidence will remain inadequate for making reliable conclusions about the effect of a ubiquitous therapy on mortality or other outcomes of importance to dialysis patients. Nephrology stakeholders have an urgent obligation to initiate well designed investigations of intravenous iron in order to ensure the safety of the dialysis population.

New Options for Iron Supplementation in Maintenance Hemodialysis Patients

“…IV iron can lead to transient oxidative stress by increasing the level of non-transferrin-bound iron in the circulation and the catalytically active labile iron pool. In US patients treated with HD, the use of IV iron as the primary route of iron supplementation following the introduction of ESAs in 1989 has led to a progressive increase in mean serum ferritin levels in this population (Table 1 30,[32][33][34][35][36] ). This has raised concerns regarding the safety of IV iron for HD patients and was a key factor in a 2014 report by the Dialysis Advisory Group of the American Society of Nephrology stressing an "urgent obligation to initiate well designed investigations of intravenous iron in order to ensure the safety of the dialysis population."…”

Iatrogenic iron overload and its potential consequences in patients on hemodialysis

“…Its consensus statements recognized the "iron overload'' entity in hemodialysis patients and called for a specific research agenda [19]. Finally, in June 2015 the Dialysis Advisory Group of the American Society of Nephrology published an updated recommendation on uncertainties of usage of high-dose of intravenous iron in hemodialysis patients [20]. It is noteworthy that the Japanese Society for Dialysis had already proposed, some years ago, that dialysis patients should receive a minimal amount of IV iron, only if they had true iron deficiency (ferritin < 100 mg/L), and had also warned against maintenance intravenous iron therapy for fear of toxicity [21].…”

“…Iron overload in hemodialysis patients has been inadvertently encouraged by reimbursement policies in the USA and many other industrialized countries, which have led to an increase in the use of IV iron in an attempt to reduce ESA dose requirements [9,20]. The situation has been compounded by excessively high recommended doses of IV iron and, possibly, by erroneous iron biomarker targets which lead to supraphysiological iron stores [8,9].…”

“…The situation has been compounded by excessively high recommended doses of IV iron and, possibly, by erroneous iron biomarker targets which lead to supraphysiological iron stores [8,9]. Also, nephrologists have come to fear the adverse effects of ESA whilst wrongly believing that iron IV products are nontoxic [20]. Major changes in the approach to iron therapy have occurred recently.…”

“…Second, the KDIGO Controversies Conference on Iron Management in Chronic Kidney Disease, which took place in San Francisco in March 2014, recognized the entity of iron overload in hemodialysis patients (together with other adverse effects) and called for a research agenda on this topic [19]. Third, the Dialysis Advisory Group of the American Society of Nephrology proposed an aggiornamento on the policy of high "blind'' usage of IV iron products in hemodialysis patients [20]. Recent reviews of anemia and iron therapy in CKD, published in hematology and nephrology journals, now give a more balanced view, emphasizing not only the benefits but also the potential risks of IV iron products, including the danger of iron overload [82][83][84].…”