More than a decade of experience and still no consensus: controversies in iron therapy.

D uring the past decade, the integration of recombinant human erythropoietin (EPO) and maintenance intravenous iron therapy into standard anemia management protocols has significantly altered the treatment of anemia in patients who are on hemodialysis (HD). Hemoglobin levels have increased inexorably and now average almost 12 g/dl (1). The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines state that intravenous iron usually is required for the provision of optimal iron stores to maximize erythropoiesis-stimulating agent (ESA) efficiency in patients who are on dialysis (2). Intravenous iron therapy is needed in patients who are on HD because these patients experience ongoing blood (iron) losses, and oral iron fails to maintain adequate iron stores. Efficient erythropoiesis requires both iron and erythropoietin (2). In these patients, intravenous iron improves iron and hematologic parameters, with health benefits of intravenous iron outweighing potential adverse effects. Use of maintenance iron improves patients’ response to EPO therapy (3), replaces patients’ ongoing iron losses, and helps to maintain patients’ target hemoglobin and hematocrit ranges. These benefits of intravenous iron therapy have been achieved at storage iron levels far below those that generally were seen with transfusions in the pre-EPO era (4). However, according to Medicare claims data from the US Renal Data System, only slightly more than half of HD patients receive intravenous iron therapy at least once a month, demonstrating that although intravenous iron therapy is being administered to the majority of HD patients, it may not be used on a regular basis (5). Although the reasons for lack of “regular” intravenous iron may be many, such as concerns about iron parameters, particularly ferritin levels, it also may reflect variation in protocols among centers. The KDOQI guidelines were a milestone in the development of effective, standardized principles for the management of anemia in patients with chronic kidney disease (CKD) (4). The KDOQI guidelines provided a framework for developing a maintenance intravenous iron protocol with sufficient flexibility in the actual dose regimen. As a result, thrice-weekly, weekly, every-other-week, or once-monthly or less frequent schedules are used to provide 25 to 125 mg/wk or 100 to 1000 mg of intravenous iron within 12 to 16 wk, depending on needs. Nevertheless, the guidelines left a number of important management questions unanswered, because of a lack of comprehensive evidence that is needed to develop particular recommendations. The increasing prevalence of comorbid conditions in an aging population, however, has made the traditional iron indices of transferrin saturation (TSAT) and serum ferritin as measures of iron sufficiency problematic, particularly so in diagnosing functional iron deficiency (6). The latest 2006 version of the KDOQI anemia guidelines (2) in fact caution about the regular administration of iron when ferritin levels exceed 500, levels that are much lower than those previously experienced by HD patients in an era of no ESA, when transfusions were the only effective means of maintaining some functional capacity in severely anemic patients. In this supplement, the first two articles examine in-depth the indices that are used to assess iron stores in patients with iron deficiency anemia. Serum ferritin and TSAT, widely used tests to measure iron levels, have significant sensitivity and specificity limitations in identifying patients with iron deficiency or iron excess. This is because both transferrin and ferritin are acute-phase reactants but in opposite directions, are affected by nutrition (7), and in the case of TSAT have significant diurnal variation. Wish (8) and Kalantar-Zadeh et al. (9) discuss the meaning of these “iron tests,” specifically serum ferritin. At issue is whether we are striking the right balance between our choices for intravenous iron therapy in anemic HD patients— enhanced treatment outcomes, minimized short-term and potential long-term safety risks, and cost-effectiveness—by focusing too much on the ferritin level. As Wish (8) emphasizes, the previous upper ferritin level of 800 ng/ml (now lowered to 500) was never evidence based but merely served as a large buffer zone between the values “desired” and values of 2000 ng/ml that are associated with tissue deposition in hemochromatosis patients (4). As reviewed by Wish (8), several studies in the past decade have evaluated additional and allegedly more accurate indices of iron status that better predict response to additional iron than the traditional ones (10,11). Although some of these markers, including the reticulocyte hemoglobin content (12) and percentage of hypochromic red cells (13), show promise for identifying iron deficiency and iron overload, none yet has the combination of accuracy, ease of use, cost-effectiveness, and widespread availability of the traditional tests. This article as Address correspondence to: Dr. Anatole Besarab, Division of Nephrology and Hypertension, Henry Ford Hospital, 2799 West Grand Boulevard., Detroit, MI 48202. Phone: 313-916-2713; Fax: 313-916-2554; E-mail: [email protected], [email protected]