Intravenous iron and chronic kidney disease
Authors: Michael Auerbach
Journal: American Journal of Hematology (2014)

To the Editor: This is the sixth in a series of short articles concerning iron deficiency and the role of intravenous (IV) iron. Those of us investigating many roles of IV iron in a host of settings associated with iron lack owe our careers to the nephrologists. Prior to the release of recombinant erythropoietin for dialysis-associated anemia, IV iron was considered dangerous and used only in those circumstances where oral iron was either not tolerated or ineffective and transfusions considered imprudent. Few realized the role IV iron would subsequently play in the standard treatment paradigm in these patients. For years, patients on dialysis had to endure the exhaustion associated with severe anemia or suffer the risks of chronic transfusions. Dialysis patients had a life expectance of approximately 3 years. The availability of erythropoietin should have generated enormous enthusiasm, however, 2 years after its release the average hemoglobin in patients on dialysis in the United States was less than 10 g, fewer than 40% were treated to target and many not treated at all due to perceived ineffectiveness. The causes of lack of benefit were not well understood and thought to be due to bleeding, absolute iron deficiency or anemia of chronic disease due to other comorbid conditions. Functional iron deficiency, better described as iron-restricted erythropoiesis due to upregulation of hepcidin had not been yet described. Then, in 1987, the seminal work of Eschbach and Adamson 1 demonstrated in patients with iron parameters ubiquitously agreed to be consistent with iron repletion, who were hyporesponsive to erythropoietin, the addition of IV iron markedly improved response rates and allowed decrements in the much more expensive erythropoietin doses. These data were corroborated by Fishbane et al. (AJKD) who not only duplicated the data but also reported that the addition of oral iron added nothing to response rate or allowed decrement in erythropoietin dosing 2. As a result, IV iron rapidly became a standard adjunct to erythropoietic therapy in dialysis patients with observed improvements in energy, activity, quality of life, sexual function, cognitive function, ability to work, and even survival with average lifespans increasing to more than 4 years. Curiously, until this year the superiority of IV iron over oral iron in nondialysis chronic kidney disease (CKD) was less clear. Several early randomized trials compared oral to IV iron in nondialysis CKD and reported inconsistent findings 3-5 resulting in no consensus on the routine use of IV iron in predialysis CKD, despite the preponderance of published evidence favoring its use. Similar conclusions were drawn by a Cochrane meta-analysis which showed an increase in hemoglobin concentration and iron stores associated with the use of IV but that the benefit was small 6. Subsequently the 2012 KDIGO guidelines for iron supplementation recommend IV iron as the preferred route of administration for dialysis-associated anemia but state that there is insufficient evidence at this to support the routine use of IV iron as an adjunct to erythropoietic therapy for anemia in nondialysis CKD. The controversy was further confounded when a large, highly powered study comparing the use of darbepoietin alpha in patients with anemia associated with nondialysis CKD to placebo reported no benefit in survival or quality of life with treatment compared to control 7. In this study, 88% of the subjects did not receive IV iron and there was an imbalance for its use favoring the control arm. Three recent prospective, randomized studies, serve to clarify this dilemma. Qunibi et al., randomized 255 subjects with glomerular filtration rates <45 mL/min to either erythropoiesis stimulating agent (ESA) alone or 1,000 mg of ferric carboxymaltose and reported that IV iron was better tolerated and significantly more effective 8. These findings were corroborated by Yessayan et al., who randomized 150 iron naïve patients with nondialysis CKD and anemia to oral or IV low molecular weight iron dextran and concluded that the IV iron group had significantly higher hemoglobin responses with fewer clinically significant adverse events 9. Strongly corroborating these findings, in the largest study ever performed on this subject, Macdougall et al., randomized 626 patients with nondialysis dependent CKD, anemia, and iron deficiency not receiving ESA to either IV ferric carboxymaltose or oral iron and concluded that compared with oral iron, IV iron targeting a ferritin of 400–600 µg/L quickly reached and maintained hemoglobin level and delayed and/or reduced the need for other anemia management tools including ESAs. Furthermore, no renal toxicity and no difference in cardiovascular or infectious events, all predefined endpoints were observed 10. At a time with diminishing resources, these compelling data from prospective, randomized trials, suggests that IV iron become a standard in the treatment paradigm for anemia in nondialysis dependent CKD, as it has in dialysis-associated anemia for the last two decades. Michael Auerbach* Auerbach Hematology and Oncology, 9110 Philadelphia Rd Suite 314, Baltimore, Maryland 21237