Erythropoiesis-stimulating agents (ESAs), such as epoetin (EPO), and iron must be present in patients with chronic kidney disease to produce red blood cells. Although administration of both is common in clinical practice, much controversy exists on how to manage dosages properly so risks do not exceed benefits. ESAs have recently been given a boxed warning by the U.S. Food and Drug Administration concerning targeting high hemoglobin (Hb) levels in patients. Thus, recent studies have examined ways in which intravenous iron administration can help lower EPO doses while still maintaining Hb levels. The Dialysis Patients Response to IV Iron with Elevated Ferritin (DRIVE) study showed that intravenous ferric gluconate was effective in improving anemia and stabilizing Hb levels. DRIVE-II—a 6-week extension study—was recently undertaken to investigate the effects of a 1-g course of intravenous ferric gluconate on Hb, transferrin saturation (TSAT), and serum ferritin.

In the DRIVE-II study, 112 of the 129 patients who participated in DRIVE were administered either intravenous iron (control) or intravenous ferric gluconate. At the end of the study, the ferric gluconate group showed a significant decrease in EPO doses compared to their initial DRIVE dose, whereas control group levels remained unchanged. Also, 23 patients in the control group did not receive intravenous iron, and these patients showed an increase in their EPO doses and no changes in Hb levels. Furthermore, Hb, TSAT, and serum ferritin levels were higher in the ferric gluconate group, suggesting that the 1-g administration had a sustaining effect after the initial DRIVE study.

The results of this study certainly indicate that administration of ferric gluconate allows patients to receive lower doses of EPO while sustaining the clinical effects. Some researchers have expressed concerns about the use of intravenous iron in patients with elevated ferritin, such as increased risk of infection and infectious complications. But, during the course of both DRIVE studies, fewer hospitalizations and adverse events were reported in the ferric gluconate group. However, the study was not sufficiently long or large enough to fully assess cardiovascular risks, and an unblinded knowledge of the treatment group may have influenced clinician treatment decisions. Further studies will be needed to better understand ESA and iron dosing strategies.

Ferric gluconate reduces epoetin requirements in hemodialysis patients with elevated ferritin. Kapoian T, O'Mara NB, Singh AK, Moran J, Rizkala AR, Geronemus R, Kopelman RC, Dahl NV, Coyne DW. J Am Soc Nephrol. 2008 Feb;19(2):372-9.

NAAC Expert Commentary:
The purpose of the DRIVE study and its six week extension, DRIVE II, was to determine the efficacy and safety of supplemental intravenous iron in anemic hemodialysis patients receiving recombinant erythropoietin who had a transferrin saturation < 25 % and a serum ferritin > 500 ng/mL. The intravenous iron group did increase their hemoglobin levels slightly more than control patients not given intravenous iron without additional toxicity, leading the authors to conclude that intravenous iron in this situation was both safe and effective. Unfortunately, the design and power of both studies were not sufficient for the investigators to reach these conclusions.

First, the decision to increase the dose of recombinant erythropoietin in each group by 25 % confuses the response to ESA and iron. In a chronic inflammatory state, such as chronic renal disease, the problem is not impaired iron availability but insufficient erythropoietin, which is required to mobilize iron and upregulate transferrin receptor expression. It is well recognized that erythropoietin trumps hepcidin in this situation and the authors merely confirmed that phenomenon.

Second, in the control groups of both DRIVE and DRIVE II, there were a disproportionate number of women, who are more likely to be iron deficient, and their response to recombinant erythropoietin proved this, reducing the effectiveness of comparisons.
Third, both DRIVE and DRIVE II were open label observational studies and in addition physician discretion was also allowed with respect to erythropoietin dosing and iron administration. This discretion can introduce significant bias, weakening the conclusions of the studies.

Fourth, no attempt to estimate blood loss, iatrogenic or otherwise, was made for either experimental group. Fifth, the difference in the hemoglobin level achieved with supplemental iron was not striking and also pushed the hemoglobin level above that currently recommended for safety reasons. Finally, since the serum ferritin and transferrin saturation increased in the iron-supplemented group, a state of iron overload was achieved that was unnecessary and the 12 week observation period was certainly not long enough to exclude the possibility of iron-induced organ toxicity.

It is clear that more data derived from larger prospective trials that are conducted for longer periods are needed. Until this data becomes available, anemic hemodialysis patients not responding to conventional doses of recombinant erythropoietin, in whom the serum ferritin is greater than 500 ng/mL, should first be evaluated for a source of blood loss or infection. Then the patient should be given a higher dose of recombinant erythropoietin for a minimum of 6 weeks with serial transferrin saturation and ferritin measurements before resorting to intravenous iron supplementation.

Last Modified: August 14, 2008