Management of anaemia in CKD—the relative importance of erythropoietin and iron

During an industry-sponsored symposium at the ERA–EDTA meeting in Munich 2010, four experts gathered to debate and provide an update on the treatment of anaemia in chronic kidney disease (CKD) patients, especially the relative contributions of erythropoiesis-stimulating agents (ESAs) and iron in its management. I chaired this symposium and invited these experts in collaboration with the sponsor to summarize their opinions. As the results of the largest of the ESA trial, TREAT, were available, many presenters focused on those results. The expert opinions were partly supported by available data, and there were, on occasions, differences in opinion between the experts on the interpretation of the data. For example, Dr Coyne’s statement that stroke risk is independent of ESA hyporesponsiveness is not a view that I share. I believe that the analysis of Solomon et al. in which Dr Coyne’s statement was based was simply not sufficiently powered to detect this relationship. Dr Locatelli states that the TREAT study was not a ‘placebo’ randomized controlled trial because the placebo group experienced an increase in haemoglobin (Hgb) over time. I disagree. The Hgb levels increased over time because the placebo group had a rescue feature which allowed administration of darbepoietin should Hgb fall below 9 g/dL. Dr Bhandari states that the profile of the ideal iron preparation should be capable of delivering sufficient quantities of intravenous iron to correct iron deficiency rapidly, with minimal potential side effects including low catalytic/labile iron release and negligible immunogenicity (risk of anaphylaxis). Yes, but I believe that the long-term safety of intravenous iron is the most important attribute which needs to be evaluated; long-term toxicity would trump any convenience afforded by the drug. Dr Kalra states that the drug should have reduced immunogenic potential and reduced risk for free iron toxicity. Although these claims may be true, they remain to be validated in larger safety studies especially among patients with multiple drug allergies. Below are opinions provided by the experts. There are several statements where consensus was not achieved. However, the experts do have a right to their opinions, and I present them below as they were presented to me, even when I am in disagreement. The highlights of this symposium, as I see it, are as follows: Normalizing Hbg among people with CKD is associated with cardiovascular and thrombotic risk. These risks can only be partially managed by correcting anaemia. Hyporesponsiveness to ESAs is associated with increased cardiovascular risk. Whether it is the dose of ESAs, poor response to ESA dose, a combination of the two or some other traits that confer this increased risk is unknown. Therefore, it should not be taken as a foregone conclusion that the dose of ESA is toxic. However, it is prudent to limit the dose of ESA to the minimum required to achieve a satisfactory Hbg response. The upper limit of ESA dose is unknown. Iron deficiency remains an important cause of ESA hyporesponsiveness. The diagnosis of iron deficiency among patients with CKD remains difficult. The pitfalls in making a diagnosis of iron deficiency anaemia are discussed. No gold standard is established. Therefore, when in doubt, a therapeutic trial of intravenous iron may be useful to establish a firm diagnosis. Among haemodialysis patients, the preferred route of iron administration is intravenous. However, it must be noted that patients with CKD who are not on haemodialysis can receive iron either orally or intravenously; there is no preference. The various parenteral irons, which are currently marketed, and their risks and benefits are discussed. Normalizing Hbg with ESAs in patients with CKD increases cardiovascular risk, whereas hyporesponsiveness to ESAs is associated with increased risk. Thus, it is logical to hypothesize that the cardiovascular risk of ESA use in patients with CKD may be mitigated with iron administration. Whether iron administration reduces ESA hyporesponsiveness or decreases or increases cardiovascular risk is currently unknown. The risk–benefit ratio of iron administration in CKD patients needs to be evaluated in well-designed prospective randomized controlled trials with cardiovascular and renal outcomes. Iron isomaltoside 1000 may be an attractive intravenous iron that may allow rapid repletion and theoretically a better safety profile.