Challenging the boundaries of anemia management: a balanced approach to i.v. iron and EPO therapy

Abstract

The integration of recombinant human erythropoietin (EPO) and intravenous (i.v.) iron therapy into standard anemia management protocols has indelibly altered the treatment landscape for patients on hemodialysis. In these patients, the introduction of EPO therapy dramatically increased measures of hematocrit and hemoglobin and reduced the need for red blood cell transfusions. Equally important, i.v. iron has been proven to improve patients’ response to EPO therapy (Figure 1), replace patients’ ongoing iron losses, and help manage patients who have iron-deficiency anemia to be within target hemoglobin and hematocrit ranges, as established by the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines published in 2000. These benefits of i.v. iron therapy have been achieved at storage iron levels far below those generally seen with transfusions in the pre-EPO era. The K/DOQI guidelines were a milestone in the development of effective, standardized principles for the management of anemia in patients with chronic kidney disease, and they effectively established i.v. iron and EPO therapy as the pillars of anemia intervention. Nevertheless, the guidelines left a number of important management questions unanswered, owing to a lack of comprehensive evidence needed to develop particular recommendations (Table 1). Since the K/DOQI guidelines were originally published, a number of studies have provided additional information on several of these outstanding issues. In this supplement, we address the continued discussions as they relate to the use of i.v. iron and EPO therapy. Many of these issues raise the question of whether we are ‘striking the right balance’ between our choices of therapy for hemodialysis patients with anemia in order to provide care that delivers enhanced treatment outcomes, minimizes both short-term and potential long-term safety risks, and is cost-effective. The first of the three articles in this supplement takes an in-depth look at the indices used to assess iron stores in patients with iron-deficiency anemia. Serum ferritin and transferrin saturation, although the most widely used tests to measure iron levels, have significant sensitivity and specificity limitations for determining iron status in patients whose laboratory results do not clearly identify iron deficiency or iron excess. Over the past 5 years, a number of studies have examined additional, and purportedly more accurate, indices of iron status. Although some of these markers, including the reticulocyte hemoglobin content, continue to show promise for identifying iron deficiency and iron overload, none has yet demonstrated the combination of accuracy, ease of use, cost-effectiveness, and widespread availability that would move it to the forefront of testing strategies. This article also addresses one of the more hotly debated issues surrounding the use of parenteral iron therapy: What is the appropriate upper limit for serum ferritin? Because available data have not demonstrated adverse effects at higher serum ferritin levels and have shown that anemia is responsive to i.v. iron at elevated serum ferritin levels and i.v. iron is associated with improved survival at higher serum ferritin levels, there are concerns that a recommendation by the K/DOQI guidelines for a lower serum ferritin ceiling will deny treatment to patients who could benefit from i.v. iron therapy, thereby increasing the health risks and the cost of health care. The second article expands on the safety concerns associated with anemia management, focusing on the purported adverse consequences associated with i.v. iron treatment and the increasingly documented cardiovascular risks that appear to be associated with EPO therapy. It has been suggested that i.v. iron can be a driver of the freeradical reaction that may lead to oxidative injury, infection, and cardiovascular disease. However, it is important to look closely at the latest clinical evidence to see whether it supports the increases in risk that were proposed by earlier laboratory studies. It is also vital to determine whether safety risks in patients receiving i.v. iron therapy are a result of i.v. iron use or they are caused by co-morbid conditions common among hemodialysis patients. Of these conditions, rapidly increasing evidence is demonstrating that malnutrition and inflammation, which are highly prevalent in patients with compromised renal function, can falsely elevate serum ferritin measures and is associated with adverse health outcomes. These studies highlight a number of key considerations when making treatment decisions for any http://www.kidney-international.org i n t r o d u c t i o n