Options for Iron Correction and Erythropoiesis Stimulation: Better Benefit:Risk Through Individualized Therapy

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PRIORITY PRESS - 2012 Kidney Week of the American Society of Nephrology (ASN)

San Diego, California / October 30 - November 4, 2012

San Diego - More sophisticated strategies for the treatment of anemia in patients with chronic kidney disease (CKD), including those on dialysis, are being driven by new options for replenishing iron and stimulating erythropoiesis. The trials that have been conducted to bring these options forward have contributed to the evidence that the therapeutic window is narrow and best defined by individual patient characteristics. Although raising hemoglobin (Hb) levels is an essential step for restoring an adequate quality of life in patients with CKD and anemia, newer guidelines have revised the Hb targets downward in appreciation for risks, particularly for stroke and cardiovascular events, which begin to increase outside the therapeutic window. For most cases of CKD anemia, new first-line iron therapy and erythropoiesis options are greatly facilitating management of the Hb level.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

According to the newly released 2012 KDIGO (Kidney Disease Improving Global Outcomes) guidelines (, correction of iron deficiency is conducted before introducing erythropoiesis-stimulating agents (ESA) in the management of chronic kidney disease (CKD)-associated anemia.

There are several reasons, including the fact that iron deficiency is a cause of hyporesponsiveness to ESA. In adult CKD patients on dialysis, intravenous (IV) iron is the preferred method of administration. In CKD patients not on dialysis, a trial of oral iron is considered reasonable for the sake of convenience, but IV iron may be more effective because it avoids problems of gastrointestinal absorption. “Anemia is a common problem in the CKD patient and many of these will require both iron therapy and an ESA, but patients responsive to iron will avoid the expense of an ESA,” observed Dr. Jeffrey S. Berns, University of Pennsylvania, Philadelphia.

Iron Treatment: Progress and Guidelines

At Kidney Week, Dr. Berns, who participated in a symposium on anemia management, recommended serial measurements of transferrin saturation (TSAT) and ferritin levels, rather than single values, to evaluate iron level. However, cautioning that the absolute predictive value of these measures is imperfect, he emphasized the value of individualized therapy.

Although IV iron has been used to treat anemia for nearly a century, there have been numerous milestones for improving tolerability and efficacy. Many of the most important, such as combining IV iron with dextran, sucrose or gluconate to reduce adverse events, were introduced after recombinant ESA was made available in 1989. In the past 3 years, another significant clinical advance has stemmed from the development of IV iron compounds which can deliver large amounts of iron rapidly without a test dose.

The first of these introduced in Canada and the US, was ferumoxytol. This agent delivers a complete 1g dose of iron in 2 doses of 510 mg administered 2 to 8 days apart. Both doses are delivered undiluted in approximately 20 seconds, improving ease of administration for both physicians and patients. The other newer compounds, ferric carboxymaltose and iron isomaltoside can also deliver large amounts of iron over somewhat longer periods. A 1 g dose of iron in the ferric carboxymaltose formulation is administered undiluted over 15 minutes. A 1 g dose of iron isomaltoside is delivered as an infusion over 1 hour or as an injection. Both of these forms have been primarily studied in Europe and are not available in Canada.

The advances in the safety and simplicity of iron administration are welcome in the context of lower hemoglobin (Hb) targets outlined in revised KDIGO guidelines, which are placing greater priority of iron treatment over ESA to control anemia-related symptoms. In emphasizing the importance of balancing symptom reduction against the cardiovascular (CV) and cerebrovascular risks imposed as Hb levels climb above 12 g/dL, the guidelines no longer recommend initiation of ESA in non-dialysis CKD patients when Hb is ≥10 g/dL. In dialysis patients with persistent anemia with Hb level of 9.0 g/dL, ESA is recommended but the guidelines specify that Hb should not be intentionally raised above 11.5 g/dL in these patients. Cases in which patients accept the potential risk in exchange for an improvement in quality of life (QoL) are possible exceptions.

Potential CV Risk Reduction

In many instances, iron therapy may be sufficient to reach current Hb goals without having to initiate ESA. If ESA is required, seeking optimal iron levels first will minimize dose levels. In addition, iron may provide some protection against CV risks, according to a subanalysis of the REPAIR-IDA randomized trial presented at Kidney Week. In the trial, first presented at the 2011 Kidney Week (Szezech et al. J Am Soc Nephrol 2011;22:5B), 2561 CKD-patients with iron deficiency were randomized to ferric carboxymaltose or iron sucrose. In this sub-analysis of 799 participants, IV iron was found to significantly reduce the levels of C-terminal fibroblast growth factor 23 (cFGF23), a predictor of CV events in patients with CKD, regardless of the form of iron to which they were randomized.

“The data suggest that IV iron may be a novel approach to reducing cFGF23 levels in certain CKD patients with anemia in order to reduce CV risk,” reported Dr. Myles Wolf, University of Miami, Florida. Although the small number of CV events over the course of this study prevented a demonstration of a protective effect directly related to IV iron, studies designed to demonstrate a protective effect are planned.

The benefit:risk ratio for raising Hb in CKD patients with anemia is generally framed by the need to treat the fatigue, shortness of breath and the potential for progressive congestive heart failure against the risk of thrombotic events as Hb levels climb above guideline-recommended levels. Uncontrolled anemia may also require blood transfusions, which carry their own risks of complications.

Keeping Hb Within the Therapeutic Window

New clinical data presented at Kidney Week indicate that emerging ESA products may facilitate the effort to keep Hb within the therapeutic window. Based on these data, the most promising of these products appears to be the pegylated synthetic peptide peginesatide, which binds to and activates the erythropoietin receptor and the hypoxia-inducible factor (HIF) stabilizers, such as FG-4592, which are not accurately characterized as ESA because of a unique mechanism of action.

Of these, peginesatide was evaluated in phase III trials for non-dialysis (PEARL 1 and 2) and dialysis patients (EMERALD 1 and 2). The key attribute of this agent is a long half-life and a longer residence time bound to the erythropoietin receptor. In 60-week data from the similarly designed EMERALD 1 and 2 trials that were presented during Kidney Week, peginesatide given once every 4 weeks was non-inferior to epoetin alfa administered 3 times weekly for maintaining Hb levels with no observed difference in rate of CV events. Interestingly, the most recent analysis found that those randomized to peginesatide required significantly less iron than those on epoetin alfa.

While the main advantage of this agent is the reduced dosing schedule, “peginesatide patients had higher TSAT levels, similar ferritin levels but required less iron therapy whether by intention-to-treat [P=0.001] or completer [P=0.005] analysis even though baseline levels were comparable,” reported Dr. Robert Provenzano, St. Clair Specialty Physicians, Detroit, Michigan. In the context of the data presented during Kidney Week, Dr. Provenzano indicated that this longer acting ESA may greatly simplify the long-term management of CKD-related anemia.

Phase II data with FG-4592, which has the potential to be the first oral strategy for increasing red blood cell production, includes follow-up out to 19 weeks. In this open-labeled study, also presented by Dr. Provenzano, 67 CKD dialysis patients who had been receiving epoetin alfa were able to maintain Hb levels over the full study period after being switched to FG-4592. This agent stabilizes HIF rather than mimicking the effects of endogenous erythropoietin like ESA. While iron therapy is typically required with traditional ESA agents for red blood cell production, the elevation in Hb with FG-4592 was maintained without iron therapy.

“This exploratory study suggests robust efficacy data on Hb maintenance when switched from epoetin alfa in end-stage renal disease patients. Treatment with FG-4592 minimizes need for IV iron supplementation which appears to be related to the suppression of hepcidin,” Dr. Provenzano reported. These and other data have provided a basis for pursing phase III studies, which are planned.

In the context of more convenient treatments to address iron deficiency, the advances in the stimulation of red blood cell production, whether through iron treatment or ESA, are expected to greatly improve the capacity of physicians to keep Hb within the relatively narrow therapeutic window that defines improvements in QoL with a low probability of exacerbating CV risk. The recent studies predict that management of CKD-related anemia has evolved and will continue to evolve.


Anemia exerts a strong negative impact on the QoL of patients with CKD. Although individualized therapy is essential in the absence of an optimal Hb level appropriate to all patients, advances in delivery of iron and in the stimulation of red blood cell production are altering the opportunities for clinicians to place Hb levels into a desirable range. Well tolerated, more convenient and more consistent treatments have the potential to exert a favourable influence on long-term outcome.

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