Ferumoxytol for Treating Iron Deficiency Anemia in CKD

Iron deficiency is a prevalent cause of anemia in 25-70% of chronic kidney disease (CKD) cases, and is caused by (1) a decreased intake or absorption of iron, (2) iron sequestration, (3) blood loss, and (4) increased iron use for red blood cell production due to erythropoiesis-stimulating agents (ESAs). Managing anemia in CKD requires both iron and ESA therapy. However, oral iron administration has limited, and sometimes adverse effects that may reduce patient compliance. Intravenous iron (IV) is recommended for patients with CKD, but is infrequently used before a patient initiates dialysis. Recently, a Phase III clinical trial by Spinowitz et al described the effects of the intravenous iron product, ferumoxytol, in CKD patients.

In the study, 304 patients were randomly assigned ferumoxytol (228) and oral iron (76). The ferumoxytol group received two 510-mg doses within 5 days, and the oral iron group received 200 mg of elemental iron for 21 days. At day 35, ferumoxytol treatment significantly increased hemoglobin (Hb) levels (0.82±1.24 g/dL; 39% achieving ≥ 1g/dL increase) compared to the oral iron group (0.16±1.02 g/dL; 18.4% achieving ≥ 1g/dL increase). Similar significant trends were found for patients both on and not on ESAs. Furthermore, in a nonrandomized readmission trial, patients who initially received ferumoxytol received a second course, while patients who initially received oral iron received a first course of ferumoxytol. The mean increase in Hb levels was 0.55±0.89 g/dL in patients receiving a second course of ferumoxytol, and 0.69±0.80 g/dL in patients receiving a first course.

The fact that many patients are anemic upon dialysis initiation points to suboptimal management in clinical settings. However, the results of this trial indicate that administration of IV iron is an effective and well tolerated treatment for anemic CKD patients. Few adverse events were reported during the course of the trial, and any serious complications were unrelated to ferumoxytol treatment. Also, ferumoxytol can be administered rapidly at high doses, and appears quickly in circulating red blood cells. The authors feel these factors will allow clinicians to dictate appropriate ESA therapies and to better address iron deficiency as a first step in the management of anemia.

Spinowitz BS, Kausz AT, Baptista J, Noble SD, Sothinathan R, Bernardo MV, Brenner L, Pereira BJ. Ferumoxytol for treating iron deficiency anemia in CKD. J Am Soc Nephrol. 2008 Aug;19(8):1599-605.

NAAC Expert Commentary:
The provision of supplemental iron to patients with chronic kidney disease (CKD), often but not always combined with an ESA, is a universal component of the therapeutics associated with successful anemia management. Patients receiving hemodialysis are typically and conveniently administered one of two IV iron preparations during a routine dialysis session. However, patients with Stage 1-V CKD, and not yet on dialysis, are most often prescribed oral iron, a strategy that is commonly associated with the presence of iron deficiency and the failure to achieve target hemoglobin levels. Although the use of IV iron for the pre-dialysis patient can overcome many of the barriers which preclude the achievement of an iron replete state, the medication regimen must be safe, effective and practical for the patient and provider if it can realistically become routine clinical care.

This randomized study of greater than 300 adult patients with CKD provides preliminary evidence of such a regimen. The finding that only 5 weeks after study initiation, there was a significantly greater increase in hemoglobin level among patients who received just two doses of ferumoxytol, compared with oral iron, highlights the positive potential of this intravenous agent in the CKD population. Contributing to this optimism is the fact that ferumoxytol can be given by rapid infusion and that the success experienced in the short-term study occurred irrespective of the use of an ESA and with few associated adverse events. It is very likely that if this agent is approved for use in CKD, with a decision expected soon, ferumoxytol will be eagerly incorporated as part of the armamentarium of CKD anemia management. Now all that is awaited is long-term data regarding the safety and efficacy of the therapy.

Immunoassay for Detecting Human Serum Hepcidin Levels

Extracellular iron concentrations are mainly controlled by hepcidin, an iron-regulatory hormone. Hepcidin mediates iron influx into the plasma from tissues involved in iron storage and transport, and is physiologically increased by elevated plasma iron concentration and inflammation. Although hepcidin is an important marker for iron homeostasis and iron-related pathologies, reliable methodologies for measuring hepcidin concentrations have been limited. However, a competitive enzyme-linked immunoassay (C-ELISA) for human hepcidin has recently been developed. This assay gives clinicians a highly improved means of detecting physiological and pathological changes in both serum and urine hepcidin levels.

To develop the assay, a highly selective antibody to human hepcidin was purified, and the resulting fitted curves of the assay were used to convert absorbance readings to hepcidin concentrations. Serum samples from healthy volunteers were then obtained to confirm the selectivity, precision, reproducibility, and stability of the assay. The serum from these volunteers was also used to establish a normal range of hepcidin (29-254 ng/mL in men and 17-286 ng/mL in women).

After establishing positive correlations with urine hepcidin and ferritin levels, plasma hepcidin concentrations were measured by C-ELISA after iron loading to examine physiologic responses. Subjects with detectable iron absorption experienced a corresponding, but more prolonged rise in serum hepcidin. Furthermore, C-ELISA measurements for hepcidin were taken in subjects with various iron disorders. In tests focusing on patients with hemochromatosis, iron-overload showed inappropriately normal levels of serum hepcidin, while iron-depletion showed low levels. Patients with inflammation, multiple myeloma, and chronic kidney disease also showed abnormal increases in serum hepcidin.

From the test results, the C-ELISA for human hepcidin has proven to be a very useful clinical tool for detecting physiologic and pathologic variations in hepcidin concentrations. Not only does the assay reliably detect expected physiological conditions, but it also provides a means of better understanding the pathology of various iron disorders. For example, hepcidin concentrations could be useful as diagnostic measurements, and may be informative about disease etiology. The authors conclude that large-scale human studies will be needed to elucidate further clinical applications.

Ganz T, Olbina G, Girelli D, Nemeth E, Westerman M. Immunoassay for human serum hepcidin. Blood. 2008 Aug 8.

NAAC Expert Commentary:
Although initially described as an antimicrobial peptide, the essential role of hepcidin as a regulator of iron homeostasis was ultimately described. Hepcidin regulates iron absorption and transport through ferroprotein. Quantification of hepcidin levels has advanced our understanding of normal and pathologic conditions of iron metabolism.

In this study, Ganz and colleagues reported on a competitive ELISA to quantify serum hepcidin levels. They first demonstrated that serum hepcidin by this assay correlates well with the more onerous urine assay used by these investigators. Hepcidin levels correlated closely with serum ferritin in normal healthy adults (r = 0.63) as the body responds to reduced iron stores by suppression of hepcidin and enhancement of iron absorption. The normal serum ranges of hepcidin levels were described in healthy adults. As expected, the median values were lower in women because of lower iron stores on average.

In various disorders of iron metabolism, hepcidin levels varied as demonstrated by other studies. For example, in iron deficiency, hepcidin levels were highly suppressed, whereas during inflammatory states, hepcidin levels were elevated. Elevated hepcidin from inflammation has been implicated in anemia of inflammation by reducing functional iron availability. Finally, hepcidin levels were also shown to be inappropriately normal in hereditary iron overload.

Measuring hepcidin is critical to understanding normal and perturbed iron metabolism. However, the currently available assays have major limitations that preclude clinical use. The serum immunoassay reported by Ganz and colleagues holds promise to translate quickly into a commercially available test. The results are in line with prior studies of hepcidin and validate the utility of hepcidin in several disorders. For now, serum ferritin and iron indices will remain the first-line tests to gauge iron stores. However, serum hepcidin may augment studies of iron stores by shedding light on iron metabolism. For example, elevated hepcidin may support a diagnosis of anemia of chronic inflammation and a functional iron deficiency that may respond to iron supplementation. Before measures of hepcidin have clinical utility, validation studies will clearly be needed to determine diagnostic thresholds.

Examining Iron's Role in Anemia of Heart Failure

Heart failure (HF) is a significant health problem that affects millions of Americans every year. Some estimates have shown that anemia is prevalent in up to 61% of patients with HF, and that this condition could lead to increased morbidity and mortality. However, the potential for improved outcome through anemia correction is not well explored. Some small-scale studies have proposed modalities for correction of anemia such as erythropoiesis-stimulating proteins (ESPs) or iron supplementation. These studies, discussed in this review by da Silva et al, have examined the mechanisms of anemia in HF and how new diagnostic and treatment strategies may be developed.

Anemia in HF patients is thought to be caused by a multitude of factors. In many instances, hemodilution, erythropoietin (EPO) deficit, the use of angiotensin-converting enzyme inhibitors, and EPO resistance may play a combined role in the development of anemia. Most commonly, insufficient iron intake or defects in iron utilization are related to mild to moderate forms of anemia. A recent study reported iron deficiency as the primary cause of anemia in HF patients in up to 73% of the cohort. Because the underlying mechanisms of anemia in HF patients are multifactorial, developing specific treatment strategies is difficult.

Thus, combined strategies involving EPO administration and intravenous (IV) iron therapy have been the most extensively studied. Many studies involving a combination of the two therapies have yielded some promising results. In some cases, patients showed increased left ventricle ejection fraction, decreased use of diuretics, and decreased incidence of hospitalizations. Darbepoetin alfa-an erythropoiesis-stimulating protein-was also shown to increase (hemoglobin) Hb levels in anemic HF patients. However, most studies to date have been restricted to patients with specific cardiorenal syndromes, and it is still unclear whether the benefits observed are due to ESP therapy or iron administration. Larger clinical trials are currently underway, including a study that will focus on the impact of iron supplementation alone in anemic HF patients. The authors contend that by determining the effectiveness of such clinical therapies, clinicians will be able to develop specific treatment strategies.

Beck da Silva L, Rohde LE, Clausell N. Etiology and management of anemia in patients with heart failure: how much iron is missing? Congest Heart Fail. 2008 Jan-Feb;14(1):25-30.

NAAC Expert Commentary:
The prevalence of anemia in the NHANES population survey was 5 %.¹ In HF clinical trials and large HF registries, the prevalence has ranged from 15-61%.^2-4 Low Hb levels are independently associated with increased mortality and hospitalizations for HF in patients with acute or chronic HF.^5-7 The prevalence and increase in poor outcomes is the same in patients with impaired or preserved left ventricular function.

As reported in the review article by Da Silva et al, relative or absolute iron deficiency may play an important role in HF patients as indicated in bone marrow studies by the low levels of iron available for erythropoiesis, despite normal ferritin and iron studies from the peripheral blood.⁸ Erythropoietin levels are normally increased in HF patients, but are still lower than expected for the degree of anemia. Several studies tracking the benefit of ESAs, including darbepoetin alfa, have not shown clear benefit in HF symptoms or outcomes. STAMINA-HeFT is the largest study of darbepoetin alpha in HF patients.⁹ In this multicenter, randomized double-blind placebo controlled study, 319 HF patients were randomized to darbepoetin (n=162) or placebo (n=157) to maintain Hb levels at 14.0 ± 1.0 g/dL. At week 27, despite a significant increase in Hb levels, the primary endpoint of change from baseline (in treadmill exercise time) was not improved; nor was there any improvement in NYHA class or MLHFQ score compared with placebo. The drug was well tolerated and adverse effects were similar in both treatment groups.

A general proinflammatory state might be responsible for an inappropriate EPO production and/or defective iron utilization in HF patients.¹⁰ Da Silva's review calls patients with a true iron deficiency in HF 'ferropenic' and cites a report of 73% prevalence for such patients from a study where bone marrow aspirates were used to diagnose iron store status in HF patients.¹¹ Intravenous iron may provide iron to the bone marrow and bypass the reticuloendothelial system, where it may be unavailable due to a chronic inflammatory state.^10,12 FERRIC-HF randomized 35 HF patients to 16 weeks of IV iron or no treatment and found that in patients with baseline anemia there was an absolute increase in peak VO2 and an overall improvement in NYHA class and patient global assessment.¹³ The IRON-HF study is a multi-center prospectively designed, randomized, double blind, placebo-controlled clinical trial among HF patients with Hb levels of 9-12 g/dL that has the potential to provide evidence for the benefit of IV iron replacement in this group of patients.

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