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Correcting Iron-Restricted Erythropoiesis and Improving Anemia in Patients on Hemodialysis: Practical Tips that Can Make a Difference Andrea Easom atients on hemodialysis with a below-target hemoglobin (Hb) level, despite receiving an erythropoiesis-stimulating agent (ESA), are an issue of increasing concern because anemia is associated with poor outcomes in this population. Observational Hb data collected from the International Dialysis Outcomes and Practice Pa t t e r n s Study (DOPPS) I and II, which included participants from over 10 countries, including the United States (U.S.), demonstrated a correlation between higher baseline Hb levels and improved outcomes (Port, Pisoni, Bommer, Locatelli, & Jadoul, 20 06 ) . The findings from this large, representative patient sample in DOPPS are in agreement with present guidelines for managing anemia. The Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines recommend an Hb level of 11 to 12 g/dL and the ESA package insert lists an Hb level of 10 to 12 g/dL in patients with renal failure (Amgen,

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Andrea Easom, MA, MNSc, APN, FNP-BC, CNN-NP, is an Instructor in Medicine, Division of Nephrology, University of Arkansas for Medical Sciences, and a Family Nurse Practitioner, Little Rock, AR. Disclaimer: This article has been peer reviewed. The information in this article does not necessarily reflect the opinions of ANNA or the sponsor. Andrea Easom is a paid consultant for Watson. The author acknowledges Fallon Medica LLC for providing assistance in preparation of this supplement with funding provided by Watson.

Note: This article is supported by a financial grant from Watson. This article has undergone peer review. The information in this article does not necessarily reflect the opinions of ANNA or the sponsor.

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In healthy individuals, the body remains in an iron-balanced state. Iron intake and loss on a daily basis is minimal, and the majority of iron in the body is recycled. However, patients on hemodialysis may have an insufficient supply of iron available to the bone marrow for erythropoiesis, a condition known as iron-restricted erythropoiesis or inflam mation-mediated reticuloendothelial blockade. This state may occur as a result of an inflammatory process and can limit the patient’s ability to respond to erythropoiesisstimulating agents (ESAs). Intravenous (IV) iron supplementation may be needed to overcome iron-restricted erythropoiesis and improve ESA response. This article focuses on the complex relationship among the three I’s in anemia management: inflammation, iron-restricted erythropoiesis, and IV iron treatment. Copyright 2009 American Nephrology Nurses’ Association Easom, A. (20 09). Correcting iron-restricted erythropoiesis and improving anemia in patients on hemodialysis: Practical tips that can make a difference. Nephrology Nursing Journal, 36(5), 529 - 537, 553 .

20 08; National Kidney Foundation [NKF], 20 07; Ortho Biotech, 20 09 ) . However, according to the annual report of the United States Renal Data System (USRDS) (20 08), only 48% of prevalent patients met the ESA package insert Hb target range, and only 40.7% met the KDOQ I recommended Hb target range. These data indicate that reaching a target Hb level is challenging, and an opportunity exists to enhance anemia management and outcomes in patients on hemodialysis. ESA therapy is a mainstay of anemia management in patients on hemodialysis, and appropriate dosing of ESAs is an essential part of overall anemia care. Iron deficiency is one cause of an inadequate response to ESA and may lead to the use of higher ESA doses ( Johnson, Pollock, & Macdougall, 20 07). Inflammation, which is common in patients on hemodialysis, can also affect a patient’s response to ESA. Inflammation can impair iron regulation in the body and lead to a state of

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iron-restricted erythropoiesis, thereby hindering ESA response and worsening anemia. It is important that nephrology nurses have a good understanding of the harmony between ESA and intravenous (IV) therapy. Studies have shown that IV iron therapy can help overcome iron-restricted erythropoiesis, resulting in improved Hb levels and reduced ESA doses. This article focuses on the three I’s in anemia management: • Inflammation. • Iron-restricted erythropoiesis. • IV iron. This article will also offer effective “tips” for nephrology nurses to better help manage anemia.

What Is Iron-Restricted Erythropoiesis? In the body, iron is present in two main sites or pools: the storage pool and the functional pool (Knutson & Wessling-Resnick, 2003; Ponka, Beaumont, & Richardson, 1998). Iron

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in the storage pool is primarily located in the reticuloendothelial (RE) cells of the liver, spleen, and bone marrow. Iron in the functional pool is circulating in plasma bound to transferrin. Most of the iron bound to transferrin is transported to the bone marrow, where it is used for red blood cell production (i.e., erythropoiesis). The exchange of iron between the two pools is a highly regulated system. Under normal conditions, iron is maintained in a state of equilibrium: when transferrin-bound iron is low, iron is released from storage. This is a model of a supply and demand process. The iron delivery system may be disrupted in patients on hemodialysis. The amount of circulating iron being mobilized to the bone marrow is not always adequate, even though there is sufficient storage iron (Andrews, 1999). A disruption in normal iron regulation can lead to a state of ironrestricted erythropoiesis. Common causes of iron-restricted erythropoiesis include ESA use and inflammation (Malyszko, Malyszko, Hryszko, Pawlak, & Mysliwiec, 2005). ESA therapy can increase erythropoiesis at a supraphysiologic rate, which greatly increases the demand for iron. Despite sufficient storage iron, the iron cannot be delivered to the bone marrow fast enough to meet the increased iron demands. Inflammation can further restrict iron availability for erythropoiesis. It is important to note that the use of ESAs and the occurrence of inflammation can be present concurrently in a patient on hemodialysis, and both can simultaneously have a profound affect on iron balance, thereby compounding the problem of anemia.

Effect of Inflammation on Iron Regulation Iron-related abnormalities can occur during inflammatory states. Inflammation increases hepcidin, a key regulator of iron delivery (Ganz, 2007). Hepcidin, a hormone produced by the liver, is an acute-phase reactant, which means its plasma con-

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centrations increase by at least 25 % during inflammatory states. Elevated hepcidin levels block iron absorption from the gut and restrict the release of iron in storage (Malyszko & Mysliwiec, 20 07). Iron retained in storage results in a decrease in circulating iron, and therefore, a reduction in the amount of iron being delivered to the bone marrow for red blood cell production. This condition is one type of iron-restricted erythropoiesis known as inflammation-mediated RE blockade. Despite its name “blockade,” the iron locked up may be a partial obstruction and not a complete block. This process can be considered in terms of the use of angiotensin-converting enzyme (ACE) inhibitors that do not completely block angiotensin II (Doulton & MacGregor, 2009). Tip #1: The administration of IV iron therapy can help overcome ironrestricted erythropoiesis/inflammation-mediated RE blockade (Coyne et al., 2007; Taylor, Peat, Porter, & Morgan, 1996). The Dialysis Patients’ Response to IV Iron with Elevated Ferritin (DRIVE) Study recruited patients who specifically met the criteria for inflammation-mediated RE b l o ckade: increased serum ferritin level (500 to 1200 ng/mL), low transferrin saturation (TSAT) level (25% or less), decreased Hb (less than 11 g/dL), and adequate ESA doses (Coyne et al., 20 07). Patients had a mean baseline C-reactive protein (CRP) level, a measure of inflammation, well above the normal range. At the start of the study, patients were randomized to receive ferric gluconate or no iron (control group), and all patients received a 25% increase in ESA dose. Results showed that the administration of a 1-gram repletion course of ferric gluconate in this patient population helped mobilize iron and improved Hb levels, demonstrating that ferric gluconate may be able to overcome inflammation-mediated RE blockade. This was evidenced by the fact that ferric gluconate improved levels of the iron marker reticulocyte Hb content (CHr), which is consistent with providing sufficient iron for red blood

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cell production (see Figure 1). The control group that had ferric gluconate withheld had a decline in CHr levels, which is consistent with worsening of inflammation-mediated RE blockade.

Role of Inflammation and Iron Restriction in ESA Resistance With the introduction of ESA therapy a few decades ago, the nephrology community has seen a marked reduction in patients with severe anemia. This includes an increase in patients who were transfusion independent (Adamson, 20 09 ; Eschbach, Egrie, Downing, Browne, & Adamson, 1987). ESAs, in conjunction with IV iron therapy, are an essential part of routine anemia care in patients on hemodialysis. Both ESA and IV iron are needed for healthy red blood cell production and offer numerous benefits. Unfortunately, response to ESAs varies among patients on hemodialysis who have anemia, and some fail to have an adequate response (Eschbach et al., 1989 ; Uehlinger, Gotch, & Sheiner, 1992 ) . These patients may maintain a relatively stable Hb level while on ESA therapy for a period of time, but then experience a drop in Hb or require higher doses of ESA to remain within a target Hb range. Specific parameters to measure ESA hyporesponse have not been established. Some considerations could include: Is ESA resistance the response of (1) a failure to obtain a desired Hb range within a certain time frame? (2) an ESA dose requirement above the median dose of the patient population? or (3) weekly ESA doses above a specific amount? The KDOQI guidelines suggest that causes of ESA hyporesponse should be investigated if a patient has an Hb level that is persistently less than 11 g/dL and is receiving ESA doses of 500 IU/kg/wk or higher (NKF, 2006). Two common reasons for ESA resistance are inflammation and limited iron availability. A study of patients on hemodialysis found that the inflammatory cytokines tumor necrosis fac-

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Figure 1 Changes in weekly reticulocyte hemoglobin content (CHr) levels in the ferric gluconate group and the control group (control group did not receive ferric gluconate) during the DRIVE Study. CHr levels increased significantly during ferric gluconate administration at weeks 2 and 3 (consistent with overcoming iron-restricted erythropoiesis/inflammation-mediated reticuloendothelial blockade), whereas CHr levels slowly declined in the control group.

Source: Reprinted with permission from Coyne et al., 2007. Note: LOCF = last observation carried forward.

tor-alpha (TNF-α) and interleukin-6 (IL-6) had a direct effect on the maturation of erythrocytes and was linked to a poor response to ESA therapy (Goicoechea et al., 1998). The study determined that patients who had elevated levels of these inflammatory markers required twice as much ES A therapy as those patients who had lower levels (see Figure 2). IL-6 has also been linked to the upregulation of hepcidin levels, which restricts iron needed for erythropoiesis (Wrighting & Andrews, 20 06). Iron-restricted erythropoiesis and inflammation-mediated RE blockade (two forms of limited iron availability) are manageable causes of poor ESA response. Tip #2: The administration of IV iron therapy can help improve ESA response and help reduce ESA requirements (Coyne et al., 20 07; Kapoian et al., 20 08). An observational extension of the DRIVE Study, the DRIVE-II 6-week study was designed to evaluate the sustained

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Figure 2 ESA requirements in the group of patients with tumor necrosis factoralpha (TNF-α) and interleukin-6 (IL-6) production. Patients with elevated markers of inflammation (TNF-α levels of 2 ng/mL or higher and IL-6 levels of 40 ng/mL or higher) required twice as much ESA therapy.

Source: Reprinted with permission from Goicoechea et al., 1998. Note: ESA = erythropoiesis-stimulating agent.

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Sponsored Educational Educational Supplement Supplement Sponsored Figure 3 Erythropoiesis-stimulating agent (ESA) doses in the ferric gluconate group versus control group during the DRIVE studies. ESA doses were significantly reduced in the ferric gluconate group by week 12 of the DRIVE-II Study.

Source: Adapted with permission from Kapoian et al., 2008.

effects of IV iron administration on ESA requirements, Hb levels, and iron parameters under usual anemia clinical management. Further, investigators were not restricted in the type of iron product administered. As a reminder, patients in the DRIVE Study had low baseline Hb levels despite receiving adequate ESA doses and low TSAT levels combined with high serum ferritin levels (suggestive of iron-restricted erythropoiesis/ inflammation-mediated RE blockade), and had received a 25% increase in ESA dose at the start of the study. Results of DRIVE-II demonstrated that patients in the ferric gluconate group had a significant reduction in ESA doses while maintaining an Hb level greater than 11 g/dL (Kapoian et al., 20 08). In fact, by the end of DRI V E - II, weekly ESA doses in the ferric gluconate group had decreased to levels similar to those before the 25% increase in ESA dose at the start of the DRIVE Study

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(see Figure 3). A cost-effectiveness analysis of these findings suggests that IV iron was one strategy for reducing anemia treatment costs associated with hemodialysis (Pizzi, Bunz, Coyne, Goldfarb, & Singh, 20 08). A reduction of ESA doses has been observed in other studies using iron dextran therapy (Besarab, Kaiser, & Frinak, 1999; Besarab et al., 20 0 0 ) . ESA responsiveness in patients on hemodialysis may also be blunted by malnutrition. Inflammation and malnutrition are closely related in patients on hemodialysis, and together are known as malnutrition-inflammation complex syndrome (MICS). One study showed that increasing severity of MICS, as measured by concurrent increases in inflammatory markers and declines in nutritional markers, is associated with higher ESA requirements (Kalantar-Zadeh, et al., 20 03).

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High ESA Doses and ESA Resistance In many patients, resistance to ESAs makes it necessary to administer higher doses to reach a sufficient Hb level. According to the results from one study that monitored over 14,000 patients on hemodialysis, those receiving the highest ESA doses had the lowest hematocrit levels, indicating that clinicians are giving increasingly higher ESA doses to patients who are unable to reach a target level (Cotter, Zhang, Thamer, Kaufman, & Hernán, 2008). Increased ESA use has been associated with undesirable clinical outcomes, such as increased risk of poorly controlled blood pressure and thrombosis (Phrommintikul, Haas, Elsik, & Krum, 20 07). Additionally, high ESA doses have been associated with increased platelet counts (Streja et al., 20 08). In a post-analysis of the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) Study, adjusted models showed high-dose ESA use was associated with a significantly increased risk of death, myocardial infarction, congestive heart failure, or stroke (Szczech et al., 20 08). Simply increasing the ESA dose in response to ESA resistance is not a good practice. High doses of ESA may not further improve Hb levels and can increase costs of anemia care. Tip #3: The KDOQI guidelines suggest that clinicians should evaluate the patient for specific causes of poor response to ESA therapy (NKF, 2006). The most common factors associated with ESA hyporeponse are iron deficiency, frequent hospitalization, hospitalization for infection, catheter use, hypoalbuminemia, and elevated CRP level (NKF, 2006). Tip #4: Maintaining higher TSAT and serum ferritin levels may help improve response to ESA therapy. A recent retrospective cohort study of over 38,000 patients on hemodialysis demonstrated that responsiveness to ESA therapy was highest at TSAT levels greater than 30% and at serum ferritin levels between 500 and 120 0 ng/mL (Kalantar-Zadeh, Lee et al.,

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20 09). This is important because many hemodialysis providers consider this serum ferritin range to be elevated and often withhold IV iron therapy at these levels.

Keep Your Eyes on the Three I’s In Anemia Management: Inflammation, Iron-Restricted E rythropoiesis, and IV Iron Nephrology nurses make every effort to help improve anemia outcomes in their patients on hemodialysis. As a result, they often face many challenges, such as helping to identify patients with iron-restricted erythropoiesis, manage inflammation, and administer appropriate IV iron therapy.

Identifying Iron-Restricted Erythropoiesis To better help manage anemia, nephrology nurses should be able to identify patients with iron-restricted erythropoiesis. Typically, this type of patient has a normal or high serum ferritin level and a low TSAT level, and remains anemic despite adequate or increasing ESA therapy (Wish, 20 06). Under these conditions, some nurses may be puzzled as to whether the patient needs iron supplementation; the normal or elevated serum ferritin level may lead the nurse to believe that the patient is iron replete, yet the low TSAT level indicates an insufficient supply of circulating iron. Inflammation, infection, and malnutrition in patients on hemodialysis can limit the diagnostic value of serum ferritin and TSAT. The difficulty of interpreting an elevated serum ferritin level can be two-fold: the increase in serum ferritin may be due to its acute-phase properties or may be a result of iron being locked up in storage. The value of the TSAT marker can be confounded because it is calculated by measuring the serum iron level divided by the total ironbinding capacity (TIBC) level, and TIBC can be decreased by MICS (Kalantar-Zadeh, McAllister, Lehn, Liu, & Kopple, 20 04). A TIBC less than 200 µg/dL can result in a falsely elevated TSAT level.

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Tip #5: Due to the limitations associated with the classic iron markers, the use of additional clinical laboratory tests may be considered. One practical approach to early identification of iron-restricted erythropoiesis is to evaluate the patient’s CHr level (Thomas & Thomas, 2002). This marker measures the amount of Hb in reticulocytes, which are 1- or 2day-old red blood cells. The CHr marker provides a reasonably accurate reflection of how much iron was available for erythropoiesis within a relevant time period. Another important marker in differentiating ironrestricted erythropoiesis is CRP, which is a marker of the presence and degree of inflammation (Yilmaz, 2007). Because inflammation can limit available iron, a patient with an above-normal CRP level may not have adequate iron to optimize erythropoiesis. Serum iron is another relevant marker when assessing iron status. This index measures the amount of iron bound to transferrin (Ponka, 1999; Ponka et al., 1998). A low serum iron level indicates that an insufficient supply of iron is being transported to the bone marrow for erythropoiesis. In addition, red blood cells are reduced in size in a state of iron deficiency/restriction, which is reflective of a low MCV value (Fishbane & Maesaka, 1997). Low levels of serum iron and MCV may indicate a deficiency in the amount of circulating iron, whereas high levels may indicate iron overload. Using indices such as CHr, CRP, and serum iron may help in making the decision to administer or hold IV iron, especially when serum ferritin levels are high. These markers are already part of many patients’ routine monthly laboratory data, which makes utilizing them even easier. Although studies have shown varying utility of serum ferritin, TSAT, and CHr at different levels, the KDOQI guidelines suggest that sufficient iron should be administered to maintain a serum ferritin level greater than 200 ng/mL and a TSAT level greater than 20% or a CHr level greater than 29 µg/cell in patients on

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hemodialysis (NKF, 20 06). According to the KDOQI guidelines, insufficient evidence exists to recommend routine IV iron administration if serum ferritin is greater than 50 0 ng/mL; however, a serum ferritin level greater than 500 ng/mL does not preclude IV iron therapy if the clinician considers it necessary (NKF, 20 06). It is important to note that the guidelines do not support an upper limit of serum ferritin at which to automatically hold IV iron therapy (Fishbane, 20 08). Higher levels of serum ferritin may not be reliable indicators of true iron status or predictors of response to IV iron therapy. In the DRIVE population (high serum ferritin, low TSAT, low Hb, and receiving adequate ESA doses), ferric gluconate was effective for improving Hb levels in cases where serum ferritin and TSAT may not have indicated a need for IV iron (Coyne et al., 20 07; Kapoian et al., 20 08). Study patients with serum ferritin levels less than 800 ng/mL were as likely to respond to ferric gluconate as patients with higher serum ferritin levels. This indicates that serum ferritin alone should not be used to guide IV iron treatment decisions. In addition, patients with TSAT levels of 19% or less were as likely to respond to ferric gluconate as patients with higher TSAT levels. The most effective predictor of improvement in anemia was whether patients in the DRIVE Study received ferric gluconate—not the baseline serum ferritin or TSAT value. A recent study showed that serum ferritin results can vary depending on which assay is used (interassay variability), and results can vary in the same patient over a period of time (intrapatient variability) (Ford, Coyne, Eby, & Scott, 20 09). These variations in results from current serum ferritin assays can compound the difficulties involved in interpreting the significance of higher serum ferritin measurements. The KDOQI guidelines recommend that treatment decisions for patients with serum ferritin levels

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greater than 500 ng/mL should include an evaluation of a number of factors, such as the patient’s clinical status (for example, fatigue or inflammation), TSAT level (for example, whether a low TSAT level combined with the elevated serum ferritin suggests a state of iron-restricted erythropoiesis), Hb level and Hb trends, and ESA response (NKF, 20 06 ) . Tip #6: The nephrology nurse should consider anemia in the context of the whole patient and not rely on laboratory values only. Foremost, it is crucial for the nephrology nurse to recognize the signs and symptoms of anemia. Even though serum ferritin and TSAT levels may be within normal ranges, a patient may experience symptoms of anemia. The nurse should take notice of patient complaints of tiredness, reduced energy, and shortness of breath. During the physical examination, the nurse should look for pale or gray skin, particularly if it is associated with pale lips, palms, and tongue, which are signs of a decreased red blood cell count. A thorough patient history with a full physical examination can assist the nurse to identify other factors that could contribute to confounding iron assessments, such as inflammation, infection, medication use, cancer, malnutrition, rheumatoid arthritis, and liver disease (Brugnara, 20 03). The information gained from the patient history and physical examination can be used in conjunction with laboratory test results to better guide treatment decisions. Tip #7: Iron-restricted erythropoiesis may be present in patients with anemia on hemodialysis who have a low TSAT and high serum ferritin, and are on ESA therapy. The use of IV iron can be a practical treatment approach.

Managing Inflammation Inflammation in patients on hemodialysis is a common occurrence and an important consideration in anemia treatment. An inflammatory process can affect iron mobilization, confound the diagnosis of whether the patient has an adequate iron supply,

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and blunt response to ESA therapy. Tip #8: The nephrology nurse should investigate underlying causes of inflammation and infection, which are not always apparent. Some inflammatory/infectious states may be minor and require more in-depth investigation (Nissenson, & Charytan, 20 03). Identified causes should be promptly treated ( Johnson et al., 20 07). This may include administration of antibiotics for infection or removal of failed renal allografts. Inflammatory and infectious states can occur with a wide variety of common disorders and can also result from the effects of maintenance dialysis (Bistrian & Khaodhiar, 1999). Several biochemical markers are frequently used to assess the presence and/or degree of inflammation in patients on hemodialysis, such as an elevated CRP level (Kalantar-Zadeh et al., 20 03). Tip #9: The nephrology nurse should also consider the presence of malnutrition. Assessing malnutrition includes measuring body composition, nutrition protein intake, and at least one measure of serum protein status. Decreased values of some nutritional markers (such as serum albumin, TIBC, and body mass index) have been found to be associated with ESA hyporesponsiveness and anemia. Some markers of iron status are influenced by malnutrition, which can have an impact on the diagnosis of iron deficiency in patients who are malnourished (KalantarZadeh et al., 20 03 ) .

Administering IV Iron Therapy The decision to provide IV iron therapy in a setting of iron-restricted erythropoiesis is a risk versus benefit evaluation: the potential safety risk of administering additional IV iron to a patient with a high serum ferritin level versus the benefit of overcoming iron-restricted erythropoiesis to improve anemia. Therefore, the nephrology nurse should be familiar with the potential risks as well as the benefits of IV iron therapy, particularly because some clinical data about

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the safety of IV iron may be interfering with providing the best possible care to anemic patients on hemodialysis. One concern associated with IV iron therapy is the development of iron overload, which is the accumulation of excess iron in tissues. This condition can occur in individuals who are anemic and require repeated red blood cell transfusions, which were common prior to ESA therapy and IV iron. Iron overload can be uncommon, however, for several reasons: (1) during ESA therapy, IV iron is taken up by red blood cell precursors, reducing the likelihood of iron being deposited in organs; (2) ESA therapy greatly increases the demand for iron and reduces iron stores; and (3) ongoing blood losses typical in the patient on hemodialysis further reduce the iron supply (Besarab, Frinak, & Yee, 1999). Another concern is that in its free elemental form, iron can be a reactive oxidizing agent and can generate toxic free radicals (Fishbane, 20 03 ) . The presence of nontransferrinbound iron (free iron) can potentially increase the risk of infection. However, the body ensures that iron is usually bound to transferrin to prevent iron from being in a free form. After IV iron is delivered into the circulation, it is quickly taken up by the RE system in its bound form, at which time the iron is dissociated from its carbohydrate ligand and stored as ferritin or hemosiderin. Next, the stored iron is turned over to transferrin, which delivers iron to red blood cell precursors in the bone marrow for incorporation into Hb production. However, IV iron use in a patient with an active infection can facilitate microbial growth. A third concern is an association between IV iron and increased levels of markers of oxidative stress, which has been demonstrated in a few studies (Agarwal, Vasavada, Sachs, & Chase, 2004; Leehey, Pa l u b i a k , Chebrolu, & Agarwal, 20 05; Roob et al., 2000). The concern surrounding oxidative stress with IV iron relates to the possibility of introducing non-

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Table 1 Regular Low Doses of Intravenous Iron Reduced ESA Doses Study Duration (Months)

Number of Patients

Braun, Hammerschmidt, Schreiber, Heidler, & Horl (1996)

6

36

40 mg/we e k

Braun, Lindner, Schreiber, Heidler, & Horl (1997)

3

52

80 mg/week for 8 weeks, then 40 m g / week for 4 weeks

Up to 23.4%

Garcia Cortés et al. (1997)

3

85

62.5 mg/week or 187 m g / week in divided doses

Up to 60.2%

Taylor et al. (1996)

6

46

62.5 mg twice weekly, eve ry week, or eve ry 2 weeks

33.3%

Study

Ferric Gluconate Dose

Reduction in ESA Dose 32%

Note: ESA = erythropoiesis-stimulating agent.

transferrin-bound iron into the circulation.

Potential IV Iron Benefits Two approaches to IV iron dosing offer numerous benefits: repletion and regular low-dose therapy. Periodic iron repletion consists of a series of IV iron doses given episodically to replenish iron stores whenever iron status tests decrease to lessthan-target range (NKF, 20 06). The benefits of this dosing option can include improved Hb levels and reduced ESA doses (Coyne et al., 20 07; Kapoian et al., 20 08). Regular low-dose administration consists of smaller IV iron doses administered at regular intervals to maintain iron status within target levels following a repletion course of therapy (NKF, 20 06). Patients on hemodialysis may require regular, low-dose IV iron therapy for several reasons. First, an ongoing iron supply is needed for Hb synthesis during red blood cell development (Kalantar-Zadeh, Streja, Miller, & Nissenson, 20 09). If iron is absent, Hb may not be synthesized, and red blood cells may not be produced or maintained at a sufficient level in the circulation. Second,

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patients on hemodialysis may have ongoing blood losses (for example, due to repeated laboratory testing and the hemodialysis procedure), which result in an average iron loss of up to 3 grams per year (Kalantar-Zadeh, Strega et al., 20 09). Finally, inflammatory conditions can interfere with access to iron stores and limit the availability of iron. A benefit of regular, low-dose IV iron therapy is that it can improve and stabilize Hb levels. In contrast, a repletion regimen initially restores iron levels and raises Hb levels, but ultimately, may lead to a “roller coaster” effect in which patients quickly return to an iron-deficient state, and anemia recurs (Canavese et al., 1999 ) . Studies have indicated that Hb target levels can be achieved and maintained with regular, low-dose IV iron therapy (Bolaños, Castro, Fa l c ó n , Mouzo, & Varela, 20 02). Maintenance use of ESA therapy without addressing the iron needs of the patient on hemodialysis can lead to poor ESA response and higher ESA doses. Regular, low-dose IV iron therapy can reduce ESA use, which may lead to cost savings in the treatment of anemia. One study investigated the effects of a regular, low-dose iron dextran regimen to maintain a

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TSAT of 30% to 50% versus a “loadand-hold” regimen to maintain a TSAT of 20% to 30% in a randomized trial of 24 patients on hemodialysis (Besarab et al., 2000). Although both regimens were effective in maintaining target Hb levels, ESA utilization was reduced by approximately 40% with the regular, low-dose IV iron regimen. Several other studies have shown that using regular, low-dose ferric gluconate reduced ESA requirements (see Table 1). One challenge facing nephrology nurses today is the lack of standardization regarding IV iron use, while allowing nurses to use clinical judgment to assess and manage individuals as well as outliers. Tip #10: The development of an integrated protocol for ESA and IV iron, with both iron repletion and regular, low-dose iron options, would greatly benefit the nephrology nurse in the management of anemia in patients on hemodialysis. This protocol should also allow for the evaluation of patients based on laboratory values and the use of clinical judgment to make treatment decisions. A computer-generated protocol that titrated both ESA and IV iron doses would provide both standardization and time savings. The nephrology

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Sponsored Educational Educational Supplement Supplement Sponsored Table 2 Summary of Tips to Help Manage Iron-Restricted Erythropoiesis and Improve Anemia Tip #1: Administration of IV iron thera py can help overcome iron-restricted erythropoiesis/inflammation-mediated RE blockade. Tip #2: The administration of IV iron thera py can help improve ESA response and help reduce ESA requirements. Tip #3: The KDOQI guidelines suggest that clinicians should evaluate the patient for specific causes of poor response to ESA thera py. Tip # 4: Maintaining higher TSAT and serum fe r ritin levels may help improve response to ESA thera py. Tip #5: Due to the limitations associated with the classic iron markers, the use of additional clinical laboratory tests may be considered. Tip #6: The nephrology nurse should consider anemia in the context of the whole patient and not rely on laboratory values only. Tip #7: Iron-restricted erythropoiesis may be present in patients with anemia on hemodialysis who have a low TSAT and high serum fe r ritin, and are on ESA therapy. The use of IV iron can be a practical treatment approach. Tip #8: The nephrology nurse should investigate underlying causes of inflammation and infection, which is not always apparent. Tip #9: The nephrology nurse should consider the presence of malnutrition. Tip #10: The development of an integrated protocol for ESA and IV iron, with both iron repletion and regular, low-dose iron options, would greatly benefit the nephrology nurse in the management of anemia in patients on hemodialysis.

nurse could then have more time to assess the small percentage of patients whose laboratory values fall out of the protocol’s parameters for root causes of their hyporesponse.

Conclusions The role of the nephrology nurse is crucial in the proper management of anemia in the patient on hemodialysis. Nephrology nurses are in the ideal position to help develop an overall anemia management plan because they have frequent contact with patients and regularly evaluate and monitor them for anemia. A successful anemia management plan may include three important considerations (the three I’s): inflammation, ironrestricted erythropoiesis, and IV iron therapy. Iron-restricted erythropoiesis is one form of iron deficiency that may result from ESA use or the presence of inflammation (also known as inflammation-mediated RE blockade). It is,

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therefore, important that the anemia management team has effective strategies for assessing patient parameters to better manage inflammation and make appropriate IV iron treatment decisions. A convenient summary of the tips suggested in this article is provided in Table 2. References Adamson, J.W. (2009). Hyporesponsiveness to erythropoiesis stimulating agents in chronic kidney disease: The many faces of inflammation. Advances in C h ronic Kidney Disease, 16, 76-82. Agarwal, R., Vasavada, N., Sachs, N.G., & Chase, S. (20 04). Oxidative stress and renal injury with intravenous iron in patients with chronic kidney disease. Kidney International, 65, 22792289 . Amgen. (20 08). Epogen® (epoetin alfa) for injection: Prescribing information. Thousand Oaks, CA: Au t h o r. Retrieved from http://wwwext. amgen.com/pdfs/misc/epogen_pi.p df

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