A field guide to iron needs in the patient on hemodialysis.
Iron deficiency, leading to low hemoglobin levels, is a pervasive problem in patients with end stage renal disease (ESRD) on hemodialysis (HD). Anemia due to various forms of iron deficiency and restricted iron availability is associated with an increased risk of morbidity and mortality, as well as reduced quality of life. Therefore, it is important for nephrology nurses to understand the basics of iron physiology, including how iron is absorbed and transported by the body to the erythroid marrow to be incorporated into hemoglobin. It is also essential for nurses to understand how the normal state of iron balance that exists in the healthy individual is altered in the patient on HD, and what the best strategies are for repleting iron stores and maintaining iron balance. A glossary of important terms used throughout this article can be found in Table 1.
Normal Iron Balance in the Healthy Individual
In the healthy individual, iron absorption, transport, and storage are regulated in a tightly controlled system. This system serves several functions: it effectively delivers iron to the bone marrow for hemoglobin building and erythrocyte production; it transports iron to and from storage sites in the macrophages of the reticuloendothelial (RE) system and the hepatocytes of the liver; it recycles iron from senescent (i.e., dying) erythrocytes; and it protects the body from free iron, which participates in chemical reactions that generate free radicals that may be potentially harmful to the body (Fauci et al., 2008).
Iron Distribution in the Body
Adult men have about 25 to 45 mg of iron per kg of body weight (approximately 3000 to 4000 mg). Pre-menopausal women have somewhat lower iron stores (Andrews, 1999). This iron is distributed into several compartments in the body (see Figure 1) (Andrews, 1999). Of the body's total iron content, more than half is incorporated into the hemoglobin of circulating erythrocytes. Another 1000 mg is stored in the cells of various organs, primarily the liver. The macrophages of the RE system contain about 600 mg of iron. An additional 300 mg of iron is incorporated into the muscle cells as myoglobin, which serves as an intracellutar storage site for oxygen and is used for metabolic purposes.
Finally, about 300 mg of iron at any given time is contained in the bone marrow, where most of it is actively being incorporated into hemoglobin. Iron forms the basis for hemoglobin production in erythrocytes, which are produced in the erythroid tissues of the bone marrow (together, the circulating erythrocytes in the blood, their precursors, and all the body elements concerned in their production are known as the erythron).
Iron in the diet is absorbed by enterocytes, which are specialized epithelial cells that take up iron as it passes through the duodenum (Fauci et al., 2008). Nearly all absorption of dietary iron occurs in the duodenum (Fleming & Bacon, 2005), although a small amount is taken up elsewhere along the tract of the small intestine. Iron entering the duodenum is moved across the cell wall of the enterocyte by a divalent metal transporter (DMT-1) (Fauci et al., 2008). Iron that enters the enterocyte is either released from the cell into the circulation through a transmembrane iron transporter known as ferroportin or is stored within the cell. Iron stored within the enterocyte is subsequently lost when the cell dies and is sloughed from the wall of the intestine.
[FIGURE 1 OMITTED]
[FIGURE 2 OMITTED]
Iron released into the circulation binds to transferrin, a small protein produced by the liver with 2 iron-binding sites (Fauci et al., 2008). Transferrin is the body's iron-transport vehicle, and it shuttles iron between those cells that are able to release iron (the enterocytes, the RE macrophages of the liver and spleen, and the hepatocytes of the liver) and those cells that are able to take up iron through transferrin receptors (e.g., the developing erythrocytes of the bone marrow and the hepatocytes of the liver) (Andrews, 1999; Fauci et al., 2008). In healthy individuals, about 20% to 50% of the total iron-binding sites on transferrin are occupied by iron at any given time. This amount of iron bound to transferrin is known as the percentage of transferrin saturation (TSAT), one of the primary measures of iron status (National Kidney Foundation [NKF], 2006).
Iron actively bound to transferrin is known as the functional iron pool. The functional iron pool represents a very small amount of the body's total iron--about 3 mg--but it is incredibly active. Transferrin takes up and turns over its iron 10 to 20 times a day, and the uptake of iron from transferrin in the presence of iron deficiency can be as short as 10 to 15 minutes (Fauci et al., 2008).
Iron that is delivered to the various body compartments (i.e., muscle, liver, and bone marrow) is either utilized or stored. In the muscle, iron is incorporated into myoglobin. In the bone marrow, the majority of iron is incorporated into hemoglobin in developing erythrocytes. Mature erythrocytes enter the circulation, where they have a life span of approximately 120 days. Dying, or senescent, erythrocytes are engulfed by RE macrophages, where hemoglobin is broken down, and the iron is separated out and recycled back over to transferrin.
[FIGURE 3 OMITTED]
Iron in excess of that incorporated into hemoglobin or turned over to transferrin by the macrophages is stored within a protein complex known as tissue ferritin. Iron is also stored within tissue ferritin in the cells of the liver. In cases where transferrin-bound iron is low, iron can be released from its stores inside tissue ferritin and maned over to transferrin as needed. A second form of ferritin, called serum ferrifin, is also produced in conjunction with tissue ferritin. Serum ferritin is an indirect measure of iron stores and is another measure used to assess a patient's iron status (NKF, 2006). Serum ferritin originates from the release of tissue ferritin, contains little or no iron, and its role is less clearly understood (Cavill, 1999; Easom, 2006).
Iron in Red Blood Cell Production
Within the erythroid marrow, adequate and healthy erythrocyte production depends on the presence of both iron and erythropoietin (EPO). Erythropoietin is a hormone produced primarily by the kidneys, with a small amount produced by the liver. It is secreted in response to the level of tissue oxygenation in the kidneys, with low oxygen levels (e.g., in the case of anemia) encouraging its production. Once stem cells in the erythroid marrow have "committed" to developing into erythrocytes, the primary roles of EPO are to stimulate the production of these erythroid progenitor cells and to protect them from apoptosis (programmed cell death) (see Figure 2) (Fauci et al., 2008; Petroff, 2005). In patients with chronic kidney disease who are unable to produce adequate EPO, erythropoiesis-stimulating agents (ESAs) are used to increase the rate of cell production.
As the erythrocyte progenitors develop into the first recognizable erythrocyte precursors, or proerythroblasts, EPO receptors are lost, and the cells begin to express a tremendous number of transferrin receptors (300,000 to 400,000/cell) (Fauci et al., 2008). During this stage of erythrocyte development, iron is incorporated into the cell, and hemoglobin is produced. As the proerythroblasts shed their genetic material and develop into reticulocytes (immature erythrocytes), the number of transferrin receptors decreases dramatically, and the cells' ability to incorporate iron is reduced accordingly. The reticulocyte hemoglobin content (CHr) measures how much hemoglobin has been incorporated into the reticulocytes and is a third means of determining a patient's iron status (NKF, 2006).
The fully developed erythrocytes do not express any transferrin receptors, and are therefore unable to take up any iron. Consequently, it is critical for iron to be available to the developing erythrocyte during the 3day window in which the proerythroblast develops into the reticulocyte. If a constant supply of iron is not available during this time period, the "window of opportunity" for hemoglobin building is lost. The resulting cells are hypochromic and microcytic, lacking adequate hemoglobin, and therefore, have a reduced ability to carry oxygen.
Release of iron from its storage sites and absorption of iron from the duodenum is regulated by the presence of hepcidin, a small peptide hormone secreted by the liver and cleared by the kidneys. Hepcidin acts by reducing the absorption of iron and blocking its release from storage sites into the functional iron pool (see Figure 3) (Donovan, Roy, & Andrews, 2006; Ganz, 2007; Park, Valore, Waring, & Ganz, 2001; Pigeon et al., 2001). Hepcidin production is believed to be controlled by a number of signals, including 1) an iron signal, which depends on the concentration of iron in transferrin; 2) a bone marrow, or erythropoietic, signal, which suppresses hepcidin when iron is needed for erythropoiesis (Donovan et al., 2006; Ganz 2007); and 3) an inflammation signal, which increases the production of hepcidin in the presence of proinflammatory cytokines, including interleukin-6 (Nemeth et al., 2003).
On the cellular level, hepcidin acts by binding to ferroportin (Donovan et al., 2006), which is found not only on the surface of the enterocyte, but on the surface of any cell that is able to release iron, including the hepatocytes of the liver, the macrophages of the spleen and liver, and the cells of the placenta (during pregnancy). Ferroportin is the only avenue through which these cells can release iron. Hepcidin binds to and causes the cell to internalize ferroportin, where it is degraded by lysosomes (Nemeth et al., 2004). As a result, iron is trapped in the cells. The functional iron pool shrinks (being unable to take up iron), the TSAT drops, and less iron is available for delivery to the bone marrow.
Alterations in Iron Balance in the Patient on HD
The system for iron absorption, delivery, and storage is designed for maximum iron conservation. In fact, there is no biologic mechanism for excretion of iron in humans. The only ways by which iron can be lost are through bleeding, menstruation, and sloughing of dying enterocytes (Andrews, 1999). As a result, in the healthy person, only a very small amount of iron needs to be absorbed daily from the duodenum to replace iron losses. If iron losses occur (e.g., through an injury or blood donation), EPO production is increased, allowing for the more rapid development of new erythrocytes; hepcidin production is decreased, allowing more iron to be absorbed from the duodenum and released from storage sites to be incorporated into hemoglobin.
In contrast, iron balance in patients on HD is significantly altered, resulting in highly increased iron needs. There are a number of reasons for this, including substantial blood losses, increased demands for iron caused by the use of ESAs, and inflammation, which causes an increase in hepcidin that decreases the absorption of iron from the duodenum and blocks the release of iron from storage sites.
Blood and Iron Loss
Because more than half of the body's total stores of iron are contained in the circulating erythrocytes (Andrews, 1999), blood loss in the patient on HD causes significant iron losses. Although the amount of iron lost in the individual patient on HD varies, estimated iron losses may be up to 3000 mg per year (Kalantar-Zadeh, Streja, Miller, & Nissenson, 2009). Considering that normally, as little as 1 mg of iron per day is lost (Andrews, 1999), the iron losses in the patient on HD are massive by comparison. This massive iron loss can lead to a state of iron deficiency (known also as absolute iron deficiency), characterized by both a low TSAT (less than 20%) and a low serum ferritin level (less than 200 ng/mL) in patients on HD (NKF, 2006).
There are several primary sources of blood loss in patients on HD. Most patients on HD undergo frequent blood draws for laboratory testing. These weekly to monthly blood tests may result in up to 1000 mg of iron to be lost each year (Kalantar-Zadeh et al., 2009). Another 1000 mg of iron are lost from blood that remains in the dialyzer tubing or catheters, as well as accidental blood losses can result in up to another 1000 mg or so of iron loss (Kalantar-Zadeh et al., 2009). Slow, chronic blood loss in the gastrointestinal tract due to platelet dysfunction, along with inadequate iron intake, also contributes to blood loss (Kalantar-Zadeh et al., 2009). Advances in the design of dialyzers have significantly reduced the amount of blood lost during the HD process. However, better anemia management has led to higher hemoglobin levels in patients over the years. Thus, despite losing less blood, the total amount of iron lost each year has remained high (Sargent & Acchiardo, 2004).
Much of the variability in blood loss among patients is due to poor clotting at the access site. Although bleeding is not a significant problem for most patients, it is estimated that one-third lose more than 10 mL of blood per HD treatment, and postdialysis bleeding may account for up to half of all blood loss (Sargent & Acchiardo, 2004). Thus, nurses should identify patients with a poor clotting history and recognize that these patients may be at higher risk for iron losses. Pre-menopausal women, as well as patients with a history of acute blood loss (e.g., due to recent injury or surgery), are also at higher risk for iron loss, and these factors should be taken into account in making treatment decisions.
Forms of Iron Deficiency
In addition to absolute iron deficiency (as discussed previously), patients on HD also experience alterations in iron homeostasis due to ironrestricted erythropoiesis and inflammation-mediated RE blockade. Ironrestricted erythropoiesis is driven by the use of ESAs and can essentially be viewed as a problem of "supply and demand." Because ESAs dramatically accelerate the number of erythrocytes produced in the bone marrow, transferrin is not able to deliver iron to these sites rapidly enough to keep up with the increase in erythrocyte production (Wish, 2006). In these patients, total body iron stores may actually be adequate, but the increased erythropoiesis will deplete the functional iron pool. Patients with iron-restricted erythropoiesis generally have low TSATs (less than 20%) hut may have normal or even elevated serum ferritin levels.
In inflammation-mediated RE blockade, underlying inflammation prevents the release of iron from the RE system (Wish, 2006). Underlying inflammation is common in patients on HD and may be due to multiple factors, both related and unrelated to the HD process itself (see Table 2) (Yilmaz, 2007). Inflammation-mediated RE blockade is most likely a protective mechanism by the body in response to inflammation. Although iron is essential for hemoglobin production, it also mediates free-radical damage in the presence of inflammation and is a nutrient source for certain bacteria. Therefore, when inflammation or infection are present, the body "locks up" iron inside its storage sites in the RE system (Wish, 2006). Because the iron in these sites cannot be released to transferrin, it cannot be delivered to the bone marrow for hemoglobin building. Hepcidin appears to be the master regulator of this response. Hepcidin levels increase in the presence of inflammation, reducing the amount of iron available for erythropoiesis both by locking up iron and by decreasing the amount of iron absorbed from the duodenum.
It is important for nurses to understand that these forms of iron deficiency are not mutually exclusive.
Patients on HD experience continuing blood loss, are on ESA therapy, and in most cases, have some degree of underlying inflammation. Therefore, all of these factors may play a role in contributing to anemia in the patient on HD.
Strategies to Restore and Maintain Iron Balance
Restoring iron losses, overcoming iron restriction, and maintaining iron balance are clear priorities for nurses caring for the patient on HD.
Restoring Iron Balance
Nurses should anticipate the need for repletion of iron stores in the patient on HD who is iron deficient, defined by the NKF's Kidney Dialysis Outcomes Quality Initiative (KDOQI) guidelines as a serum ferritin level of 200 ng/mL or less plus a TSAT of 20% or less or a CHr of 29 pg/cell or less (NKF, 2006). This is also true for patients who are new to HD, many of whom are already in an iron-deficient state, even when iron measures, such as the serum ferritin level, suggest they have sufficient iron stores (Fudin, Jaichenko, Shosak, Bennett, & Gotloib, 1998). One study in patients who were new to HD showed that 42% already had severe iron deficiency, with a TSAT less than 16%; an additional 25% had a TSAT between 16% and 25% (Hutchinson & Jones, 1997).
It has been well established that the iron needs of the patient on HD cannot be met with the use of oral iron supplements (Fudin et al., 1998; NKF, 2006). Instead, repletion courses of IV iron should be given to bring the patient who is iron-deficient into the target Hb range of 11 to 12 g/dL as recommended by the NKFKDOQI (NKF, 2007).
Repletion IV Iron Therapy
Repletion therapy consists of a total of 1g of IV iron, given in divided doses (e.g., 125 mg given over 8 consecutive HD sessions or 100 mg given over 10 consecutive HD sessions). The benefits of repletion therapy in iron-deficient patients on HD were most recently shown with ferric gluconate in the Dialysis Patients' Response to IV Iron with Elevated Ferritin (DRIVE) Study (Coyne et al., 2007). The 6-week DRIVE Study included anemic patients on HD with lower TSAT levels (25% or less) combined with higher serum ferritin levels (500 to 1200 ng/mL) and receiving adequate ESA therapy. Patients were randomized to no iron (control) or a repletion course of ferric gluconate. At randomization, both groups received a 25% increase in ESA dose; further dosage changes were prohibited. All patients had shown a poor response to ESA therapy, despite doses of at least 22,500 U/week (Coyne et al., 2007).
In the DRIVE Study, the ferric gluconate group showed a significantly greater increase in hemoglobin over 6 weeks than the control group (1.6 vs. 1.1 g/dL; P = 0.028), as well as a significantly greater increase in TSAT level (7.5% vs. 1.8%; P< 0.001). Further, significantly more patients in the ferric gluconate group responded with an increase in hemoglobin of at least 2 g/dL than the control group (46.9% vs. 29.2%; P = 0.041). A significant drop in the CHr level in the control group showed that these patients who did not receive IV iron had worsening iron deficiency over the 6 weeks of the study (Coyne et al., 2007).
The DRIVE-II Study was a 6-week follow-up extension to the DRIVE Study, designed to determine the impact of the repletion course of ferric gluconate given during DRIVE on ESA doses. All patients assigned to the control and ferric gluconate groups in DRIVE returned to routine use of IV iron. Any IV iron product could be used, and dose adjustment was at the discretion of the investigator. Overall, 112 patients participated, and the results for these patients were analyzed over the entire 12-week course of DRIVE and DRIVE-II (Kapoian et al., 2008).
By the end of DRIVE-II, patients in the ferric gluconate group required significantly lower doses of ESA: their mean ESA dose had decreased from 43.7 U/week at week 6 to 36.1 U/week at week 12 (Kapoian et al., 2008). In comparison, ESA doses were unchanged in the control group. Despite the reduction in ESA doses, significantly more patients in the ferric gluconate group were able to maintain a hemoglobin level greater than 11 g/dL (83.90/0) compared with the control group (67.9%; P < 0.05). Together, DRIVE and DRIVE-II showed that ferric gluconate helped bring patients on HD who were anemic and who had TSAT levels of 25% or less and serum ferritin levels between 500 and 1200 ng/mL and receiving adequate ESA doses into target hemoglobin levels, and mainmined these targets and reduced ESA doses (Kapoian et al., 2008).
The results of the DRIVE/ DRIVE-II studies are important, given the characteristics of the study population. The participants in this trial had evidence of absolute iron deficiency. They also had evidence of iron-restricted erythropoiesis, as shown by a combination of low TSAT levels and high serum ferritin levels. In addition, the patients had highly elevated C-reactive protein levels at baseline (mean of 25.5 to 29.3 mg/L), a strong indicator of inflammation-mediated RE blockade (Coyne et al., 2007). Thus, a repletion course of ferric gluconate appeared to benefit patients who had any of these forms of iron deficiency.
The DRIVE/DRIVE-II studies used a complex cost-savings analysis that took into account not only the costs of ESA and IV iron over the 12-week study period, but also the increase in hemoglobin level and the costs associated with hospitalizations due to serious adverse events. The total cost per patient in the ferric gluconate group was $3675 per g/dL increase in hemoglobin, whereas the total cost per patient in the control group was $5065 per g/dL increase in hemoglobin. The net savings for the ferric gluconate group was $1390 per g/dL increase in hemoglobin over the 12-week period. The findings indicate the use of IV iron may represent an effective strategy for reducing Medicare treatment costs associated with HD (Pizzi, Bunz, Coyne, Goldfarb, & Singh, 2008).
[FIGURE 4 OMITTED]
During the 12-week study period of DRIVE/DRIVE-II, 20 patients in the control group experienced 38 serious adverse events, and 15 patients in the ferric gluconate group experienced 22 serious adverse events. Of these serious adverse events, 24 occurred in 13 patients in the control group, and 10 occurred in 8 patients in the ferric gluconate group during DRIVE-II. No significant difference was observed in the incidence of serious adverse events occurring during the DRIVE-II 6-week period alone. However, a post-hoc analysis using Poisson regression over the entire DRIVE/DRIVE-II 12-week study period showed a 0.58 incidence rate ratio for having a serious adverse event in the ferric gluconate group compared with the control group (P = 0.041). It is important to note that this study was not powered for either a safety assessment or for sufficient duration to assess long-term safety (Kapoian et al., 2008).
Maintaining Iron Balance with Regular Low-Dose IV Iron Therapy
Once patients on HD reach an iron-replete state, the clinician is faced with a choice on how these patients should be managed in order to maintain iron balance, which is essential to ensure optimal anemia management. The NKF-KDOQI guidelines estimate that in order to maintain a proper balance of iron, patients on HD require an average of 22 to 65 mg/week of IV iron (NKF, 2006).
One possible strategy to deliver this average dose of iron is through regular low-dose IV iron therapy, which delivers smaller amounts of IV iron on a consistent (e.g., weekly) basis. This treatment option may be more effective than "loading and holding" of IV iron, in which IV iron is given in periodic repletion regimens followed by long periods without any iron.
Regular low-dose IV iron therapy can have a number of advantages over a load-and-hold strategy. First, regular low-dose IV iron therapy satisfies the needs of the bone marrow to have a constant supply of iron for developing erythrocytes, making it more likely that the hemoglobin level will be maintained within the desired range. In contrast, with a load-andhold strategy, the patient may experience an initial rapid rise in hemoglobin levels, followed by a drop, as ongoing blood loss continues and the iron pool is depleted (see Figure 4) (Fishbane & Berns, 2005). This may cause the patient to experience fluctuations in hemoglobin levels both above and below target ranges, a phenomenon known as hemoglobin cycling.
[FIGURE 5 OMITTED]
Hemoglobin cycling can be a product both of poorly designed ESA dosing strategies and poorly designed IV iron dosing strategies (Fishbane & Berns, 2005; Sargent & Acchiardo, 2004). Overuse of ESAs, or intermittent use of ESAs or IV iron, may set up a situation where iron status becomes unstable, resulting in over-shooting hemoglobin levels and falling short of hemoglobin targets. More than 90% of patients on HD have been shown to experience hemoglobin cycling, defined as an upward or downward change in hemoglobin greater than 1.5 g/dL for longer than 8 weeks. It has been shown that discontinuation of IV iron therapy contributes to downward cycling of hemoglobin levels, whereas increases in ESA and IV iron doses contribute to upward cycling (Fishbane & Berns, 2005).
Preventing hemoglobin cycling is an important part of anemia management, as this phenomenon has been associated with poor clinical outcomes. In a 6-month study of 152,846 Medicare patients on HD, those who experienced high-amplitude fluctuations in their hemoglobin levels had much higher rates of hospital admissions and admissions for infections, and a longer length of hospital stay than those who maintained a target hemoglobin level of 11 to 12.5 g/dL over the entire 6 months (see Table 3) (Ebben, Gilbertson, Foley, & Collins, 2006).
Second, regular low-dose IV iron therapy can help decrease ESA usage, which is important for a number of reasons. Numerous studies have indicated that ESAs, when used in high doses in an attempt to achieve higher target hemoglobin levels, are associated with elevations in all-cause and cardiovascular-related mortality (see Figure 5) (Besarab et al., 1998; Regidor et al., 2006; Szczech et al., 2008; Zhang, Thamer, Stefanik, Kaufman, & Cotter, 2004). The apparent association between high ESA usage and increased mortality risk has led the U.S. Food and Drug Administration (FDA) to mandate a black box warning on the labeling of all ESAs, emphasizing that high doses of ESAs do not further improve hemoglobin levels and are associated with an increased risk of adverse cardiovascular outcomes. The warnings note that individualized dosing to achieve and maintain hemoglobin levels within the range of 10 to 12 g/dL should be used (Amgen, 2008; Ortho Biotech, 2009).
ESA use is also associated with high costs of care in patients on HD. Under the current way that Medicare pays for HD, medications such as ESAs are reimbursed separately from the HD procedure itself. It is estimated that ESAs currently represent 25% of the more than $8 billion in total expenditures paid by Medicare for dialysis (Leavitt, 2008). Under a proposed new reimbursement scheme, dialysis-related medications, including ESAs, would be included in a new "bundled" payment to HD facilities. One goal of this new bundled payment is to control costs related to the use of ESAs.
A number of studies have shown that IV iron, when given in a regular low-dose regimen, can achieve these goals of maintaining target hemoglobin levels, while simultaneously reducing ESA requirements and associated costs. A study by Taylor and colleagues examined the use of regular low-dose IV iron in 46 stable HD patients receiving ESA therapy (Taylor, Peat, Porter, & Morgan, 1996). These patients were assigned to receive 62.5 mg of ferric gluconate twice weekly if their serum ferritin was less than 100 ng/mL, weekly if their serum ferritin was 100 to 250 mg/mL, and every 2 weeks if their serum ferritin was 250 to 600 ng/mL. Patients were also stratified according to low (less than 100 ng/mL) and high (100 to 600 ng/mL) serum ferritin levels. Patients were observed for 6 months, with their ESA doses adjusted upward or downward by 30% to 50% in order to maintain a hemoglobin level of 11 to 13 g/dL (for men) and 10 to 12 g/dL (for women) (Taylor et al., 1996).
Significant improvements in hemoglobin levels with regular low-dose IV iron were seen in both the low and high serum ferrifin groups (both P < 0.05). At the start of the study, the median dose of ferric gluconate was 62.5 mg twice weekly for the low serum ferritin group and 62.5 mg weekly for the normal serum ferritin group. By the end of 6 months, the median dose was 62.5 mg every 2 weeks for both groups (Taylor et al., 1996).
A prospective study by Bolanos, Castro, Falcon, Mouzo, and Varela (2002) randomized patients on HD with serum ferritin levels greater than 100 ng/mL and TSAT greater than 20% to receive regular low-dose ferric gluconate therapy at doses of up to 21.3 mg per HD session or to doses of 62.5 mg every 1 to 4 weeks. Hemoglobin levels were measured every 4 weeks over the 16-week duration of this study. All patients were being treated with ESAs and were considered iron replete at the beginning of the study. At the end of 16 weeks, the patients assigned to the regular low-dose IV iron regimen experienced a significant increase in hemoglobin over baseline compared with those randomized to more intermittent use of IV iron. TSAT levels were maintained within NKFK-DOQI-recommended ranges (i.e., 20% to 50%) in both groups (Bolanos et al., 2002).
Finally, Canavese and colleagues (1999) conducted a prospective study in 40 ESA-treated patients on HD who were iron deficient, with a mean hemoglobin level of 9.8 g/dL. This study, conducted in Italy, was unique in that it was started after a period in which IV iron was unavailable. Thus, at the start of the study, patients were being managed only with ESAs. The previous practice among these patients on HD was to use a "priming" dose of IV iron of 3 mg/kg/week, followed by cessation of IV iron for 2 to 3 months. Predictably, this led to a pattern of stopping ESA doses after the priming IV iron regimen, followed by a need to restart and dramatically increase the ESA dose as iron stores became depleted between IV iron doses. This study sought to change the dosing strategy to offer a priming regimen of ferric gluconate for 6 weeks, followed by regular low doses of ferric gluconate over the next 6 months.
The initial 3 mg/kg/week regimen of IV iron brought these iron-deficient patients into target TSAT ranges within 6 weeks, with a mean TSAT of 26%. Over the next 3 months, the IV iron dose was reduced to 1.2 mg/kg/week. The TSAT was maintained and improved to 36% over the final 3 months, even as the IV iron dose was reduced to 1 mg/kg/week (Canavese et al., 1999). Numerous earlier studies demonstrated that the use of regular low-dose IV iron had an ESA-sparing effect, reducing usage by as much as 70% (Fishbane, Frei, & Maesaka, 1995; Sepandji, Jindal, West, & Hirsch, 1996; Sunder-Plassman & Horl, 1995).
In the series of studies, the improvements in hemoglobin and iron measures were indeed associated with significant reductions in ESA usage. In the study by Taylor and colleagues (1996), the median ESA dose was reduced by one-third, both in the low serum ferritin group (reduction, 9000 to 6000 U/week) and in the high serum ferritin group (reduction, 6000 to 4000 U/week). In the study by Canavese et al. (1999), the mean ESA dosage was reduced from 100 to 77 U/kg/week. In this study, the use of regular low-dose IV iron allowed 15 patients to stop ESA therapy altogether.
These reductions in ESA usage have also been associated with cost reductions. In the study by Canavese and colleagues (1999), by factoring in the price of both ESAs and IV iron, an estimated $3500 per month was saved in the treatment of 40 patients on HD. Similar reductions in costs associated with ESA use have been seen in other IV iron studies (Besarab et al., 2000).
Taken together, the studies of IV iron suggest that patients who are iron deficient during HD, whether due to significant losses of iron, iron-restricted erythropoiesis, or inflammation-mediated RE blockade, all can benefit significantly from repletion of their iron stores. Once patients on HD are iron replete, a strategy that delivers regular low doses of IV iron can maintain iron stores, thus maintaining hemoglobin and TSAT levels. These strategies also reduce ESA use and may minimize the risk of hemoglobin cycling, thereby potentially reducing the health risks associated with persistently or transiently low hemoglobin levels.
No IV iron regimen can precisely mimic the body's normal physiologic mechanisms of iron delivery to the bone marrow for erythrocyte production. However, these studies suggest that giving IV iron in regular low doses that are sufficient to maintain body iron stores can avoid "gaps" during the process of erythropoiesis in which available iron is low. Our knowledge of the process of erythrocyte production and hemoglobin building shows that developing cells can only take up iron during a short window of time. If iron is not available during this time, the opportunity to incorporate sufficient hemoglobin into the cells is lost. Once the elythrocyte is mature and enters the circulation, it cannot take up iron, no matter how much IV iron is given. Thus, because the manufacturing of erythrocytes is continuous, the supply of iron should be continuous.
Nephrology nurses play a critical role in ensuring that IV iron is used as part of comprehensive anemia management program. The nursing staff is in the best position to observe patients on an ongoing basis, to evaluate them clinically for signs of possible anemia, and to track their hemoglobin and iron indices (TSAT and serum ferritin) over time. In addition, nurses can identify those patients who may be at high risk of excessive blood loss during HD and assess their individual iron needs.
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.
Statement of Disclosure: The author disclosed that she is on the Speakers' Bureau for Watson.
Amgen. (2008). Epogen[R] (epoetin alfa) for injection: Prescribing information. Thousand Oaks, CA: Author. Retrieved June 30, 2009, from http://www.ext.amgen.com/pdfs/misc/epogen-pi.pdf
Andrews, N.C. (1999). Disorders of iron metabolism. The New England Journal of Mediane, 341(26), 1986-1995.
Besarab, A., Amin, N., Ahsan, M., Vogel, S.E., Zazuwa, G., Frinak, S., et al. (2000). Optimization of Epoetin therapy with intravenous iron therapy in hemodialysis patients. Journal of the American Society of Nephrology, 11(3), 530-538.
Besarab, A., Bolton, W.K., Browne, J.K., Egrie, J.C., Nissenson, A.R., Okamoto, D.M., et al. (1998). The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and Epoetin. The New England Journal of Medicine, 339(9), 584-590.
Bolanos, L., Castro, P., Falcon, T.G., Mouzo, R., & Varela, J.M. (2002). Continuous intravenous sodium ferric gluconate improves efficacy in the maintenance phase of EPOrHu administration in hemodialysis patients. American Journal of Nephrology, 22(1), 67-72.
Canavese, C., Grill, A., De Costanzi, E., Martina, G., Buglione, E., Valente, D., et al. (1999). How to save money for erythropoietin therapy by changing from 'roller coaster' to continuous iron supplementation. Nephron, 81(3), 362-363.
Cavill, I. (1999). Iron status as measured by serum femtin: The marker and its limitations. American Journal of Kidney Diseases, 34(Suppl. 2), S12-S17.
Coyne, D.W., Kapoian, T., Suki, W., Singh, A.K., Moran, J.E., Dahl, N.V., et al. (2007). Ferric gluconate is highly efficacious in anemic hemodialysis patients with high serum ferritin and low transferrin saturation: Results of the Dialysis Patients' Response to IV Iron with Elevated Ferritin (DRIVE) Study. Journal of the American Society of Nephrology, 18(3), 975-984.
Donovan, A., Roy, C.N., & Andrews, N.C. (2006). The ins and outs of iron homeostasis. Physiology (Bethesda), 21, 115-123.
Easom, A. (2006). The challenge of using serum ferritin to guide IV iron treatment practices in patients on hemodialysis with anemia. Nephrology Nursing Journal, 33(5), 543-552.
Ebben, J.P., Gilbertson, D.T., Foley, KN., & Collins, A:J. (2006). Hemoglobin level variability: Associations with comorbidity, intercurrent events, and hospitalizations. Clinical Journal of the American Society of Nephrology, 1(6), 1205-1210.
Fauci, A.S., Braunwald, E., Kasper, D.L., Hauser S.L., Eongo D.L.,Jameson, J.L., et al. (2008) Harrison's principles of internal medicine (17th ed.). New York NY, McGraw Hill.
Fishbane, S., & Berns, J.S. (2005). Hemoglobin cycling in hemodialysis patients treated with recombinant human erythropoietin. Kidney International 68(3), 1337-1443.
Fishbane, S., Frei, G.L., & Maesaka, J. (1995). Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation. American Journal of Kidney Diseases, 269 (1), 41-46.
Fleming, R.E., & Bacon, B.R. (2005). Orchestration of iron homeostasis. The New England Journal of Medicine, 352(17), 1741-1743.
Fudin, R., Jaichenko, J., Shostak, A., Bennett, M., & Gotloib, L. (1998). Correction of uremic iron deficiency in hemodialyzed patients: A prospective study. Nephron, 79(3), 299-305.
Ganz, T. (2007). Molecular control of iron transport. Journal of the American Society of Nephrology, 18(2), 394-400.
Hutchinson, F.N., & Jones, W.J. (1997). A cost-effectiveness analysis of anemia screening before erythropoietin in patients with end-stage renal disease. American Journal of Kidney Diseases, 29(5), 651-657.
Kalantar-Zadeh, K., Streja, E., Miller, J.E., & Nissenson A.R. (2009). Intravenous iron versus erythropoiesis-stimulating agents: Friends or foes in treating chronic kidney disease anemia? Advances in Chronic Kidney Disease, 16(2), 143-151.
Kapoian, T., O'Mara, N.B., Singh, A.K, Moran, J., Rizkala, A.R., Geronemus, R., et al. (2008). Ferric gluconate reduces Epoetin requirements in hemodialysis patients with elevated ferritin. Journal of the American Society of Nephrology, 19(2), 372-379.
Leavitt, M.O. (2008). Report to Congress: A design for a bundled end-stage renal disease prospective payment system, 2008. Retrieved June 29, 2009, from http://www.cms.hhs.gov/ESRDGeneralInformation/Downloads/ ESRDReportToCongress.pdf National Kidney Foundation (NKF). (2006).
KDOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease. American Journal of Kidney Diseases, 47(5 Suppl., 3), S11- S145.
National Kidney Foundation (NKF). (2007). KDOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease: 2007 update of hemoglobin target. American Journal of Kidney Diseases, 50(3), 471-530.
Nemeth, E., Tuttle, M.S., Powelson, J., Vaughn, M.B., Donovan, A., Ward, D.M., et al. (2004). Hepcidin regulates cellular iron efllux by binding to ferroportin and inducing its expression. Science, 306(5704), 2090-2093.
Nemeth, E., Valore E.V., Territo M, Schiller, G., Lichtenstein, A., & Ganz, T. (2003). Hepcidin, a putative mediator of inflammation, is a type II acute-phase protein. Blood, 101(7), 2461-2463.
Ortho Biotech. (2009). Procrit Horsham, PA: Author. Retrieved July 16, 2009, from www.orthobiotech.com/orthobiotech/procrit.html
Park, C.H., Valore, E.V., Waring, A.J., & Ganz, T. (2001). Hepcidin, a urinary antimicrobial peptide synthesized in the liver. The Journal of Biological Chemistry, 276(11), 7806-7810.
Petroff, S. (2005). Evaluating traditional iron measures and exploring new options for patients on hemodialysis. Nephrology Nursing Journal, 32(1), 65-73.
Pigeon, C., Ilyin, G., Courselaud, B., Leroyer, P., Turlin, B., Brissot, P., et al. (2001). A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. The Journal of Biological Chemistry, 276(11), 7811-7819.
Pizzi, L.T., Bunz, T.J., Coyne, D.W., Goldfarb D.S., & Singh, A.K (2008). Ferric gluconate treatment provides cost savings in patients with high ferritin and low transferrin saturation. Kidney International 74(12), 1588-1595.
Regidor, D.L., Kopple, J.D., Kovesdy, C.P., Kilpatrick, R.D., McAllister, C.J., Aronovitz, J., et al. (2006). Associations between changes in hemoglobin and administered erythropoiesis-stimulating agent and survival in hemodialysis patients. Journal of the American Society of Nephrology, 17(4), 1181-1191.
Sargent, J.A., & Acchiardo, S.R. (2004). Iron requirements in hemodialysis. Blood Purification, 22(1), 112-123.
Sepandj, E, Jindal, K, West, M., & Hirsch, D. (1996). Economic appraisal of maintenance parenteral iron administration in treatment of anaemia in chronic haemodialysis patients. Nephrology Dialysis Transplantation, 17(2), 319-322.
Sunder-Plassmann, G., & Horl, W.H. (1995). Importance of iron supply for erythropoietin therapy. Nephrology Dialysis Transplantation, 10(11), 2070-2076.
Szczech, L.A., Barnhart, H.X., Inrig, J.K., Reddan, D.N., Sapp, S., Patel, U.D., et al. (2008). Secondary analysis of the CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes. Kidney International, 74(6), 791-798.
Taylor, J.E., Peat, N., Porter, C., & Morgan, A.G. (1996). Regular low-dose intravenous iron therapy improves response to erythropoietin in haemodialysis patients. Nephrology Dialysis Transplantation, 11(6), 1079-1083.
Wish, J.B. (2006). Assessing iron stares: Beyond serum ferritin and transferrin saturation. Clinics of the Journal of the American Society of Nephrology, 1(Suppl. 1), S4-S8.
Yilmaz, M.I. (2007). The causes of inflammation and possible therapeutic options in dialysis patients. Gulhane Tip Dergisi, 49, 271-276.
Zhang, Y., Thamer, M., Stefanik, K., Kaufman, J., & Cotter, D.J. (2004). Epoetin requirements predict mortality in hemodialysis patents. American Journal of Kidney Diseases, 44(5), 866-876.
Gail Wick, MHSA, BSN, RN, CNN, is a Consultant in Atlanta, GA. She is a Past President of ANNA and a member of ANNA's Dogwood Chapter.
Table 1 Glossary of Important Terms Absolute iron deficiency A form of iron deficiency in which the (i.e., iron deficiency) body's total iron stores are depleted. Generally indicated by a TSAT less than 20% and a serum ferritin of less than 200 ny/mL in patients on HD. Anemia A deficiency in the quality or amount of hemoglobin in circulating erythrocytes. Various forms of iron deficiency are a major cause of anemia in patients on HD. Apoptosis A genetically programmed form of cell death (as opposed to necrosis, which is cell death caused by traumatic insult or injury). C-reactive protein (CRP) A protein produced in the liver in response to inflammation. One role is to enhance the ability of macrophages to destroy damaged or foreign cells. A marker for inflammation in patients with CKD on HD. DMT 1 A transporter on the surface of enterocytes in the duodenum that allows the enterocytes to absorb iron. Duodenum The 10 to 12-inch first portion of the small intestine. Plays an essential role in digestion of food and taking up iron. Enterocyte Specialized cells that form the lining of the duodenum. Most iron absorbed from the diet is taken up by enterocytes. Erythropoietin (EPO) A hormone secreted by the kidneys that regulates the production of erythrocytes by encouraging the division of erythrocyte progenitors and preventing apoptosis. Erythrocyte precursor Cells that develop from erythrocyte progenitors and eventually into mature erythrocytes. Iron is incorporated into developing erythrocytes in the erythrocyte precursor stage. Erythrocyte progenitor Cells that develop in the erythron from stem cells and are "committed" to developing into erythrocytes (as opposed to white blood cells or platelets). Erythropoietin plays an important role in regulating the production of erythrocyte progenitors. Erythron The total mass of circulating red blood cells, their precursors, and the tissues in the bone marrow that produce them. Erythropoiesis- Agents, such as recombinant human stimulating agent (ESA) erythropoietin, that can be given to encourage erythrocyte production if the body has an inadequate supply of natural erythropoietin. ESA resistance A condition characterized by a failure to reach target hemoglobin levels despite adequate doses of ESAs. Ferritin (tissue) A protein that serves as the primary storage site for iron within cells. Ferroportin A protein that transports iron from inside the cell to the cell membrane and allows for its release. Ferroportin is the only known "exporter" of iron. Free radicals Highly reactive atoms or molecules that can cause damage to body cells. Functional iron pool The iron that is actively bound to transferrin in the circulation. Hemoglobin The iron-containing protein in erythrocytes that is the body's primary mechanism for delivering oxygen to cells. Hemoglobin cycling An upward or downward fluctuation in hemoglobin, generally defined as a shift of greater than 1.5 g/dL for longer than 8 weeks. Hepatocyte The cells that make up the majority of the mass of the liver. The hepatocytes play an important role in synthesizing transferrin and storing iron. Hepcidin A protein produced by the liver that is the "master regulator" of iron homeostasis. Hepcidin acts by binding to feroportin, preventing cells from releasing iron. If iron levels are low, hepcidin is decreased, allowing for greater iron availability. Iron-restricted A form of iron deficiency caused by the use erythropoiesis of ESAs, in which the elevated rate of erythropoiesis outstrips the rate at which transferrin can deliver iron to the bone marrow. Thus, while the body's total iron stores may be normal, the developing erythrocytes lack the necessary iron to produce hemoglobin. Inflammation-mediated A condition in which the release of iron reticuloendothelial from its storage sites is prevented in the blockade presence of inflammation. This is believed to be a protective mechanism by the body to prevent iron from participating in free-radical formation and serving as a nutrient for bacterial growth. Macrophage A type of white blood cell that engulfs pathogens and cellular debris by phagocytosis. Macrophages engulf senescent, or dying, erythrocytes in order to recycle their iron. Myoglobin A protein related to hemoglobin that serves as a storage site for oxygen within muscles. Reticulocyte Immature red blood cells that develop from erythrocyte precursors and enter the circulation after shedding their nucleus. Reticulocytes have fragments of genetic material and a limited ability to take up iron. Reticuloendothelial Part of the immune system that consists of system macrophages and monocytes located in reticular connec- tive tissues. These cells accumulate in the lymph notes and the spleen. Serum ferritin A form of ferritin that is found outside of cells and is an indirect indicator of how much iron is stored inside cells and therefore is used as an indirect measure of iron status. Not a reliable marker of iron stores because it can be increased due to inflammation and malnutrition. Stem cell Cells that have the ability to differentiate into various cell types. Stem cells play a critical role in the repair and replacement of body cells, including all types of blood cells. Transferrin A small protein produced by the liver that serves as the body's means to transfer iron between storage sites and the bone marrow. Each transferrin protein contains 2 iron binding sites. Transferrin saturation The percent of transferrin binding sites (TSAT) that are actively bound to iron. Table 2 Causes of Inflammation in the Patient on HD Reduced renal function (e.g., causing reduced excretion of inflammatory cytokines) Infections/inflammatory diseases, including: * Mycobacterium tuberculosis * Chlamydophila pneumoniae * Systemic lupus erythematosus * Rheumatoid arthritis * Underlying malignancies * Diabetes * Periodontitis Intercurrent clinical events * Surgery * Injury Uremic retention Unpure dialysate Bioincompatible dialysis membranes Access site infections Bacterial infections in thrombosed fistulae or grafts Acidosis Protein-energy malnutrition Source: Yilmaz 2007 Table 3 Risks of Comorbidity and Hospital Admission Associated with Various Hemoglobin Levels and Degrees of Fluctuation Hospital Admission Average Hemoglobin Admission for Infecfion Length of to (Hb) (%) (%) (Days) Low 69.2 29.5 12.7 Target 25.3 6.2 1.9 (11 to 12.5 g/dL) High 29.8 29.5 12.7 Low amplitude fluctuation with 51.1 17.6 6.5 low Hb Low amplitude 33.5 9.3 2.8 fluctuation with high Hb High amplitude 54.0 17.7 6.4 fluctuation Average Hemoglobin Number of (Hb) Comorbidities Low 2.4 Target 1.1 (11 to 12.5 g/dL) High 2.4 Low amplitude fluctuation with 1.8 low Hb Low amplitude 1.3 fluctuation with high Hb High amplitude 1.8 fluctuation Source: Adapted with permission from Ebben et al., 2006.
|Printer friendly Cite/link Email Feedback|
|Title Annotation:||Sponsored Educational Supplement: Watson Nephrology[TM]|
|Publication:||Nephrology Nursing Journal|
|Date:||Jul 1, 2009|
|Previous Article:||Experiences of Hmong patients on hemodialysis and the nurses working with them.|
|Next Article:||Patient empowerment and motivational interviewing: engaging patients to self-manage their own care.|