Iron requirements in erythropoietin therapy

Best Practice & Research Clinical Haematology Vol. 18, No. 2, pp. 347–361, 2005 doi:10.1016/j.beha.2004.09.005 available online at http://www.sciencedirect.com

14 Iron requirements in erythropoietin therapy Joseph Wetherill Eschbach*

MD

Senior Research Advisor, Clinical Professor of Medicine, Emeritus Northwest Kidney Centers, University of Washington, Seattle, WA, USA

When erythropoietin (epoetins or darbepoetin) is used to treat the anemias of chronic renal failure, cancer chemotherapy, inflammatory bowel diseases, HIV infection and rheumatoid arthritis, functional iron deficiency rapidly ensues unless individuals are iron-overloaded from prior transfusions. Therefore, iron therapy is essential when using erythropoietin to maximize erythropoiesis by avoiding absolute and functional iron deficiency. Body iron stores (800–1200 mg) are best maintained by providing this much iron intravenously in a year, or more if blood loss is significant (in hemodialysis patients this can be 1–3 g). There is no ideal method for monitoring iron therapy, but serum ferritin and transferrin iron saturation are the most common tests. Iron deficiency is also detected by measuring the percentage of hypochromic red blood cells, content of hemoglobin in reticulocytes, soluble transferrin receptor levels, and free erythrocyte protoporphyrin values, but iron overload is not monitored by these tests. Iron gluconate and iron sucrose are the safest intravenous medications. Key words: erythropoietin; epoetin; anemia; iron therapy; functional iron deficiency; safety of intravenous iron.

NORMAL IRON METABOLISM Iron, in addition to erythropoietin, is needed for hemoglobin formation. The human body contains approximately 4000 mg iron: 3000 mg circulating in red blood cells, and 800–1200 mg as storage iron, depending on body size.1 Small amounts of iron also occur in myoglobin and cytochrome enzymes. The body conserves iron since only approximately 1 mg is lost daily via intestinal endothelial cell shedding, and 1 mg is absorbed daily from food. The menstruating female loses approximately 1.5 mg of iron daily (prorated), which accounts for the higher incidence of iron deficiency in females.

* Tel.: C1 206 292 2771x2097; Fax: C1 425 454 5952/206 292 2164. E-mail address: [email protected]. 1521-6926/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved.

348 J. W. Eschbach

Other reasons for iron losses, such as occult or active gastrointestinal bleeding or blood losses related to surgical procedures, may lead to iron deficiency. Iron absorption is inversely related to iron stores and directly related to the rate of erythropoiesis, allowing for maintenance of adequate but not excessive iron stores and enough iron to meet the rate of red blood cell production. However, if blood losses are excessive, or erythropoiesis is markedly accelerated (as in chronic hemolytic anemic states: e.g. supraphysiological amounts of erythropoietin), then iron absorption may not be able to compensate for the increased demand for iron. The iron requirements related to erythropoietin therapy implies that an underlying anemia exists requiring erythropoietin therapy. In the context of this chapter, erythropoietin therapy refers to several erythropoietic stimulating substances: epoetin (recombinant human erythropoietin, or rHuEPO, epoetin-a and epoetin-b) and darbepoetin. While the pharmacokinetics differ between epoetin and darbepoetin, their action is similar in stimulating new red blood cell formation, therefore only epoetin will be discussed, since there is very little information about iron requirements associated with darbepoetin. Epoetin is the therapeutic agent, whereas erythropoietin refers to the native hormone secreted by the kidney and to a lesser extent by the liver. Since the iron requirements may vary depending upon the amount and frequency of epoetin therapy, an understanding of the various epoetin-responsive anemias is in order.

EPOETIN-RESPONSIVE CONDITIONS The main anemias helped by epoetin are those associated with erythropoietin deficiency; these conditions have serum erythropoietin levels that fail to increase in response to the degree of anemia present. † Renal disease resulting in renal insufficiency and eventually chronic renal failure (CRF) is the condition most responsive to epoetin therapy2 † The anemia of prematurity is also an erythropoietin deficiency state in which treatment with epoetin and intravenous iron prevents severe anemia from occurring post delivery3 Other anemias having an inadequate increase in serum erythropoietin levels may benefit from epoetin therapy: † The anemias of chronic disease, including chronic inflammatory conditions such as rheumatoid arthritis, chronic inflammatory bowel disease, and HIV infection, and in cancer patients following chemotherapy4–8 Epoetin is given in pharmacological quantities since it is given intermittently and in amounts generally larger than those secreted by the kidney under normal conditions. Epoetin can be given either intravenously or subcutaneously, the latter route generally being thought to be the more efficient. It is not known whether iron requirements differ between the two routes of epoetin administration. Because iron metabolism may vary in the epoetin-responsive anemias, it is necessary to review these conditions in relation to their iron needs.

Iron requirements in erythropoietin therapy 349

Iron metabolism in the anemia of chronic renal disease Iron metabolism in chronic renal disease varies between progressive renal disease, CRF (hemodialysis or peritoneal dialysis patients), transplant patients, and patients receiving epoetin. Erythroid function is subnormal (varying from one-third to two-thirds of normal) in CRF due to insufficient erythropoietin production in response to anemia.9 As anemia progresses in renal insufficiency, iron present in senescent RBCs becomes sequestered in the reticuloendothelial cells, and storage iron levels increase (even more so if RBC transfusions are given).10 Therefore, by the time dialysis is needed to maintain life, most patients have increased iron stores, although up to one-third maybe irondeficient11, presumably because of prior excessive blood losses. Before the advent of epoetin, hemoglobin levels were often 5–7 g/dL, and RBC transfusions were given to maintain higher hemoglobin levels. Excessive iron stores or iron overload resulted. Iron overload easily occurred because erythropoiesis was subnormal (thus less iron was directed to hemoglobin formation) in conjunction with periodic RBC transfusions (which provides approximately 1 mg of iron for every 1 mL RBCs). Red blood cell losses in the hemodialyzer varied from 1 to 3 g per year12, but this was often replaced by up to 12 units of packed RBCs infused in a year. Many patients received 1–4 units of RBCs per month.9 Iron absorption is physiological, in that absorption is inversely related to iron stores.13 In the pre-epoetin era, oral iron improved iron stores and corrected iron deficiency because erythropoiesis was sluggish, so the demand for iron by the erythroid marrow could be met by whatever iron was absorbed.9 Iron metabolism in CRF since the advent of epoetin therapy is characterized by the following points14: † Iron (blood) losses remain high, particularly in the hemodialysis patient † Oral iron usually cannot maintain adequate iron stores, particularly in the hemodialysis patient treated with epoetin † When erythropoiesis is stimulated by epoetin to levels greater than normal (because epoetin is given in pharmacological amounts), functional iron deficiency often occurs † Maintenance of optimal iron stores prevents functional and absolute iron deficiency and improves erythropoiesis Iron metabolism in other anemias There are at least two differences between iron metabolism in CRF and that in other anemias treated with epoetin. On one hand, the iron (blood) losses are probably higher in the hemodialysis patient, requiring more iron to replenish and maintain iron stores. But, on the other hand, functional iron deficiency is probably more prevalent in nonrenal disease anemias because the amount of epoetin required to stimulate erythropoiesis is much greater than in renal anemia. Functional iron deficiency This is a difficult concept for many physicians treating epoetin-responsive anemias. Absolute iron deficiency is characterized by serum ferritin levels !12 ng/mL associated with transferrin saturation values of !15%.15,16 In CRF, absolute iron deficiency is diagnosed when the serum ferritin is !100 ng/mL based on iron absorption studies in hemodialysis patients.13

350 J. W. Eschbach

Functional iron deficiency was first noted in CRF when epoetin failed to continue to increase the hemoglobin level in an anemic, hemodialysis patient iron-overloaded from previous RBC transfusions.17 The serum ferritin had decreased from 885 to 578 ng/mL, associated with a decline in transferrin saturation from 52 to 13% after only 9 weeks of epoetin at 50 U/kg given intravenously thrice weekly. Following administration of 1000 mg iron dextran, intravenously, without any change in epoetin dose, the hemoglobin and reticulocyte count again increased (Figure 1). An important point of confusion is the differentiation of functional iron deficiency from inflammatory/infectious effects on iron parameters. Infection or inflammation results in an acute-phase reactant causing serum ferritin to artificially increase, while at the same time the serum iron, total iron-binding capacity (TIBC), and percent transferrin saturation decreases, but usually the serum iron and the transferrin saturation decrease more than the TIBC (Table 1). To make this differentiation clinically, it is essential to have serial measurements of serum ferritin and transferrin saturation. Functional iron deficiency is due to the inability of reticuloendothelial cells to release enough iron to transferrin when the erythroid cell needs more iron to meet the stimulating effect from bolus or non-physiological doses of epoetin. This effect has not only been noted in various disease states treated with epoetin, but also in normal subjects given short-term courses of epoetin.18,19 The mechanism that prevents the release of more iron out of adequate storage sites to meet the demands of

Hematocrit

45

PATIENT # 016

Anephric

35

1.0 gm Imferon

25 15 Transfusion: 200 ml RBCs

rHuEpo 50 units/kg 3x/wk Serum fe TIBC %sat Ferritin

147 289 152 885

38 287 13 578

53 205 26 1036

Reticulocytes, corrected (%)

6.0 4.0 6.0 0 –12

–8

–4

0

+8 +4 Weeks

+12 +16

+20 +24

Figure 1. Functional iron deficiency induced within 9 weeks of epoetin therapy (50 U/kg three times weekly) in a hemodialysis patient initially with more than adequate iron stores from previous transfusions. See text for details. Imferon was the commercial name for an iron dextran product no longer available. Reprinted from Eschbach JW et al (1987, New England Journal of Medicine 316: 73–78) with permission.

Iron requirements in erythropoietin therapy 351

Table 1. Differentiation of functional iron deficiency from inflammation by serial laboratoy tests. Functional iron deficiency Serum ferritin Serum iron Transferrin saturation

Decreased Decreased Decreased

Inflammation/infection Increased Decreased Decreased

supraphysiological stimulation of the erythroid cells by epoetin is not well defined, but seems to be corrected by providing more iron intravenously.

EFFECT OF EPOETIN ON IRON METABOLISM IN HEALTHY SUBJECTS Studies in normal subjects and in autologous blood donors prior to elective surgery disclose that functional iron deficiency develops quite rapidly following epoetin administration. In six normal subjects, 150 U/kg of epoetin was administered intravenously every other day for four doses, resulting in significant decreases in serum ferritin and transferrin saturation diagnostic of functional iron deficiency (Figure 2).18 The reduction in effective erythropoiesis by functional iron deficiency was dramatically illustrated when red blood cell production, quantified by ferrokinetics, was far less than that of five patients with primary hemochromatosis (with more than adequate iron stores) given the same dose and frequency of epoetin. This effect resulted in a marked decline in serum ferritin and percent transferrin saturation levels between baseline and 24 hours after the fourth dose of epoetin. The serum ferritin decreased from 58G38 to 23G18 ng/mL, and transferrin saturation decreased from 30G9 to 13G3%, a 60 and 57% decrease, respectively.18 It is impressive that with just four doses of a modest dose of epoetin such marked changes in iron status occurred, leading to functional iron deficiency. This is in contrast to 15 hemodialysis patients who were iron-replete, if not overloaded from prior transfusions, receiving the same dose and frequency of epoetin. Serum ferritin decreased from 508G451 to 357G440 ng/mL, and transferrin saturation decreased from 47G29 to 33G21%, only a 30% decrease in each of these parameters. This marked change in iron parameters following epoetin administration in normal subjects was confirmed by Rutherford et al.19 They administered larger doses of epoetin (1200 U/kg over 10 days in divided doses, subcutaneously) to 24 subjects, in contrast to 600 U/kg over 8 days to six normal subjects in the above study by Eschbach et al.18 Nevertheless, the results were similar: serum ferritin declined from 81G53 to 21G15 ng/mL, a decrease of 74% versus a 60% decrease noted with half as much epoetin.18 Transferrin saturation also decreased dramatically by approximately 40–15% 3 days after the last dose of epoetin. These changes are even more striking when considering that all subjects took 300 mg of elemental iron for the 10 days of epoetin administration, and they illustrate the marked functional iron deficiency that occurs even in iron-replete normal subjects after just several doses of epoetin. Hemoglobin content of reticulocytes (CHr) was also shown to decrease significantly in the above 24 normal subjects following epoetin administration: from a normal 28.4 pg/individual cell to approximately 23 pg/cell.20 The authors conclude that this was compatible with iron-deficient erythropoiesis.

352 J. W. Eschbach

Erythron transferrin uptake µmol Fe/L WB/d

175

150

150

125

125

n=5

100

75

n=6

n=5

n=6

100

75

50

50 n=4 n=15 25

25

n=5

post pre

pre 15U/kg

post 50U/kg

post

pre 150U/kg

Recombinant Human Erythropoietin Figure 2. Erythropoietic response, as measured by ferrokinetics (the erythron transferrin uptake expressed as mmol of iron per liter of whole blood per day), following graded doses of epoetin. Emphasis is on the third, or far right panel, in which the erythropoietic response of six normal subjects is blunted, when compared to five subjects with primary hemochromatosis and 15 hemodialysis patients, the last two groups having sufficient iron for optimal epoetin stimulation, in contrast to the subjects who had normal iron balance at the beginning of epoetin exposure. The difference in ETU between the normal subjects and patients with hemochromatosis after four doses of epoetin indicates the magnitude of functional iron deficiency after just four epoetin doses. Reprinted from Eschbach JW et al (1992, Kidney International 43: 407–416) with permission.

Studies in other autologous blood donors prior to elective surgery also illustrates the impact of epoetin on iron metabolism. Epoetin 500 IU/kg was given subcutaneously twice a week for 3 weeks to subjects prior to hip-replacement surgery. Two units of blood (approximately 900 mL) were removed by phlebotomy during this time. Despite oral elemental iron (as ferrous fumarate) 200 mg a day, effective erythropoiesis declined during the last week of epoetin administration, as shown by a decrease in reticulocyte counts, which was preceded by a decrease in transferrin saturation from 22 to 16% and by a marked increase in free erythrocyte protoporphyrin values.21

IRON REQUIREMENTS ASSOCIATED WITH EPOETIN THERAPY The goal of iron therapy is to maintain adequate, but not excessive, iron stores that optimize epoetin therapy. There are several reasons for this goal. Optimal hemoglobin levels require both epoetin and iron, the latter best given intravenously. Also, epoetin is

Iron requirements in erythropoietin therapy 353

more expensive than intravenous iron, so maximal, yet safe, amounts of iron are needed to minimize epoetin requirements. Iron stores can best be assessed by iron staining of marrow reticuloendothelial cells. However, once intravenous iron therapy is initiated, this is no longer the best diagnostic tool for iron deficiency, particularly if repetitive analysis of iron stores are desired. Therefore, the best assessment of iron stores and iron availability for erythropoiesis is the serum ferritin15 and the transferrin saturation16, respectively. However, once epoetin therapy has been initiated, functional iron deficiency easily develops, which may not be detected by these measurements unless a serial decline in both values occurs associated with a transferrin saturation of less than 20–25%. The percentage of hypochromic red blood cells increasing to more than 6–10% is also indicative of functional iron deficiency, even if serum ferritin levels indicate adequate iron stores.22 Chronic renal disease/failure The largest experience with iron requirements associated with epoetin therapy is in chronic renal disease. Epoetin has been used since 1986 in clinical trials and for all dialysis patients and those with progressive renal disease and anemia since June 1989. Oral iron is poorly tolerated by dialysis patients already requiring many medications, so intravenous iron dextran was employed to treat iron deficiency when diagnosed. Usually 500–1000 mg was administered intravenously on dialysis in divided doses over 5–10 dialysis sessions (e.g. three times per week). Eventually, it was noted that because of the ongoing blood losses related to the dialysis procedure (approximately 5–20 mL of RBCs remain entrapped in the hemodialyzer at the end of each treatment), as much as 1–3 g iron loss/year occurred, resulting in iron deficiency.12 Functional iron deficiency also occurred in almost every patient as the result of the non-physiological administration of epoetin, given as a bolus injection and in rather large amounts. By 1997, there had been enough reports showing that maintaining serum ferritin and percent transferrin saturation levels above 100 ng/mL and 20%, respectively, resulted in reaching and maintaining better target hemoglobin levels and/or lowering the amount of epoetin required.23 Therefore, intravenous iron should be given to every hemodialysis patient treated with epoetin (unless allergic to all intravenous iron preparations) in order to maintain normal iron balance. By definition, this means maintaining the serum ferritin and transferrin saturation at O100 ng/dL and 20%, respectively, but ideally O200 ng/dL and 25%, respectively. Because hemodialysis patients are dialyzed three or more times a week, it is easy to repetitively use an intravenous iron product. Because it is impossible to determine how much iron loss is occurring with hemodialysis, the amount of intravenous iron necessary to maintain optimal iron stores will vary between patients. Therefore, 1 g iron may be prorated at weekly intervals over 3–12 months. For instance, some patients requiring relatively low doses of epoetin may need only 12.5–15.6 mg iron sucrose or iron gluconate weekly, respectively, whereas others will require 25/32.25, 50/62.5 or even 100/125 mg weekly, respectively. If absolute iron deficiency develops, then it is recommended to give intravenous iron with each hemodialysis for a total of 1 g (e.g. enough to replenish iron stores). Intravenous iron (200 mg/week!5) has also been shown to be effective with relatively low-dose epoetin (2000 U/week) therapy in patients with progressive renal insufficiency.24 The increase in hemoglobin from 9.7 to 11.05 g/dL indicated a fairly rapid improvement in a relatively short time. Serum ferritin and transferrin saturation were maintained as a result of the intravenous iron administration.

354 J. W. Eschbach

Table 2. Protocol for the intravenous administration of iron gluconate at the Northwest Kidney Centers, Seattle, WA, USA. If transferrin saturation !20% and/or serum ferritin !100 ng/mL, infuse 125 mg of iron gluconate every week!8 Administer iron gluconate intravenous weekly for 10 weeks if transferrin saturation O20, !50%, and serum ferritin O100 ng/mL, !800 ng/mL; begin with 125 mg/week if values in lower range, 32.25 mg/week if values in upper range After 10 doses, or weeks of intravenous iron therapy, wait 2 weeks and re-measure serum ferritin and transferrin saturation When ferritin O500 ng/mL, transferrin saturation O35%, reduce weekly dose of intravenous iron by half When serum ferritin and transferrin saturation decrease to !200 ng/mL and !25%, respectively, double dose of iron gluconate When either transferrin saturation O50% or ferritin O800 ng/mL, hold intravenous iron for 3 months, then repeat iron tests; when transferrin saturation !50% and ferritin !800 ng/mL, resume weekly intravenous iron at half the previous dose Stop oral iron

On the other hand, oral iron may be just as effective as intravenous iron with epoetin therapy in the ‘pre-dialysis’ patient, assuming that there are no significant blood losses and that iron stores are normal at baseline. Stoves et al found that 600 mg oral ferrous sulfate daily was equivalent to 300 mg of iron sucrose given intravenously monthly to 23 and 22 patients, respectively, in increasing the hemoglobin from 9.8 to 12.2 g/dL.25 Serum ferritin levels were higher in the intravenous iron group (330 ng/mL versus 95 ng/mL with oral iron). If oral iron is used, a minimum of 200 mg elemental iron/day is necessary when also using epoetin. A summary of the recommended intravenous iron dosing in chronic renal disease is given in Table 2. Cancer-related chemotherapy The anemia related to cancer chemotherapy is an anemia of chronic disease: that is, there is an inflammatory component in which erythropoietin secretion is blunted by inflammatory cytokines, and the erythroid marrow response to erythropoietin is blunted by cytokines.26 In general, epoetin in doses three times that required by dialysis patients is necessary to elicit an erythropoietic response27, and then only up to 50% of such patients respond to epoetin. Therefore, other anemic factors need to be ruled out and/or treated, such as nutritional factors and gastrointestinal bleeding28, and especially functional iron deficiency.29 Intravenous iron, in contrast to oral iron or placebo, appears to be more effective in increasing hemoglobin levels in cancer chemotherapy anemia treated with epoetin.30 There was no difference in hemoglobin response between giving intravenous iron (iron dextran) as a total dose infusion of 1–3 g versus 100 mg weekly intravenously for a total of 1.1–2.4 g.30 Those with the improved hemoglobin levels treated with intravenous iron and epoetin achieved a higher quality of life—more energy and activity—when compared to those patients treated with either oral iron or placebo and epoetin. Patients with lymphoproliferative disorders treated with cytotoxic drugs who become anemic may also respond to epoetin, but functional iron deficiency is common, limiting the epoetin response unless treated with either oral or intravenous iron.29

Iron requirements in erythropoietin therapy 355

The patients developing functional iron deficiency were treated with doses of epoetin that varied between 50 and 150 U/kg daily 5 days/week, which in general is more epoetin than is given to most CRF patients. Therefore, functional iron deficiency seems to be more common with larger doses of epoetin. Cazzola et al noted that functional iron deficiency in their patients was characterized by a reduced serum iron (!50 mg/dL) and transferrin saturation (!20%), as well as an increase in serum transferrin receptor associated with a stable hemoglobin level.29 Inflammatory bowel disease A randomized, controlled trial of epoetin or placebo therapy in anemic patients with Crohn’s disease who were also iron-deficient disclosed that a higher percentage of patients (91%) responded to epoetin and intravenous iron compared to 75% that responded to only intravenous iron.31 Anemia associated with ulcerative colitis is often due to iron deficiency related to chronic bleeding. Intravenous iron (200 mg iron saccharate for 10 infusions over 8 weeks) resulted in an increase in the mean hemoglobin from 8.5 to 12.7 g/dL after 8 weeks in 15 of 20 patients. Three of the other four patients (a fifth was lost to follow up) then responded to epoetin with an increase in hemoglobin from 9.5 to 12.8 g/dL.32 In a case report of chronic radiation enteropathy, anemia (Hb 8.6 g/dL) was associated with a low transferrin saturation (7.6%) and a relatively high serum ferritin (488 ng/mL), compatible with the anemia of chronic inflammation. Intravenous iron alone had no effect, but epoetin (10 000 IU three times a week, subcutaneously) with intravenous iron (iron sucrose, 200 mg/week) resulted in an increase in hemoglobin to 13.4 g/dL. This response was observed twice, recurring after epoetin was discontinued with a decline in Hgb to 7.8 g/dL.33 Rheumatoid arthritis The anemia related to rheumatoid arthritis was one of the first non-renal anemias to be studied in the context of its response to epoetin.4 As with other anemias of chronic disease, larger doses of epoetin and longer duration of therapy are needed to achieve appropriate erythropoietic responses, in contrast to epoetin treatment of the anemia of chronic renal failure. On the other hand, both of these anemias also have impaired iron metabolism in that epoetin without iron is usually ineffective (unless pre-existing iron overload is present). This is well illustrated by the study of Nordstrom et al, who noted that epoetin (150 IU/kg, twice weekly) plus oral iron (200 mg elemental iron daily) resulted in a better hemoglobin response than epoetin without iron.34 The hemoglobin rose from 9.5 to 10.7 g/dL with epoetin and no iron, in contrast to an increase from 9.9 to 12.0 g/dL when oral iron was given with the epoetin. In addition, many of those treated with just epoetin had additional increases in hemoglobin levels when oral iron was subsequently administered. Severe chronic heart failure Anemia worsens as the severity of chronic heart failure declines, as judged by the New York Heart Association (NYHA) classification.8 The etiology of this anemia is probably related to mild erythropoietin deficiency, since renal function is altered in most patients with advancing forms of chronic heart failure. As is true for the anemia of progressive

356 J. W. Eschbach

renal insufficiency without heart failure, the anemia of chronic heart failure responds better to epoetin plus supplemental iron therapy than with epoetin alone. Silverberg et al treated 26 NYHA class IV patients with epoetin (2000 IU weekly, subcutaneously) and intravenous iron sucrose (200 mg/week) for up to a mean of 7 months. The mean serum creatinine at onset of study was 2.6 mg/dL, mean serum ferritin was 177 ng/mL, and mean transferrin saturation was 20.5%. The hemoglobin increased from 10.2 to 12.1 g/dL.8 While the anemia in these patients was similar to that observed in progressive renal insufficiency (erythropoietin levels were not determined), several important clinical differences were apparent: cardiac dysfunction was the primary issue, which improved with improvement in anemia, and the number of hospitalizations was markedly reduced once anemia was almost eliminated.

MONITORING IRON THERAPY The goal of iron therapy associated with chronic epoetin dosing is to maintain optimal iron balance to support maximal erythropoiesis, and therefore, a stable, target hemoglobin. Thus, both absolute iron deficiency and iron excess are to be avoided. These endpoints are not difficult to diagnose, but the more difficult task is to prevent the functional iron deficiency which occurs in almost all epoetin-treated patients even if initially iron-overloaded. The time-honored method for monitoring iron therapy is to measure serum ferritin and serum iron and TIBC. Percent transferrin saturation is derived from dividing the serum iron into the TIBC and multiplying by 100. The serum ferritin, in a steady state, is directly related to tissue iron stores (although it does not contain iron) and the transferrin saturation indicates the amount of iron available for erythropoiesis. In otherwise healthy people, a transferrin saturation !16% is diagnostic of absolute iron deficiency16, assuming the serum ferritin is also below 15 ng/mL.15 Iron overload is diagnosed primarily by a transferrin saturation in excess of 50% and more typically O80%. There is no physiological or clinical rationale for maintaining the transferrin saturation O50% with intravenous iron therapy. There are few data in the literature detailing the upper limit of safety for serum ferritin. The guidelines for intravenous administration of iron to hemodialysis patients in the United States is to discontinue iron if and when the serum ferritin exceeds 800 ng/mL.23 This value was arbitrarily determined from the fact that functional iron deficiency developed when the ferritin decreased from 885 to 578 ng/mL in an epoetin-treated hemodialysis patient.17 More recently, using very refined technological assessment of liver iron by magnetic susceptometry, iron excess was determined to be associated with a serum ferritin O400 ng/mL.35 However, this methodology does not differentiate between parenchymal and reticuloendothelial iron sequestration. Most nephrologists now try to maintain iron stores with a serum ferritin between 200 and 500 ng/mL. Even if the ferritin exceeds some defined upper limit, there is no fear of parenchymal iron excess unless the transferrin saturation is chronically elevated above 50%. Since serum ferritin levels decrease with epoetin therapy and dialyzer blood losses continue, discontinuing intravenous iron for up to 3 months will result in a decline in the serum ferritin and transferrin saturation. There are other markers for monitoring iron therapy, but these are only diagnostic of iron deficiency. The percentage of hypochromic red blood cells increases to above 2.5%, usually O6–10%, if absolute or functional iron deficiency exists.22

Iron requirements in erythropoietin therapy 357

Soluble transferrin receptor protein increases with iron deficiency but also increases with epoetin administration. It can be suggestive of functional iron deficiency if the hemoglobin level remains stable at a stable epoetin dose.21 The hemoglobin content of reticulocytes (CHr) has been championed by some36,37 but not all38 as a means of following epoetin therapy to diagnose iron deficiency. The aim is to maintain the CHr O29 pg.37 These three tests are limited because they are not available in all clinical laboratories, and they do not provide data as to whether too much body iron is present. Bone-marrow examination of iron stores is the most reliable test in this regard, but is not functionally diagnostic once intravenous iron therapy has been initiated and does not diagnose functional iron deficiency.

POTENTIAL ADVERSE EFFECTS OF IRON THERAPY Oral iron is safer and cheaper than intravenous iron, but gastrointestinal intolerance often limits adequate intake, even though iron absorption is normal in chronic renal failure39 and probably in most other conditions. But, even if oral iron is tolerated, intravenous iron is often necessary to correct and prevent functional iron deficiency in patients on epoetin therapy. Therefore, a critical examination of the potential adverse effects of intravenous iron is indicated. Adverse effects can be subdivided into two categories: acute, hypersensitivity reactions, and possible long-term effects unrelated to iron overload; iron overload, although a possible long-term complication, is avoidable by proper monitoring and adjustment of intravenous iron dosing. Of the three commercially available intravenous iron compounds, iron dextran is associated with the most allergic reactions, occurring in approximately one in 150 people exposed40, but causing serious, life-threatening problems in 20 per 100 000 doses.41 Most of these reactions occur within minutes after the first dose, but reactions occasionally may occur after several uneventful doses. Therefore, medications to counteract anaphylaxis should always be available when administering intravenous iron dextran, since a number of deaths have occurred following this reaction. There may also be a delayed reaction consisting of myalgias and arthralgias that is dose-dependent, rarely occurring with doses of 100 mg or less.42 Iron gluconate and iron sucrose have been used in Europe for 30–40 years, and in the United States for the past several years. Anaphylactic reactions are extremely rare, although some patients have not been able to continue therapy because of an ‘allergic’ reaction. This suggests that it is the dextran component of intravenous iron dextran that is the immunological stimulant. A few studies have been undertaken to examine the immediate adverse effects of iron gluconate and iron sucrose. One of the largest studies involved almost 2500 hemodialysis patients that received either 125 mg iron gluconate or placebo intravenously.43 Only one patient sustained a life-threatening reaction requiring intravenous anti-anaphylactic medication but not hospitalization, a reaction rate 90% less than that with iron dextran. It appears that iron sucrose also has a similar safety record, although the number of patients studied is less than with iron gluconate. No anaphylactoid reactions occurred after 1000 doses (not patients) of 100 mg of iron sucrose given by intravenous ‘push’.44,45 There have been a number of possible long-term adverse effects from intravenous iron therapy. These include increased cardiovascular disease and atherosclerosis, increased infections, and increased oxidative stress from free radical generation.

358 J. W. Eschbach

While there are theoretical reasons for the above associations, a review of these possible effects in 1999 failed to disclose convincing empirical data.46 More recently, phagocytic function of polymorphonuclear leukocytes isolated from dialysis patients given 300 mg of iron sucrose intravenously were unable to kill Escherichia coli in vitro.47 However, this phagocytic dysfunction occurred only up to 1–2 hours after intravenous infusion. Another study with intravenous iron sucrose (100 mg) in hemodialysis patients claimed that oversaturation of transferrin occurs, resulting in the presence of catalytically active ‘free’ iron within 3.5 hours of intravenous injection. This also promoted bacterial growth of Staphylococcus epidermidis. The assumption that oversaturation of transferrin occurred was based on a bleomycin-detectable iron assay.48 The long-term signficance of oxidative stress in renal (and any other) disease is difficult to determine. Intravenous iron, as well as epoetin, have been thought to enhance oxidative stress in hemodialysis patients.49,50 However, anemia itself increases oxidative stress51, whereas increasing hemoglobin levels to O11 g/dL reduces oxidative stress, and intravenous iron is needed to optimize erythropoiesis to achieve higher hemoglobin levels. Furthermore, regular administration of intravenous iron has been shown to decrease tumor necrosis factor-a, and to increase the anti-inflammatory cytokine interleukin-4.51 To date, the benefits of improving anemia with erythropoietin products and intravenous iron outweigh the potential for long-term iron toxicity. However, further research is indicated to better clarify those long-term toxicities that might occur from each of the three commercially available intravenous iron products.52 SUMMARY Iron is needed to optimize erythropoietin (epoetin and darbepoetin) therapy. The epoetin-responsive anemias include chronic renal insufficiency and failure (ESRD), anemia of prematurity, and the anemias of chronic disease (which include cancer chemotherapy, rheumatoid arthritis, inflammatory bowel disease and HIV/AIDS). Functional iron deficiency is prevalent following epoetin administration and is best treated by intravenous iron and prevented by repetitive use of intravenous iron. Iron gluconate and iron sucrose are safer products than iron dextran for intravenous use. It is essential to monitor oral iron therapy to make sure that enough iron is given, and for intravenous iron therapy to prevent iron overload and functional iron deficiency. While not ideal, serum ferritin and transferrin saturation remain the most convenient laboratory tests for such monitoring. Research agenda † are iron requirements different between subcutaneous and intravenous administration of epoetin? † is there a difference between epoetin and darbepoetin in iron requirements? † is the magnitude of iron requirement related to dosing amounts of epoetin? † what limits the release of iron from reticuloendothelial storage sites to transferrin under epoetin stimulation? † how does intravenous iron overcome this ‘blockade’ when there is still storage iron present in the reticuloendothelial cell? † for patients requiring long-term erythropoietin therapy and concomitant intravenous iron therapy, how can we monitor for possible iron toxicities?

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