Oncologist. The. Iron Supplementation in Nephrology and Oncology: What Do We Have in Common?

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1 The Oncologist Iron Supplementation in Nephrology and Oncology: What Do We Have in Common? IAIN C. MACDOUGALL Department of Renal Medicine, King s College Hospital, London, United Kingdom Key Words. Anemia Anemia management Disclosures: Iain C. Macdougall: Consultant/advisory role: Vifor Pharma, Takeda; Honoraria: Vifor Pharma, Takeda; Research funding/contracted research: Vifor Pharma, AMAG Pharma. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the independent peer reviewers. ABSTRACT Anemia is frequently seen in patients with chronic kidney disease and also in those with cancer. There are factors in the pathogenesis of anemia that are common to both clinical conditions, with iron insufficiency, inflammation, and upregulation of hepcidin activity playing a part in both chronic disease states. Diagnostic laboratory markers for detecting functional iron deficiency in renal disease and oncology are not ideal, and the most widely available tests, such as serum ferritin and transferrin saturation, have poor sensitivity and specificity. Other tests incorporating a surrogate for iron sufficiency in the RBC and reticulocyte (such as percentage hypochromic RBCs or reticulocyte hemoglobin content) have greater sensitivity/specificity, but unfortunately these tests are not widely available in many hospital laboratories. Iron supplementation may be given via the oral route, i.m., or i.v., but it is now clear that, in both the nephrology and oncology settings, i.v. iron is superior to oral iron in terms of efficacy. Oral iron is associated with a high incidence of gastrointestinal side effects, and although large epidemiological studies of i.v. iron are reassuring, the long-term safety of parenteral iron is not established in well-designed adequately powered randomized controlled trials. The Oncologist 2011;16(suppl 3):25 34 INTRODUCTION Both nephrologists and oncologists treat many patients who have chronic, often debilitating, anemia. This anemia is multifactorial, and many of the contributory factors are common to both clinical disciplines [1, 2]. Thus, in patients with chronic kidney disease (CKD), there is inappropriately low production of erythropoietin by the diseased kidneys [3], and many patients receive supplemental erythropoietin therapy either with recombinant human erythropoietin or one of the newer erythropoietin analogs. Cancer patients may also show inappropriately low erythropoietin levels [4], and can be treated with erythropoietin therapy, although there have been concerns about shorter survival and a greater risk of venous thromboembolism in this patient group [5]. Other factors common to both nephrology and oncology include the availability of iron to proliferating Correspondence: Iain C. Macdougall, B.Sc., M.D., F.R.C.P., Renal Unit, King s College Hospital, London SE5 9RS, United Kingdom. Telephone: ; Fax: ; iain.macdougall@nhs.net Received March 14, 2011; accepted for publication May 16, AlphaMed Press /2011/$30.00/0 doi: /theoncologist.2011-S3-25 The Oncologist 2011;16(suppl 3):

2 26 Iron Supplementation in Nephrology and Oncology erythroblasts in the bone marrow, whereas the presence of chronic inflammation in both conditions is known to induce a state of functional iron deficiency [1]. Our understanding of this latter condition has been greatly enhanced over the last decade with the discovery of the 25-amino-acid peptide hormone hepcidin, which is secreted by the liver in response to proinflammatory cytokines, particularly interleukin-6 [6]. The latter mechanism is also relevant for administration of iron supplementation and is largely responsible for the greater efficacy of i.v. administration of iron compared with oral iron supplementation. The aim of this short article is to review how our understanding of the science of iron metabolism, the characterization of iron status, and the treatment of iron deficiency has developed over the last few years, in both the nephrology and the oncology settings. IRON METABOLISM AND THE ROLE OF HEPCIDIN In the last decade, huge advances have been made in our understanding of how iron is processed in the body that have implications for both nephrology and oncology. Because iron is potentially harmful, largely through the generation of highly toxic free radicals, its metabolism in humans is a tightly regulated process. Two main levels of regulation have been described: (i) cellular regulation, which controls the synthesis of transferrin receptor (necessary for cellular iron procurement) and ferritin (the iron storage protein), and (ii) a mechanism that modulates intestinal iron absorption and iron mobilization from macrophages and tissue stores. The peptide hormone hepcidin, produced by hepatocytes and acting on target cells situated both within and outside the liver, plays a pivotal role in this latter process. Hepcidin was initially identified as a cysteine-rich urinary antimicrobial peptide [7, 8]. Subsequent observations in mice demonstrating that hepcidin is overexpressed by hepatocytes in iron overload [9] and that knockout animals accumulate excess iron [10] confirmed a key role for hepcidin in iron homeostasis. Several studies showed that hepcidin modulates the release of iron from different cell sources, including enterocytes, macrophages, and hepatocytes, to plasma. Through these effects, hepcidin controls iron absorption, the recycling of iron derived from senescent and damaged erythrocytes, and the release of iron from tissue stores. These effects are accomplished through a unique biochemical mechanism: the interaction of hepcidin with ferroportin, a transmembrane protein that represents the sole known cellular iron exporter in vertebrates [11]. By triggering ferroportin internalization, ubiquitination, and degradation, hepcidin blocks the release of iron from cells. Because ferroportin is expressed at the highest levels by iron-exporting cells such as enterocytes and macrophages, hepcidin represents a negative regulator of iron absorption and macrophage iron release. The interest in hepcidin increased dramatically following the demonstration that the peptide represents the final common pathway on which the components of the regulatory network converge to control tissue iron exchange and iron absorption. In fact, increased erythropoietic activity and reduced tissue oxygen delivery suppress hepcidin production, thereby stimulating iron absorption/mobilization, whereas increased iron stores and inflammation act in the opposite way. The relevance of these new insights to nephrology and oncology derives from the realization that a major factor in the pathogenesis of the inflammatory anemia associated with CKD [12] and malignancy is a result of dysregulation of hepcidin production. There are several pathways involved in the regulation of hepcidin production, but one of the most important upregulators of hepcidin production is interleukin-6, which is itself upregulated in both acute and chronic inflammation [6]. This explains why many patients with CKD and malignancy show little or no response to oral iron, because of hepcidin-mediated inhibition of gut absorption, thus exacerbating their chronic anemia. WHY DO CKD AND CANCER PATIENTS DEVELOP IRON DEFICIENCY? Both CKD patients and those with malignancy are prone to develop iron deficiency, which may have significant secondary effects on a number of physiological systems [13, 14]. The most widely recognized is in the production of hemoglobin, which, if deficient as a result of reduced iron availability, leads to anemia. It is, however, increasingly recognized that iron has an important physiological role in a number of other processes, including oxygen availability in tissues (myoglobin) and energy use in mitochondria [15, 16]. The various contributory causes to the development of iron deficiency in both nephrology and oncology can be considered under two main headings, those of reduced iron intake and those of increased iron loss. In healthy individuals, obligatory iron loss from the gut, which amounts to 1 2 mg/day, is compensated for by the absorption of dietary iron from the gut, which also amounts to 1 2 mg/day [2]. The absorption of iron from the gut is tightly regulated by hepcidin, and this prevents excessive iron being absorbed, leading to iron overload. In certain genetic conditions, such as hereditary hemochromatosis, this mechanism is deficient, and patients suffering from this condition develop massive iron deposition in critical body tissues [17]. There are a number of reasons why patients with CKD and cancer have a reduced intake of iron. First, patients with both conditions often have a poor appetite, and thus their

3 Macdougall 27 daily intake of iron in the diet is lower. Second, many drugs concomitantly taken by patients interfere with iron absorption, such as proton pump inhibitors and (in CKD patients) phosphate binders, which also chelate iron. Third, and perhaps most important, is the fact that both sets of patients have an enhanced inflammatory state, with increased hepcidin activity [2]. Hepcidin binds to the iron exporter protein in enterocytes (ferroportin), thereby preventing the efflux of iron from gut mucosal cells into the bloodstream [11]. This also accounts for why even increasing dietary iron intake or taking supplemental oral iron salts does not improve the iron status of patients on dialysis or those with advanced malignancy. Increased iron loss is also common in both sets of patients. Renal patients are known to have a higher incidence of upper gastrointestinal inflammation and peptic ulceration than normal individuals, and many cancer patients have increased bleeding from either the gastrointestinal tract or gynecological system. Patients on hemodialysis have blood and iron loss through the dialyzer during every dialysis session. Many patients take aspirin, heparin, or warfarin therapy for thromboprophylaxis, which may increase gastrointestinal iron loss. Thus, it is easy to see why many kidney and cancer patients develop a state of negative iron balance, which then leads to frank iron deficiency. ABSOLUTE AND FUNCTIONAL IRON DEFICIENCY It has been helpful to consider iron deficiency under two subcategories, with very different pathogenetic mechanisms and with very different profiles of iron status [18]. Thus, absolute iron deficiency is characterized by a state in which the total body iron stores are depleted or exhausted. This may be detected by measurement of serum ferritin, which will be low, or alternatively by staining of the bone marrow for iron, which will show undetectable storage iron. Functional iron deficiency is characterized by normal or elevated total body iron stores but a failure to release the storage iron rapidly enough to support the demands of the proliferating erythroid bone marrow [18]. Iron is normally stored in the cells of the reticuloendothelial system, such as in the liver (Kupffer cells), spleen, and macrophage. Again, hepcidin has a pivotal role in the export of iron from these cells, via its interaction with ferroportin [11]. Because many patients with kidney disease and cancer have a chronic inflammatory state with upregulation of proinflammatory cytokines and hepcidin, functional iron deficiency is commonly seen [18]. These patients have a normal or elevated serum level of ferritin, but a lower level of transferrin saturation (usually 20%). Other laboratory markers have been investigated to improve the sensitivity and specificity of the detection of this condition, including serum transferrin receptor, percentage hypochromic RBCs, and reticulocyte hemoglobin content [18]. In the context of nephrology, measurement of the percentage of hypochromic RBCs in the blood has generally been found to be the optimal test, followed by reticulocyte hemoglobin content [19, 20]. Serum transferrin receptor is of less value in the CKD setting, because many patients are on erythropoietin-like drugs, and enhanced erythropoiesis is one of the factors evoking an increase in serum transferrin receptor, confounding its use as a marker of iron insufficiency. In cancer-related anemia, a combination of percentage of hypochromic RBCs, serum transferrin receptor, and reticulocyte hemoglobin content has been used to create a diagnostic plot for the detection of functional iron deficiency [21, 22]. This was subsequently simplified to include only percentage hypochromic RBCs and transferrin receptor index [23], and an even more recent report suggests that the percentage of hypochromic RBCs alone may be optimal [24]. There are, however, two problems with the latter measurement. First, it requires testing on a fresh blood sample, and any delay in transportation to the laboratory significantly affects the result. Second, the automated blood count analyzers that can perform this measurement are not widely available in many hospital laboratories. Newer markers such as the RET-Y, which can be analyzed with the Sysmex system (Sysmex, Mundelein, IL), have also been proposed [25] because it correlates well with the reticulocyte hemoglobin content, but this parameter has not been evaluated as a marker of functional iron deficiency in either the oncology or nephrology clinic setting. IRON SUPPLEMENTATION It is logical to correct an iron-deficient state with supplemental iron. There are three routes of administration that can be used for this purpose, namely, oral, i.m., and i.v. [18, 26]. Intramuscular administration of iron is generally not recommended in either the nephrology or oncology setting. The injections are painful, they result in a brownish discoloration of the skin, and a concern has been raised about a possible risk for the development of a sarcoma at the injection site. The injection may also be complicated by bleeding into the muscle, causing an i.m. hematoma. Oral iron is the simplest and most physiological means of administering iron. It is also by far the cheapest therapy in terms of drug acquisition costs [18]. Unfortunately, in both the cancer and CKD settings, it is often ineffective. This was recognized by nephrologists nearly 20 years ago, even prior to the discovery of hepcidin. It is, however, now very apparent that upregulation of hepcidin resulting from inflammation is the explanation for this clinical finding at a molecular level [6]. Thus, although

4 28 Iron Supplementation in Nephrology and Oncology many patients may religiously take up to 200 mg elemental iron per day via iron tablets or syrup, often negligible or no iron is absorbed. Oral iron salts also have a high incidence of gastrointestinal side effects, resulting from the local oxidative stress evoked by the Fenton reaction in the gut mucosa [18]. This results in abdominal pain as well as other gastrointestinal side effects. In a study of CKD patients receiving oral iron, the incidence of constipation was 35%, nausea was 13%, vomiting was 8%, and diarrhea was 6% [27]. Patients often attribute these side effects to ingestion of their oral iron, and compliance with this treatment is therefore poor. For all these reasons, i.v. iron has been extensively investigated in both the nephrology and oncology settings. Shortly after the introduction of recombinant human erythropoietin as a therapeutic agent, nephrologists recognized that the enhanced erythropoietic activity was inducing functional iron deficiency, such that many patients taking oral iron were unable to keep pace with the requirements of the bone marrow. Anecdotal case reports began to appear showing effective treatment of functional iron deficiency with administration of i.v. iron [28] (Table 1). I.V.IRON PREPARATIONS Several i.v. iron preparations are available worldwide for the treatment of iron deficiency anemia. All these are characterized by the coating of iron oxyhydroxide using a protective carbohydrate shell containing sugar polymers [18]. Iron salts are highly toxic if injected i.v., and although this was attempted 80 years ago in man, it is clear that it was associated with violent reactions. Modern-day iron compounds all rely on the same principle: following the injection of the iron carbohydrate complex into the circulation, the iron is then slowly released from the complex and becomes attached to plasma transferrin. The rate of dissolution of iron from the complex varies according to the iron preparation used [18]. Thus, iron gluconate is the most labile iron preparation, with the most rapid release of iron from the complex, and doses of mg are the maximum that can be given at any one time. Iron sucrose is more stable, and higher doses can be given, but the most stable iron preparations are the iron dextrans, which very tightly bind the iron oxyhydroxide core [18]. Unfortunately, iron dextran is associated with anaphylactic reactions when given i.v., and although this has become much less common with the use of low molecular weight dextrans rather than the previous high molecular weight dextrans, the concern still remains. Although some physicians have reported that they have administered low molecular weight iron dextran safely to thousands of patients in an outpatient setting [29], a recent pharmacovigilance report suggested Table 1. Potential benefits of i.v. iron preparations in nephrology and oncology Enhanced erythropoiesis Greater increases in hemoglobin concentration than with oral iron Lower dose requirements of erythropoiesis-stimulating agent therapy Increased exercise capacity (independent of hemoglobin correction) Improved muscle function (independent of hemoglobin correction) Increased quality of life (independent of hemoglobin correction) an odds ratio of 17.7 (confidence interval [CI], ) for anaphylaxis with iron dextran versus iron sucrose in North America and an odds ratio of 16.9 (CI, ) for iron dextran versus iron sucrose in Europe [30]. The latter data are particularly relevant because only the low molecular weight iron dextran is sold in Europe, whereas both low and high molecular weight iron dextrans are available in North America. All i.v. iron compounds can cause anaphylactoid reactions, characterized by nausea, lightheadedness, and hypotension, which are thought to be a result of the release of iron too rapidly from the complex. In contrast to the IgE-mediated anaphylaxis seen with iron dextran, labile iron reactions are not immunologically mediated and are thought to result from the vasodilating properties of free iron in the circulation [18]. In recent times, several new i.v. iron preparations have become available, including ferric carboxymaltose (Ferinject) (Vifor Pharma, Glattbrugg, Switzerland) and iron isomaltoside 1000 (Monofer) (Pharmacosmos, Holbaek, Denmark) in Europe, and ferumoxytol (Feraheme) (AMAG, Lexington, MA) in the U.S. All these preparations allow much higher doses of iron to be administered i.v. in a shorter period of time, and this has particular advantages for nondialysis CKD patients as well as cancer patients [31]. EXPERIENCE WITH I.V.IRON IN NEPHROLOGY The use of i.v. iron dramatically increased in the 1990s, and it has continued to be used extensively, particularly in hemodialysis patients. Indeed, all national and international guidelines make it clear that oral iron is ineffective in the dialysis population and that i.v. iron is mandatory in order to optimize the response to erythropoietin therapy [32, 33]. Several randomized controlled trials have generated evidence to this effect [34 36]. Thus, in a population of hemodialysis patients, Fishbane et al. [34] randomized half the

5 Macdougall 29 patients to receive supplementation with i.v. iron dextran and the other half to receive oral iron. The patients were already stable on erythropoietin therapy. The i.v. iron supplemented group had a significant increase in their hemoglobin level, with a halving of their erythropoietin dose requirements, whereas the oral iron group only maintained their hemoglobin concentration with a steady increase in erythropoietin dose [34]. In another randomized controlled trial, Macdougall et al. [35] studied a population of nondialysis and dialysis patients, randomizing patients to receive i.v. iron, oral iron, or no iron supplementation. The patients were erythropoietin naïve at the start of the study, and the hemoglobin response to erythropoietin was significantly greater in the i.v. iron supplemented patients. The oral iron and no iron patient groups showed identical hemoglobin and ferritin responses, again suggesting that oral iron was ineffective in these patients [35]. Many other studies, both controlled and observational, have added credence to the concept that i.v. iron can augment the response to erythropoietin therapy and significantly impact the dose requirements of erythropoietin in dialysis patients. The situation in nondialysis patients is less clear cut [36]. Many units, particularly in the early stages of CKD, try oral iron supplementation first, reserving i.v. iron only for those patients who cannot tolerate oral iron, or in whom it is ineffective. Other units, particularly in the U.K., advocate i.v. iron therapy for all iron-deficient patients, concerned that the incidence of side effects, particularly gastrointestinal side effects, is less for i.v. iron than for oral iron supplementation. There has also been some discussion as to whether or not i.v. iron might be effective in CKD patients with mild anemia, perhaps delaying the need for erythropoietin replacement therapy. In a small uncontrolled study, Mircescu et al. [37] treated a population of 60 nondialysis CKD patients (32 males, 28 females) with monthly i.v. iron injections of iron sucrose, 200 mg, and observed a significant increase in hemoglobin concentration over a 12-month period (9.7 g/dl 1.1 g/dl at baseline to 11.3 g/dl 2.5 g/dl at 12 months). The serum ferritin level increased from 98.0 g/l to g/l and the transferrin saturation increased from 21.6% 2.6% to 33.6% 3.2%. No worsening of kidney function or other adverse effects were seen. None of these patients received erythropoietin therapy. An international multicenter study recently commenced to investigate this issue further in a randomized controlled trial [38]. That study (the Ferric Carboxymaltose Assessment in Subjects With Iron Deficiency Anemia and Nondialysis- Dependent CKD [FIND-CKD] study) aims to recruit 1,016 patients who will be randomized to one of three arms: group 1 will be given high-dose i.v. ferric carboxymaltose, aiming to maintain a ferritin target of g/l; group 2 will be administered lower doses of i.v. ferric carboxymaltose, aiming for a ferritin target of g/l; and group 3 will receive oral iron supplementation (with no ferritin target). Patients will be followed up for 12 months, and both efficacy and safety will be assessed [38] (Fig. 1). EXPERIENCE WITH I.V.IRON IN ONCOLOGY As erythropoietin therapy became used in cancer patients, oncologists also began to investigate whether i.v. iron might reduce the dose requirements of erythropoietin. This has become all the more relevant given recent concerns about the use of erythropoietin in the oncology setting and the desire to keep dose requirements of erythropoietin as low as possible. Several studies have together generated strong evidence that the erythropoietic response may be enhanced by i.v. iron versus oral iron supplementation in cancer patients receiving erythropoietin [39 46]. The first study, published in 2004, randomized 157 patients with solid tumors and chemotherapy-induced anemia to one of four arms [39]. All patients received erythropoietin. Group 1 received no iron, group 2 received oral iron containing 65 mg elemental iron, group 3 received 100 mg i.v. iron dextran at each visit, and group 4 received a total dose infusion of iron dextran. The response rate in that study was 68% for i.v. iron versus 36% for oral iron versus 25% for no iron [39]. Henry et al. [40] reported on a randomized study of 187 patients with solid tumors and chemotherapy-induced anemia, again in patients receiving 40,000 units of epoetin s.c. every week. Patients were randomized to no iron, oral ferrous sulphate, or i.v. iron gluconate. The response rates in that study were 73%, 45%, and 41%, respectively, for the i.v. iron, oral iron, and no iron groups [40]. Hedenus et al. [41] investigated the addition of i.v. iron to erythropoietin therapy in anemic patients with lymphoproliferative malignancies in a randomized multicenter study, and again found higher hemoglobin response rates and lower erythropoietin dosage requirements than in a group receiving no iron (hemoglobin response, 93% versus 53% in the per protocol population) [41]. In another open-label randomized study including 396 patients with mainly nonmyeloid malignancies receiving chemotherapy and darbepoetin alfa, patients were randomized to receive either standard care with no or oral iron supplementation or a total i.v. dose supplement of 1,000 mg given as divided doses [42]. In that study, a faster and larger mean change in hemoglobin from baseline was seen in the i.v. iron treated group, and the need for blood transfusion was also half that of the no i.v. iron group (9% versus 20%) [42]. Recently, Pedrazzoli et al. [43] published the results of their randomized trial of i.v. iron supplementation in patients with chemotherapy-induced anemia, but

6 30 Iron Supplementation in Nephrology and Oncology The FIND-CKD trial Screening (up to 4 weeks) ND-CKD ESA-naïve Hb 9 11 g/dl Ferritin <100 µg/ L or ferritin<200 µg/ L and TSAT < 20% R Ferric carboxymaltose: high dose (ferritin target = µg/l) 254 patients Ferric carboxymaltose: low dose (ferritin target = µg/ L) 254 patients Oral iron, daily ferrous sulphate 508 patients End of Study Week 56 (or 4 weeks after last dose of study drug) without iron deficiency, treated with darbepoetin alfa. The hemopoietic response rate was greater in the i.v. iron group than in the no iron group (93% versus 70% in the per protocol analysis) [43]. Bellet et al. [44] reported a randomized study of i.v. iron sucrose in 375 patients with chemotherapy-induced anemia who were receiving darbepoetin alfa or epoetin alfa therapy. Again, patients who received i.v. iron experienced a greater hemoglobin increase than those not receiving iron, and the results indicated a significant improvement in fatigue and iron stores in the iron sucrose group [44]. Two further studies were published very recently. Auerbach et al. [45] evaluated the efficacy and safety of darbepoetin alfa administered every 3 weeks at fixed doses of 300 g or500 g with or without i.v. iron in treating anemia in patients receiving multicycle chemotherapy. That phase II, double-blinded, 2 2 factorial study randomized patients to one of four treatment arms darbepoetin alfa, 300 g (n 62); darbepoetin alfa, 300 g, plus i.v. iron (n 60); darbepoetin alfa, 500 g(n 60); and darbepoetin alfa, 500 g, plus i.v. iron (n 60). More patients receiving i.v. iron (82%) than not receiving i.v. iron (72%) achieved the hemoglobin target. The final study, by Steensma et al. [46], was negative for any benefit of i.v. iron. In that study, 502 patients with a Visits: every 2 weeks (weeks 0 8), then every 4 weeks (weeks 8 52). Dosing every 4 weeks No ESA (weeks 0 8) Anemia management per standard practice Primary objective: To evaluate the long-term efficacy of ferric carboxymaltose (using targeted ferritin levels to determine dosing) or oral iron to delay and/or reduce ESA use in ND-CKD patients with iron deficiency anemia Secondary objectives: To evaluate the ESA requirements, to evaluate the long-term safety and tolerability of iron therapy and evaluate the health resource and economic burden of the treatment of anemia of ND-CKD Figure 1. The Ferric Carboxymaltose Assessment in Subjects With Iron Deficiency Anemia and Nondialysis-Dependent CKD trial. Abbreviations: CKD, chronic kidney disease; ESA, erythropoiesis-stimulating agent; ND-CKD, nondialysis dependent CKD; TSAT, transferrin saturation. hemoglobin level 11 g/dl who were undergoing chemotherapy for nonmyeloid malignancies received darbepoetin alfa once every 3 weeks and were randomly assigned to receive either ferric gluconate (187.5 mg i.v. every 3 weeks), oral daily ferrous sulfate (325 mg), or oral placebo for 16 weeks. There was no difference in the erythropoietic response rate among the three groups. There were also no differences in the proportion of patients requiring RBC transfusion, changes in quality of life, or the dose of darbepoetin administered [46]. Given the other seven positive studies for i.v. iron, discussions have evolved around why that study showed the opposite effect. Although there is no definitive explanation, it has been suggested that the doses of i.v. iron in that study may have been insufficient to show a positive result. SAFETY OF I.V.IRON One of the limitations of all the studies in the nephrology and oncology literature is that they were designed to demonstrate efficacy rather than safety. Thus, the primary objective of the studies was to show a greater hemoglobin response, with or without a reduction in erythropoietin dose requirements. Quality of life and/or fatigue scores were also assessed in some of the studies. However, none of the studies was designed or powered

7 Macdougall 31 Table 2. Potential safety concerns with i.v. iron preparations in nephrology and oncology Short term Anaphylactic reactions (iron dextran only; less common with low molecular weight iron dextran; dextran antibodies) Free iron reactions (all i.v. irons too much, too quickly) Long term Susceptibility to infection Impaired bacterial killing by polymorphonuclear leukocytes Increased formation of hydroxyl radicals Increased oxidative stress Proteinuria Tubular toxicity Iron overload Increased cancer cell multiplication to look at the safety of i.v. iron, and the follow-up in all the studies was too short to assess this. Both short-term and longer term concerns have been raised in relation to the administration of i.v. iron [18] (Table 2). The short-term concerns relate to anaphylactic reactions, seen with i.v. iron dextran, and anaphylactoid or labile iron reactions, seen with all i.v. iron preparations when given too rapidly for the dose administered. The longer term concerns have been generated from much in vitro laboratory research. These include such safety concerns as increasing the risk for infection, enhancing oxidative stress, worsening proteinuria in kidney disease, and increasing carcinogenicity in oncology patients [47]. It is certainly evident that bacteria proliferate more rapidly in iron-rich culture media than in unenhanced culture media. Iron is an essential growth factor for bacteria as it is for humans. There is also evidence that i.v. iron may reduce polymorphonuclear leukocyte function in patients receiving this therapy [48], and this might reduce their ability to fight bacteria. Set against this laboratory evidence are reassuring data from large observational and epidemiological studies. Hoen and colleagues [49] studied a population of nearly 1,000 hemodialysis patients with the aim of determining factors predisposing these patients to bacterial infections. Several factors were found to be a significant risk factor for bacteremia, including the use of dialysis catheters, but the use of i.v. iron was not associated with a higher risk for bacteremia [49]. Nevertheless, guidelines suggest that it is inadvisable to give supplemental i.v. iron in patients with active bacterial infections [32, 33]. Both oral and i.v. iron carry the potential to increase oxidative stress [18], which in turn could increase the risk for lipid peroxidation, free radical generation, and atherogenesis. Many studies have generated data to suggest that i.v. iron can increase circulating levels of markers of oxidative stress, although there is some debate about what the critical markers are in this context. Scheiber-Mojdehkar et al. [50] studied a cohort of hemodialysis patients across a dialysis session in which half the patients received i.v. iron and the other half received no i.v. iron. There was a mild but transient increase in oxidative stress in both groups of patients associated with dialysis treatment, but no greater oxidative stress in patients receiving i.v. iron [50]. However, this was a single i.v. iron administration and it does not address the issue of whether long-term cumulative i.v. iron exposure could be harmful in this context. Feldman et al. [51], in an observational study of 32,566 hemodialysis patients, investigated the effect of i.v. iron exposure on survival using a sophisticated time-lag model to reduce confounding. There was absolutely no hint of any effect on survival in patients heavily exposed to i.v. iron, versus those receiving little exposure. Similarly, in another observational study, Kalantar- Zadeh et al. [52] performed a multivariate analysis on the effect of i.v. iron on mortality in 58,000 hemodialysis patients, and again did not find a higher death rate in patients with serum ferritin levels as high as 1,200 g/l [52]. Finally, and more specifically in the oncology setting, the question has been raised about whether or not i.v. iron might promote cancer growth. In vitro data suggest that iron might be carcinogenic because of its catalytic effect on the formation of hydroxyl radicals, suppression of host defense cell activity, and promotion of cancer cell multiplication [53]. As in the nephrology setting, there are no randomized controlled trials to investigate this issue, and epidemiological studies are conflicting. Four have reported a positive association with a higher risk for malignancy, whereas three have not [54]. In hereditary hemochromatosis, the risk for liver cancer is at least 200 times greater in patients than in normal individuals. However, liver cirrhosis results from extensive iron accumulation and the risk for other malignancies in these subjects is not greater [54, 55]. As with the concerns about oxidative stress, it requires randomized controlled trials rather than simply observational and in vitro data to answer the question about whether of not i.v. iron supplementation can enhance tumorgenicity. GUIDELINES REGARDING I.V.IRON IN NEPHROLOGY AND ONCOLOGY Many guidelines have been published on the use of i.v. iron in both nephrology and oncology [32, 33, 56, 57]. Both U.S. and European guidelines in CKD patients [32, 33] recom-

8 32 Iron Supplementation in Nephrology and Oncology mend a ferritin level of g/l for patients on chronic dialysis, with i.v. iron supplementation recommended if the ferritin level falls to 200 g/l. The question about an upper safe ferritin level has always been problematic. The guidelines suggest an upper limit of 800 g/l, despite the absence of hard evidence for harm above this. The Dialysis Patients Response to IV Iron with Elevated Ferritin (DRIVE) study [58] suggested efficacy at levels up to 1,200 g/l, although safety was not adequately addressed in that study. It is also recognized that high ferritin levels in dialysis patients are often driven more by inflammation than by iron loading and this confounds the use of ferritin as a good marker of iron repletion. Several oncology guidelines have addressed the issue of iron sufficiency. The National Comprehensive Cancer Network [56] and the European Organisation for Research and Treatment of Cancer [57] recommend i.v. iron supplementation for patients with serum ferritin levels 100 g/l or transferrin saturation levels 20%. In normal clinical practice, mg i.v. iron once weekly or once every second week is commonly given alongside erythropoiesisstimulating agent (ESA) therapy in cancer patients. Further research, however, is required to determine whether or not these target levels are optimal, and whether or not other biomarkers may be more useful in guiding the need for i.v. iron. Measurement of serum hepcidin has been suggested as a potential alternative in this regard, although there have been recent concerns about its variability in hemodialysis patients [59] and whether or not it is in fact any better than measurement of hypochromic RBCs [20]. THE FUTURE At the present time, it is clear that i.v. iron is generally superior to oral iron in both the nephrology and oncology settings. The only exception to this is that some patients with early CKD may derive some benefit from oral iron, albeit with more side effects. The greater efficacy of i.v. iron is almost certainly a result of the limiting action of hepcidin on absorption of iron from the gut in patients with CKD and malignancy [2, 12]. At least three new strategies are under investigation for the delivery of iron to patients with iron deficiency. These include hypoxia inducible factor stabilizers, which are currently in phase II clinical trials and which (in addition to their effect in boosting erythropoietin levels) may also reduce hepcidin levels [60] and improve oral iron absorption. In hemodialysis patients, the concept of adding iron to the dialysate and allowing it to diffuse across the dialysis membrane during a dialysis session is also under clinical investigation [61]. The iron compound for this latter strategy is iron sodium pyrophosphate. Finally, several strategies are under investigation in the laboratory for antagonizing or silencing hepcidin. These include a monoclonal antibody, which has been tested in rats with inflammatory anemia [62], and small molecule inhibitors of hepcidin, which have been tested in an anemic inflammatory model in cynomolgus monkeys [63]. Whether or not any of these new strategies will replace the need for i.v. iron remains to be seen. CONCLUSIONS i.v. iron supplementation has an important role in the management of anemia associated with CKD and cancer. In both clinical conditions, it enhances the response to erythropoietin replacement therapy, allowing lower doses to be used. 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