Safety in Iron Management
`
`Steven Fishbane, MD
`
`● Intravenous (IV) iron therapy has become an integral part of hemodialysis management during the past several
`decades, and the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative guidelines recognize that
`most patients undergoing hemodialysis will require IV iron therapy on a regular basis to reach target hemoglobin
`(Hgb) levels. There now are three IV iron compounds available in the United States: iron dextran, sodium ferric
`gluconate, and iron sucrose. Although all have been proven effective for increasing Hgb/hematocrit levels, recent
`data show differences in their relative safety profiles. During the past two decades, more than 30 deaths have been
`attributed to the use of IV iron dextran. The two newer compounds available in the United States, sodium ferric
`gluconate and iron sucrose, have more favorable safety profiles, with the largest prospective safety comparison to
`date showing sodium ferric gluconate to be similar to placebo in the incidence of serious anaphylactoid-type
`reactions. This article reviews safety data surrounding the IV iron therapies. Am J Kidney Dis 41(S5):S18-S26.
`© 2003 by the National Kidney Foundation, Inc.
`
`INDEX WORDS: Kidney Disease Outcomes Quality Initiative (K/DOQI); iron therapy; sodium ferric gluconate; iron
`sucrose; iron dextran.
`
`ALL TREATMENT decisions that physicians
`
`make involve the weighing of risks and
`benefits, including nephrologists’ treatment deci-
`sions involving the use of intravenous (IV) iron
`therapy. Benefits of IV iron therapy for hemodi-
`alysis patients are well established; IV iron is
`essential for enabling most iron-deficient hemo-
`dialysis patients to achieve target hemoglobin
`(Hgb) levels of 11 to 12 g/dL (110 to 120 g/L).1
`Correction of anemia may provide numerous
`benefits, including a significant decrease in left
`ventricular mass index and septal wall thickness;
`increased work capacity; improvements in fa-
`tigue, depression, and relationships; reduced hos-
`pitalization; and normalization of increased car-
`diac output.2-6 Because iron is vital for normal
`energy use by cells and has an important role in
`oxygen delivery and overall health status, it is
`important for hemodialysis patients to maintain
`adequate levels of storage iron.
`Both the European Anemia Best Practices
`Panel7 and the National Kidney Foundation-
`Kidney Disease Outcomes Quality Initiative
`guidelines in the United States1 have conducted
`an analysis of risks versus benefits of IV iron
`
`from
`
`From Winthrop-University Hospital, Mineola, NY.
`Supported by an unrestricted educational grant
`Watson Pharma, Inc.
`Address reprint requests to Steven Fishbane, MD, Direc-
`tor of Dialysis Services, Winthrop-University Hospital, 200
`Old Country Rd, #135, Mineola, NY 11501. E-mail:
`sfishbane@winthrop.org
`© 2003 by the National Kidney Foundation, Inc.
`0272-6386/03/4106-0504$30.00/0
`doi:10.1016/S0272-638(03)00373-1
`
`therapy for the treatment of anemia. In each case,
`it was concluded that IV iron forms a cornerstone
`of hemodialysis therapy. Nevertheless, questions
`remain in some nephrologists’ minds about the
`possible risks associated with IV iron therapy,
`including the risk for adverse reactions, cardio-
`vascular disease (CVD), and infection. Much of
`the concern relates to problems of iron in its
`free-circulating form, in which iron can create
`reactive oxygen species that can result in inflam-
`mation, endothelial damage, and a potential in-
`creased risk for infection. This article discusses
`the evidence surrounding the potential risks of
`IV iron therapy.
`
`ADVERSE REACTIONS TO IV IRON THERAPY
`
`Good quantitative data from several analyses
`of adverse reactions to IV iron therapy have
`emerged during the past several years. Although
`a number of adverse reactions have been re-
`ported with the use of IV iron compounds, includ-
`ing injection-site reactions, diarrhea, and nau-
`sea,8,9 reactions that pose the greatest danger to
`patients and thus are of greatest concern are
`anaphylactoid or allergic-type reactions. These
`are generally characterized by signs and symp-
`toms that include urticaria, rash, dyspnea, hypo-
`tension, and, in the most severe cases, shock and
`death. The risk for anaphylactoid reactions ap-
`pears to be greatest with IV iron dextran, prob-
`ably because of the dextran component of the
`compound. High-molecular-weight dextran com-
`plexes alone are known to be antigenic even
`when not complexed to iron.10 Possibly, the im-
`
`S18
`
`American Journal of Kidney Diseases, Vol 41, No 6, Suppl 5 (June), 2003: pp S18-S26
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`IRON SAFETY
`
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`
`Fig 1. The molecular struc-
`ture of sodium ferric glu-
`conate consists of an iron
`core surrounded by sac-
`charate networks, which are
`linked together by a glu-
`conate function. The result
`is a stable complex of high
`molecular weight (289,000 to
`440,000 d) that resists disso-
`ciation in serum and is non-
`dialyzable. (Data from Watson
`Pharma, Inc.13)
`
`mune response is caused by a direct effect on
`mast cells and basophils.
`The risk for immediate severe anaphylactoid
`reactions appears to be, at a minimum, approxi-
`mately 0.6% with IV iron dextran, and this agent
`has been associated with a number of deaths
`during the past several decades. A 1980 review
`by Hamstra et al11 examined the use of IV iron
`dextran in 481 hemodialysis patients adminis-
`tered a total of 2,099 doses of 250 or 500 mg. In
`this patient group, life-threatening reactions oc-
`curred in 3 patients (0.6%), characterized by
`respiratory arrest, hypotension, syncope, and
`wheezing. Eight additional patients had delayed
`nonlethal reactions that included myalgia, arthral-
`gia, and pulmonary embolus. These data were
`borne out in later IV iron dextran studies by
`Woodman et al,12 in which anaphylactoid reac-
`tions were seen in 1.8% of 1,260 patients, and by
`Fishbane et al,9 in which such reactions were
`seen in 1.7% of 573 patients treated during a
`2-year period.
`Even with IV iron dextran, the expected risk
`for serious anaphylactoid reactions, approxi-
`mately 6/1,000 patients, is relatively low, and the
`risk to the individual patient is low. However, the
`risk is far from negligible, and viewed in the
`context of a large hemodialysis practice that
`treats several hundred patients, it is likely that
`several severe reactions will be encountered over
`the course of time with IV iron dextran. Data by
`Faich and Strobos,10 published in 1999, have
`illustrated this significant risk for potentially
`fatal reactions. Using a database drawing on the
`
`US experience with IV iron dextran during a
`two-decade period (1976 to 1996), a total of 196
`serious anaphylactoid reactions and 31 deaths
`were reported with the use of this compound.
`Among patients administered iron dextran who
`experienced allergic reactions, there was a mini-
`mum case fatality rate of 15.8%. (Because data
`from this study were drawn from retrospective
`reports, many of which did not list final out-
`comes, the actual case fatality rate may have
`been even greater.10)
`The two newer compounds introduced in the
`United States, sodium ferric gluconate and iron
`sucrose, appear to be associated with a far lower
`risk for anaphylaxis. This reduced risk appears to
`be related to the absence of dextran chains in
`these molecules; both compounds consist of a
`sucrose network surrounding a ferric ion core. In
`the case of sodium ferric gluconate, sucrose
`networks are linked by a gluconate function to
`create a highly stable nondialyzable macromo-
`lecular complex (Fig 1).13
`This reduced risk has been shown in data
`published on sodium ferric gluconate. In 2002,
`Michael et al14 published results of the largest
`prospective safety analysis conducted in hemodi-
`alysis patients. The study, which involved 2,493
`hemodialysis patients, compared the rate of ad-
`verse reactions prospectively with placebo and
`with a historical control group of IV iron dextran
`users. Patients in this study were administered
`placebo or a 125-mg single dose of sodium ferric
`gluconate delivered by IV push at a rate of 12.5
`mg/min during one session and then were crossed
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`S20
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`STEVEN FISHBANE
`
`over to the opposite treatment at the next session.
`The IV iron dextran comparison was drawn from
`four published trials involving 3,768 drug expo-
`sures to different forms of this compound.
`The rate of life-threatening adverse reactions
`(immediate reactions requiring institution of re-
`suscitative measures) was reduced from 0.61%
`in the IV iron dextran study population to 0.04%
`in the sodium ferric gluconate study population
`(⬃4/10,000 patients). The relative risk reduction
`was 93% (Table 1).14 The single life-threatening
`reaction associated with sodium ferric gluconate
`consisted of shortness of breath, hypotension,
`and lower back pain. It resolved within 20 min-
`utes, enabling the patient to complete the dialysis
`treatment and return home the same day.
`In the placebo-controlled portion of this study,
`there was no significant difference in incidence
`of life-threatening reactions with sodium ferric
`gluconate compared with placebo (Table 2).14
`Although there was a statistically significant dif-
`ference in incidence of drug-intolerance events
`(ie, any event that would preclude further study
`drug administration), most of these reactions
`consisted of lower-level gastrointestinal tract re-
`actions.
`Fewer safety data are available on the newest
`agent, IV iron sucrose. Unlike sodium ferric
`gluconate, iron sucrose has not been tested in a
`large-scale prospective study since its introduc-
`tion in the United States. However, available
`data suggest a similar safety profile. In studies by
`Van Wyck et al8 and Charytan et al15 involving a
`total of approximately 1,000 doses of 100 mg of
`iron sucrose administered through IV infusion or
`push, no deaths and no potentially fatal anaphy-
`
`Table 1. US Safety Study of Sodium Ferric
`Gluconate: Adverse Events for Sodium Ferric
`Gluconate Versus Iron Dextran
`
`Sodium Ferric
`Gluconate
`
`Iron Dextran
`
`P
`
`Life-
`threatening
`Drug
`intolerance
`
`0.04, 1/2,493,
`0.00-0.22
`0.44, 11/2,493,
`0.21-0.71
`
`0.61, 23/3,768,
`0.36-0.86
`2.47, 64/2,589,
`1.87-3.07
`
`0.0001
`
`⬍0.0001
`
`NOTE. Comparison with iron dextran was taken from
`historical controls in published studies of iron dextran.
`Values expressed as percent, number/total number, 95%
`confidence interval.
`Reprinted with permission.14
`
`Table 2. US Safety Study of Sodium Ferric
`Gluconate: Adverse Events for Sodium Ferric
`Gluconate Versus Placebo
`
`Sodium Ferric
`Gluconate
`(N ⫽ 2,493)
`
`Placebo
`(N ⫽ 2,487)
`
`P
`
`Life-threatening
`Drug intolerance
`
`1 (0.04)
`11 (0.4)
`
`0 (0)
`2 (0.1)
`
`Not available
`0.02
`
`NOTE. Values expressed as number (percent).
`Reprinted with permission.14
`
`lactoid reactions were attributed to use of this
`compound. In the largest analysis of IV iron
`sucrose use, encompassing 1,004,477 patients
`worldwide from 1992 to 2001, a total of 788
`adverse events were reported (incidence,
`0.028%), including 52 anaphylactoid reactions.
`No deaths were reported.16 Data for these two
`compounds strongly suggest that they are signifi-
`cantly safer than IV iron dextran in terms of
`serious adverse reactions, and the use of IV iron
`dextran should be restricted to selected patients
`in whom there is a particular need to treat with
`this compound.
`
`CVD RISK
`The link between CVD and IV iron therapy
`has good biological plausibility, at least in theory.
`Iron is an element with a high degree of acute-
`phase reactivity that can lead to a state of in-
`creased oxidative stress. Catalytically active iron
`is involved in the production of hydroxyl radical,
`a damaging reactive oxygen species. Hydroxyl
`radicals, in turn, lead to lipid peroxidation and
`the development of additional lipid-derived free
`radicals, which generate still other free radicals
`in a chain reaction.17
`Most of the data associating iron with an
`increased risk for CVD have been drawn from
`population-based studies involving serum fer-
`ritin level as a measure of iron stores. A series of
`Finnish studies by Salonen et al18-20 were among
`the first to test the “iron hypothesis” of an in-
`creased risk for CVD with increased iron stores.
`In these studies, an increased risk for myocardial
`infarction (MI) was found in men with greater
`serum ferritin levels compared with those with
`lower levels.18 Subsequent studies by this same
`group showed that regular blood donors had a
`lower average serum ferritin level and decreased
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`IRON SAFETY
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`risk for acute MI over time compared with non–
`blood donors.19,20 A large-scale Canadian survey
`by Morrison et al21 that followed up nearly
`10,000 participants also showed an increased
`risk for fatal MI in those in the highest category
`of serum ferritin level (⬎175 ␮g/dL).
`Nevertheless, it is exceedingly difficult to draw
`reasoned conclusions from these data about the
`risk for CVD in hemodialysis patients on IV iron
`therapy. First, these studies were population-
`based analyses that in most cases involved only
`male patients. An equal number of population-
`based studies that have examined the relation-
`ship between serum ferritin level and MI con-
`cluded there is no increased risk for CVD with
`greater iron stores and no protective effect with
`blood donation.22-26
`Second, serum ferritin levels may not be a
`reliable marker for actual elevations in iron stores.
`Chronic inflammatory conditions, such as CVD,
`tend to elevate serum ferritin measures, making
`it questionable whether observational studies are
`measuring an increase in iron levels or results of
`an occult inflammatory process.
`Third, such population-based studies also have
`not controlled for the presence of hemochromato-
`sis, a hereditary disorder that results in massive
`accumulation of storage iron over a period of
`decades. Because this disorder is fairly common
`(1 of 300 Caucasians are homozygous for the
`Cys282Tyr mutation of HFE, one of the genes
`involved in hemochromatosis), failure to control
`for its presence may influence the outcomes of
`population-based analyses.
`Finally, population-based studies involving
`body iron stores contribute little to our knowl-
`edge of the specific CVD risk associated with IV
`iron therapy in hemodialysis patients. The few
`studies to date conducted in the hemodialysis
`population tended to show a slight, but signifi-
`cant, increase in relative risk (⬃ 1.1 to 2.4).27-29
`However, this modest increase in risk must be
`weighed against
`the serious and well-docu-
`mented health consequences of failing to correct
`iron-deficiency anemia in these patients.
`
`RISK FOR INFECTION
`Iron is crucial for survival in most organisms
`and is necessary for erythrocyte production and
`the making and storage of adenosine triphos-
`phate. Oxidative phosphorylation, the produc-
`
`Fig 2. An iron-protein complex. Such complexes
`tend to be large glycoprotein complexes wrapped
`around a central core of iron that protects the body
`from exposure to free iron.
`
`tion of usable energy, is highly dependent on
`iron. Therefore, the body strives to obtain iron
`and is very resistant to iron elimination. Of the
`estimated 4,000 mg of iron in the body, only
`approximately 1 mg/d is lost in healthy individu-
`als. Nevertheless, the potent oxidizing ability of
`iron makes it a potentially toxic compound in the
`body in its free form. Because of this potential
`toxicity, the majority of iron that is not actively
`circulating as Hgb in red blood cells is safely
`sequestered in the form of ferritin and hemosid-
`erin in macrophages of the reticuloendothelial
`system (RES). Molecules that hold iron tend to
`be very large, containing a central core of iron
`with a proteinaceous envelope that insulates the
`body from the iron atom (Fig 2). In healthy
`individuals, free iron rarely is a problem. Con-
`versely, in cases of hemochromatosis, in which
`serum ferritin levels can increase to more than
`10,000 ng/mL, the body is presented with unman-
`ageable levels of free iron.
`In hemodialysis patients on IV iron therapy,
`although iron is introduced directly into the circu-
`lation as opposed to the gastrointestinal tract, the
`body generally retains its ability to protect against
`free-iron release by taking up the iron-carbohy-
`drate complex into the RES in its bound form. In
`the RES, iron is dissociated from its carbohy-
`drate ligand, stored as ferritin or hemosiderin,
`and only then is turned over to transferrin, the
`body’s primary serum buffer against free iron,
`for delivery to the erythroid marrow for use in
`Hgb production. A series of pharmacokinetic
`analyses by Seligman et al30 and Kimko et al31
`showed that sodium ferric gluconate delivered at
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`STEVEN FISHBANE
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`a dose of 125 mg by IV infusion or push follows
`this normal pathway of iron distribution. In these
`studies, the sodium ferric gluconate complex
`was taken up directly by the RES before being
`delivered back to transferrin. Release of free iron
`directly into the circulation was negligible, and
`no transferrin oversaturation was observed, even
`at an infusion rate greater than 15 mg/min. After
`the iron was taken up by the RES, turnover to
`transferrin was orderly: The majority of iron
`(⬃80%) was delivered back to transferrin and
`made available to the erythroid marrow within
`24 hours of infusion.30,31
`An increasing number of studies during the
`past 2 years have shown that the same protection
`against free-iron release may not be seen with IV
`iron sucrose. A pharmacokinetic study by Daniel-
`son et al32 showed that iron sucrose follows two
`pathways after administration: Although part of
`the iron is transported directly to the RES in its
`carbohydrate-bound complex, a portion is re-
`leased directly into the circulation, existing as
`nontransferrin-bound free iron. Subsequent stud-
`ies have shown the potential detrimental effects
`of this method of iron release in terms of infec-
`tion risk and oxidative damage. In 2000, Parkki-
`nen et al33 published results of an elegant series
`of studies on the release of free iron with iron
`sucrose and risk for infection. This study ana-
`lyzed 12 stable hemodialysis patients with fer-
`
`(A) Transferrin
`Fig 3.
`saturation and (B) percent-
`age of patients with free iron
`after administration of iron
`sucrose, 100 mg, by IV push.
`Reprinted with permission.33
`
`ritin levels less than 400 ng/mL who received
`treatment with 100 mg of iron sucrose adminis-
`tered by IV push. Transferrin saturation was
`measured at 5, 30, 90, and 210 minutes postinjec-
`tion, and serum iron was measured by means of
`two spectrophotometric methods using ferozine
`and ferene-S as the chromogenic agents.
`Transferrin saturation increased rapidly imme-
`diately after injection (Fig 3A),33 a phenomenon
`that would only occur if iron was moving di-
`rectly to transferrin. Transferrin saturation contin-
`ued to increase, averaging more than 80% within
`3.5 hours. In addition, there was a consistent
`increase in number of patients with measurable
`free iron in the circulation as detected by bleomy-
`cin assay, climbing to 50% at 3.5 hours (Fig
`3B).33
`These findings have several clinical implica-
`tions. First, patients with lower transferrin levels
`(which may occur in hemodialysis patients be-
`cause of inadequate transferrin production in the
`liver) are likely at greater risk for having free
`iron in the circulation with IV iron sucrose.
`Second, the presence of free iron in the circula-
`tion may increase the risk for infection. This
`increased risk was shown by this group by intro-
`ducing Staphylococcus epidermidis into serum
`samples in patients with free iron. Although S
`epidermidis normally does not grow in serum in
`the absence of free iron, the organism grew
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`IRON SAFETY
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`Fig 4. Growth of Staphy-
`lococcus epidermidis in se-
`rum samples of patients with
`catalytically active free iron
`after administration of IV iron
`sucrose. The addition of apo-
`transferrin to bind free iron
`reduced the growth of S epi-
`dermidis to normal
`levels.
`Reprinted with permission.33
`
`rapidly in samples from patients with free iron
`and in direct proportion to the level of free iron
`in serum (Fig 4).33 Adding apotransferrin to the
`samples to bind free iron prevented S epidermi-
`dis growth in these samples. The investigators
`concluded from this study that an iron sucrose
`dose of 100 mg delivered by IV push may be too
`large.
`Damiani et al34 compared clinical infection
`outcomes between IV iron sucrose and sodium
`ferric gluconate in a study of 61 hemodialysis
`patients treated at a single center. Baseline char-
`acteristics of the two patient groups were similar,
`with the exception of a greater mean recombi-
`nant human erythropoietin dose at baseline in the
`iron sucrose group. At follow-up, there were no
`significant differences in recombinant human
`erythropoietin dose requirements or Hgb levels.
`However, at months 6 and 8, transferrin satura-
`tions and serum ferritin levels were greater in the
`iron sucrose group. The infection rate in the iron
`sucrose group was significantly greater than in
`the sodium ferric gluconate group: 1 for every 10
`patient-months versus 1 for every 17 patient-
`months.34
`Zager et al35 conducted a series of in vitro
`studies of four IV iron compounds: iron sucrose,
`sodium ferric gluconate, iron dextran, and iron
`oligosaccharide (which is not available in the
`United States). Using isolated mouse proximal
`tubule segments and cultured human proximal
`tubule (HK-2) cells,
`the researchers assessed
`oxidant injury through malondialdehyde (MDA)
`generation, as well as lethal cell injury through
`
`lactate dehydrogenase (LDH) release and cell
`proliferation/viability through tetrazolium dye
`(MTT) assay. All four IV iron compounds were
`found to cause some degree of lipid peroxida-
`tion, measured by MDA generation, with iron
`dextran and iron oligosaccharide causing slightly
`greater levels of oxidation than the other two
`compounds.
`However, when cellular toxicity was exam-
`ined based on LDH release, IV iron sucrose was
`shown to cause a dramatic increase in mouse
`proximal tubule cell death compared with the
`other three compounds (which were similar to
`placebo; Fig 5).35 This significant increase in cell
`death with IV iron sucrose also was seen in
`human proximal tubule cells, measured by both
`LDH release (Fig 6A) and MTT uptake (Fig
`6B).35 The response was robustly dose depen-
`dent.
`Two additional studies, both published in 2002,
`have addressed the issue of free iron and oxida-
`tive stress with IV iron sucrose. Kooistra et al36
`examined effects of iron sucrose in IV push
`administration of 100 mg in 6 minutes in 10
`hemodialysis patients. In these patients, an in-
`crease in transferrin saturation ranging from 26%
`to 491% was observed. A slower infusion (100
`mg in 60 minutes) did not affect the increase in
`transferrin saturation; abundant free iron was
`seen in both methods of administration. In a
`study by Rooyakkers37 involving 20 healthy vol-
`unteers administered IV iron sucrose, 100 mg in
`60 minutes, a 400% increase in non–transferrin-
`bound iron was seen, accompanied by an in-
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`STEVEN FISHBANE
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`crease in superoxide levels ranging from 53% to
`70%. Moreover, Tovbin et al38 studied iron su-
`crose at a dose of 100 mg administered to 19
`hemodialysis patients on high-flux dialysis
`therapy. They found significant increases in pro-
`tein oxidation. Recently, Dru¨eke et al39 studied
`79 hemodialysis patients administered IV iron
`sucrose and found significant evidence for oxida-
`tive stress and acceleration of atherosclerosis in
`proportion to the amount of iron sucrose admin-
`istered.
`
`CONCLUSIONS
`Viewed together, these data show several po-
`tential risks of IV iron administration, including
`anaphylaxis, CVD, and increased risk for infec-
`tion. Risks for adverse events generally have
`been quantifiable, with the newer IV iron com-
`
`Fig 5. Cell death in mouse proximal tubule cells
`shown by the percentage of LDH release with four IV
`iron preparations (iron oligosaccharide [OS], sodium
`ferric gluconate [Gluc], iron dextran [Dext], and iron
`sucrose [Sucr]) compared with placebo. Abbreviation:
`Cont, continued. Reprinted with permission.35
`
`Fig 6. Lethal cell injury to
`cultured human proximal tu-
`bule (HK-2) cells determined
`by (A) LDH release and (B)
`MTT uptake with varying
`doses of iron (Fe) oligosac-
`charide (OS), sodium ferric
`gluconate (Gluc),
`iron dex-
`tran (Dext), and iron sucrose
`(Sucr). For (A), *P < 0.05 and
`†P < 0.001. For (B), *P <
`0.001. Modified and reprinted
`with permission.35
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`pounds, sodium ferric gluconate and iron su-
`crose, having a lower incidence of allergic and
`anaphylactoid-type reactions. A number of stud-
`ies during the past 2 years have pointed to a risk
`for free-iron release and infection with iron su-
`crose. Further research is needed to quantify the
`risk of this free-iron release in terms of clinical
`outcomes. Nevertheless, in weighing risks ver-
`sus benefits of IV iron therapy, it is clear that IV
`iron is not only a beneficial component of hemo-
`dialysis, but also a necessary one for the majority
`of patients who are iron deficient. Specific risks
`and benefits should be balanced on an individual
`patient basis.
`
`REFERENCES
`1. National Kidney Foundation: K/DOQI Clinical Prac-
`tice Guidelines for Anemia of Chronic Kidney Disease,
`2000. Am J Kidney Dis 37:S182-S238, 2001 (suppl 1)
`2. Cannella G, La Canna G, Sandrini M, et al: Reversal of
`left ventricular hypertrophy following recombinant human
`erythropoietin treatment of anaemic dialysed uraemic pa-
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