J Am Soc Nephrol 15: S91–S92, 2004
`
`Making Sense: A Scientific Approach to Intravenous Iron
`Therapy
`
`DAVID B. VAN WYCK,* BO G. DANIELSON,† and GEORGE R. ARONOFF‡
`*Department of Medicine and Surgery, University of Arizona College of Medicine, Tucson, Arizona;
`†Department of Renal Medicine, University Hospital, Uppsala, Sweden; and ‡Department of Medicine;
`University of Louisville Kidney Disease Program, Louisville, Kentucky
`
`More than 100 yr have passed since parenteral iron was first
`given to humans (1). Fifty yr ago, carbohydrate was first
`coupled to iron oxide (2), reducing the fierce toxicity of ferric
`iron and introducing the era of parenteral therapy with carbo-
`hydrate-iron agents (3,4). This is sufficient time to consider
`what we have learned about the risks and benefits of intrave-
`nous (IV) iron therapy; to review what we know and what we
`don’t; and, most important, to develop a comprehensive, uni-
`fying view that makes sense of the chemistry, biology, and
`pharmacology of IV iron agents.
`Although treatment of iron deficiency certainly is not con-
`fined to patients with kidney disease, the majority of published
`evidence on IV iron therapy resides in the nephrology litera-
`ture. Anemia is common among all patients with chronic
`kidney disease, expected among those with advanced kidney
`disease, and nearly universal among those who undergo dial-
`ysis. Evidence of iron deficiency is currently quite common in
`patients with chronic kidney disease–associated anemia (5).
`However, before treatment with erythropoietin receptor ago-
`nists (ERA; including epoetin ␣, epoetin ␤, and darbepoetin ␣),
`it was iron excess, not deficiency, that afflicted most dialysis
`patients. Because anemia was severe, transfusion dependence
`was common, and transfusional hemosiderosis resulted.
`ERA therapy ended transfusion dependence, unmasked iron
`loss as the dominant feature of iron balance in hemodialysis
`patients, converted iron overload to iron deficiency as the
`prevailing disorder, highlighted the failure of oral iron supple-
`mentation to sustain iron sufficiency, and thereby thrust IV
`iron agents to the forefront of iron replacement. Two additional
`developments have heightened IV iron use in dialysis patients.
`The first is evidence that a maintenance IV iron schedule
`designed to prevent iron deficiency is more effective than a
`periodic treatment schedule in achieving target hemoglobin
`and minimizing doses of ERA therapy. The second is accep-
`tance and implementation of anemia management guidelines,
`including those of the National Kidney Foundation Dialysis
`Outcomes Quality Initiative (K/DOQI) and European Best
`
`Correspondence to Dr. David B. Van Wyck, Kidney Health Institute, LLC,
`6720 North Nanini Drive, Tucson, AZ 85704-6128. Phone: 520-906-8262;
`Fax: 520-498-5027; E-mail dvanwyck@sprynet.com
`1046-6673/1512-0091
`Journal of the American Society of Nephrology
`Copyright © 2004 by the American Society of Nephrology
`
`DOI: 10.1097/01.ASN.0000143813.03529.EC
`
`Practice Guidelines (EBPG). Publication of the first K/DOQI
`anemia guidelines in 1997 (6) and the EBPG anemia guidelines
`in 1999 (7) has been followed by gradual adoption of iron
`maintenance protocols. IV iron use in the United States has
`increased every year since 1996. By 2002, the proportion of
`patients who received IV iron within a single quarter ap-
`proached 65%, and the average annual IV iron dose for all
`hemodialysis patients exceeded 2300 mg (8).
`Increasing use of IV iron has prompted concerns for the
`potential hazards of iron therapy and the risks of iron overload
`and has stimulated a new and welcome wave of inquiry into
`iron safety. From in vitro studies to epidemiologic examination
`of large dialysis databases, evidence has accumulated rapidly.
`At the same time, new techniques to examine the structure and
`chemistry of iron carbohydrate compounds have helped to
`resolve decades-old controversies about how, for good or for
`bad, IV iron agents deliver biologically active iron.
`A coherent, unifying view of IV iron agents, based soundly
`on an understanding of structure and chemistry, to encompass
`in vitro findings, explain in vivo observations, evaluate risks
`and benefits, and compare existing IV iron agents is urgently
`needed. During Renal Week in San Diego, California, in No-
`vember 2003, Bo Danielson, George Aronoff, and David Van
`Wyck outlined one such view at a symposium sponsored and
`organized by the American Society of Nephrology. The current
`review arises from that collaboration. The groundbreaking
`work of Mary Cowman and Dina Kudasheva (9,10) on carbo-
`hydrate-iron structure and chemistry plays a central role in
`formulating our review. The findings of these two colloid
`chemists make possible a remarkable synthesis of the chemis-
`try, biology, and clinical use of IV iron agents.
`Our conclusions are reassuring. No IV iron compounds
`generate detectable free iron. All IV iron agents release bio-
`logically available or labile iron. The rate of labile iron release
`in each agent is inversely related to the size of its iron core. The
`clinical consequences of labile iron release have little signifi-
`cance at low iron doses but limit the maximum tolerated single
`dose and rate of infusion of each IV iron agent. All evidence
`suggests that, in regard to iron release, IV iron use within
`current guidelines is safe and that K/DOQI limits for iron
`supplementation (11,12) should continue to be observed.
`
`References
`1. Stockman R: The treatment of chlorosis by iron and some other
`drugs. Br Med J 1: 881– 885, 1893
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`

`
`S92
`
`Journal of the American Society of Nephrology
`
`J Am Soc Nephrol 15: S91–S92, 2004
`
`2. Nissim JA: Intravenous administration of iron. Lancet 1: 49 –51,
`1947
`3. Fierz F: Contribution concerning the intravenous iron therapy. In-
`vestigations with Ferrum-Hausmann. Praxis 22: 469–472, 1950
`4. Beutler E: The utilization of saccharated Fe59 oxide in red cell
`formation. J Lab Clin Med 51: 415– 419, 1958
`5. Hsu CY, McCulloch CE, Curhan GC: Iron status and hemoglo-
`bin level in chronic renal insufficiency. J Am Soc Nephrol 13:
`2783–2786, 2002
`6. Eschbach JW, DeOreo P, Adamson J, Berns J, Biddle G, Com-
`stock T, Jabs K, Lazarus JM, Nissenson AR, Stivelman J, Van
`Wyck DB, Wish J: NKF-DOQI clinical practice guidelines for
`the treatment of anemia of chronic renal failure. Am J Kidney Dis
`30: S192–S240, 1997
`7. Barany P, Carrera F, Chanard J, Eckardt KU, Hadjicontantinou
`V, Leenaerts P, Leunissen ML, Locatelli F, MacLeod A, Rut-
`kowski B, Sanz D, Schaefer RM, Schmieder R, Winearls CG:
`European best practice guidelines for the management of anae-
`
`mia in patients with chronic renal failure. Nephrol Dial Trans-
`plant 14: 1–50, 1999
`8. Wish JB, Johnson CA, Frankenfield DL: Intravenous iron use
`among adult hemodialysis (HD) patients: Results from the 2002
`ESRD Clinical Performance (CPM) Project [Abstract]. J Am Soc
`Nephrol 14: 458A, 2003
`9. Kudasheva DS, Lai J, Ulman A, Cowman MK: Structure of
`carbohydrate-bound polynuclear iron oxyhydroxide nanopar-
`ticles in parenteral formulations. J Inorgan Biochem 2004, in
`press
`10. Kudasheva DS, Cowman MK: Structures of iron-carbohydrate
`complexes used as parenteral formulations [Abstract]. J Am Soc
`Nephrol 14: 856A, 2003
`IV. NKF-K/DOQI Clinical practice guidelines for anemia of
`chronic kidney disease: Update 2000. Am J Kidney Dis 37:
`S182–S238, 2001
`12. Van Wyck DB: Lessons from NKF-DOQI: Iron management.
`Semin Nephrol 20: 330 –334, 2000
`
`11.
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`

`
`Labile Iron: Manifestations and Clinical Implications
`
`DAVID B. VAN WYCK
`Department of Medicine and Surgery, University of Arizona College of Medicine, Tucson, Arizona
`
`J Am Soc Nephrol 15: S107–S111, 2004
`
`As Dr. Danielson discussed in the article “Structure, Chem-
`istry, and Pharmacokinetics of Intravenous Iron Agents” in this
`supplement, the pharmacokinetics and internal iron disposition
`of all intravenous (IV) iron agents are characterized by initial
`clearance from the plasma space into fixed phagocytic cells of
`the reticuloendothelial system (RES) followed by intracellular
`liberation of iron from the iron-carbohydrate complex, release
`of iron from RES cells to circulating transferrin (Tf), and,
`finally, donation of Tf-bound iron to erythroid precursors in
`marrow. In the iron-avid patient, utilization of IV iron by this
`stepwise mechanism is rapid and relatively complete. All IV
`iron agents, however, show evidence of a second, limited
`pathway in which iron passes directly from the iron-carbohy-
`drate compound to Tf. Evidence that iron-carbohydrate agents
`can directly release biologically active iron and bypass the
`presumed safety of RES uptake has prompted a series of
`questions with potentially important implications for IV iron
`administration in patients
`
`Do IV Iron Agents Release Free Iron?
`Concern that parenteral iron-carbohydrate compounds re-
`lease free iron is neither new nor confined to a single iron
`agent. In the mid-1960s, examination of iron dextran Imferon
`by polarography and high-voltage electrophoresis suggested
`that 0.3% of the total iron in the compound consists of ionic
`iron in the ferrous (Fe⫹2) state, probably weakly bound to
`dextran (1). These investigators were the first to predict that a
`small fraction of weakly bound or labile iron could provoke
`iron-mediated hypotension if large doses were injected rapidly.
`Subsequent efforts to identify free, ionic iron in iron-carbo-
`hydrate agents have proved unsuccessful. No dialyzable iron
`has been found in iron dextran (2,3), ferric gluconate (4), or
`iron sucrose (5). The product package insert for ferric glu-
`conate reports that ⬍1% of iron in ferric gluconate is dialyz-
`able in vitro (6). Neither iron sucrose nor iron dextran release
`detectable iron to dialysate using high-flux or high-efficiency
`dialyzers (7).
`
`Evidence for a Labile, Bioactive Iron Fraction
`Although there is no convincing evidence of unbound, dia-
`lyzable, or free iron in any IV iron agent, all agents show
`
`Correspondence to Dr. David B. Van Wyck, Kidney Health Institute, LLC,
`6720 North Nanini Drive, Tucson, AZ 85704-6128. Phone: 520-906-8262;
`Fax: 520-498-5027; E-mail: dvanwyck@sprynet.com
`1046-6673/1512-0107
`Journal of the American Society of Nephrology
`Copyright © 2004 by the American Society of Nephrology
`
`DOI: 10.1097/01.ASN.0000143816.04446.4C
`
`evidence of a labile, biologically active iron fraction. In vitro
`and in vivo manifestations of a labile iron fraction in iron-
`carbohydrate compounds include iron assay interference
`(agents falsely elevate serum iron results), oversaturation of Tf
`(true increase in iron available for Tf binding exceeds unbound
`iron-binding capacity), non–Tf-bound iron (NTBI), direct iron
`donation to Tf, altered intracellular iron homeostasis, cytotox-
`icity, neutrophil impairment, bacterial growth enhancement,
`oxidant stress, or catalytic iron (Table 1).
`The results in Table 1 prompt several conclusions. Each
`manifestation of labile iron is shared by all IV iron agents
`tested, but not all agents have been tested for each manifesta-
`tion. Not all attempts to demonstrate labile iron effects have
`shown positive results, and some positive results more likely
`are due to tissue iron excess, total iron dose, or underlying
`disease than to the tested IV iron agent itself.
`Serum iron assays falsely detect a portion of iron in iron-
`carbohydrate compounds as if it were Tf bound. The degree of
`interference varies by agent class, by agents within the same
`class, and by assay method. The consequent false elevation of
`serum iron has confounded assessment of Tf oversaturation
`after IV iron administration in patients. Of course, assay inter-
`ference does not exclude a true increase in serum Tf-bound
`iron. Iron agents convincingly donate iron directly to Tf, and
`the resulting increase in Tf-bound iron is both theoretically (8)
`and demonstrably (9) sufficient to saturate Tf fully after rapid
`IV iron injection.
`The relationship among Tf saturation, NTBI, and biologi-
`cally active iron defies simplicity. Tf oversaturation is not a
`prerequisite for the appearance of either NTBI or labile iron.
`Indeed, although both NTBI and biologically active labile iron
`appear transiently after IV iron administration, each may also
`arise in patients who do not undergo IV iron therapy, without
`iron overload, or early after oral iron administration. Neither
`NTBI nor labile iron has been characterized chemically: NTBI
`reflects the results of assays for that portion of serum iron that
`is not bound to Tf, and labile iron is identified only by the
`biologic activity that it manifests in vitro or in vivo. Although
`labile iron may contribute to NTBI, not all NTBI shows evi-
`dence of biologic activity, and in some assays, NTBI and labile
`iron seem to be distinct entities.
`It is also apparent that labile iron released from iron-carbo-
`hydrate compounds in the extracellular space shows evidence
`of transport into non-RES cells. Exposure of hepatic parenchy-
`mal cells to IV iron agents in tissue culture produces an abrupt
`increase in the intracellular labile iron pool. The increase in
`intracellular iron activates key regulatory responses to restore
`iron homeostasis.
`Cytotoxicity to cells in tissue culture has been demon-
`
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`

`
`S108
`
`Journal of the American Society of Nephrology
`
`J Am Soc Nephrol 15: S107–S111, 2004
`
`IN,intravenous;HD,hemodialysis;Tf,transferrin;NTBI,non–Tf-boundiron;ID,irondextran;SFGC,sodiumferricgluconatecomplex;IS,ironsucrose;IP,ironpolymaltose;
`
`BDI,bleomycin-detectableiron;TSAT,transferrinsaturation;TIBC,totalironbindingcapacity;DMT-1,divalenttransporter1;PMN,polymorphonuclearleukocyte.
`
`ferritin⬎650ng/mlassociatedwithimpairedPMNkillingcapacity
`
`10mgIVaftereachdialysisinHDpatientswithTSAT⬍20%and
`300-mgIVinfusioninPDpatientsimpairsPMNkillingcapacity
`IDattenuatesPMNfromHDpatientsbutnotcontrols
`
`Invivo
`Invivo
`Invitro
`
`Patrutaetal.(35)
`Deicheretal.(34)
`Guoetal.(33)
`
`Ironsaccharate
`Ironsucrose
`ID
`
`Comparative
`Ironsucrose
`FerricgluconateMasinietal.(27–30)
`
`Sengoelgeetal.(32)
`Zageretal.(31)
`
`Sturmetal.(26)
`
`Neutrophilimpairment
`
`Cytotoxicity
`
`homeostasis
`
`Labileironpool,ferritin,DMT-1:FePPⱖSFGC⬎ISⱖIDINFeD
`
`ComparesferricgluconatewithironsaccharateFerrivenin.Inhibition
`IS⬎SFGC⫽ID
`
`ofPMNmigration:ironsaccharate⬎SFGC
`
`Invivo
`Invitro
`InvitroOxidant-inducedactivationofaspecificCa2⫹effluxpathway
`Invitro
`
`Ferritin,DMT-1expression:FeAC⬎SFGC⬎IS⬎IDINFeD
`Imferon
`Imferon
`Imferon
`SFGC⬎IS⬎IDINFed⬎IDDexferrum(quantitative)
`
`SFGC⬎IS⬎IP(semiquantitative)
`
`ascorbate
`
`Invitro
`Invivo
`Invitro
`Invivo
`Invitro
`
`Invitro
`
`Scheiberetal.(25)
`JacobsandAlexander(15)
`Kind((24))
`HendersonandHillman(23)
`VanWycketal.(8)
`
`Comparative
`
`Alteredintracellulariron
`
`ID
`
`Espositoetal.(20)
`
`Comparative
`
`Directirondonationto
`
`Tf
`
`InvitroRateofdegradationSFGC⬎IS⬎IP⬎IDinthepresenceof
`Invivo
`Invivo
`Invivo
`Invivo
`Invivo
`Invivo
`Invivo
`Invivo
`Invivo
`Invivo
`Invivo
`InvitroDetects77%asserumironusingconstant-voltagecoulometry
`InvitroDetects3.1–100%Imferon;diothionateincreasesdetection
`InvitroDetects1–2.5%Imferonasserumironbyautomatedmethod
`Invivo
`
`NTBIinmalignancy;BDIpresentifTSAT⬎80%
`LabileplasmaironindialysispatientsifTSAT⬎30%
`NTBIpositivein4.3%ofcontrolgroupwithoutirontherapy
`NTBIpositiveinonepatientshortlyaftertakingoraliron
`NTBInotassociatedwithoxidativestress,vasodilationdefect
`TSAT⬎100%withlowTIBC,dose⬎50mgFerrivenin
`TSAT80–100%in9/12HDpatientsafter100-mgIVpush
`TSAT⬎100%ifdose⫽125mg/4hor62.5–125mg/30min
`TSAT⫽100%whenagentironconcentration⫽8400␮g/dl
`TSAT⬎100%7dafter500-mgdose.Methodnotdescribed.
`Detects57.5%asserumiron
`
`Detects0.3%Imferonasferrousiron
`
`Geisseretal.(22)
`vonBonsdorffetal.(21)
`Espositoetal.(20)
`Breueretal.(19)
`Breueretal.(19)
`Rooyakersetal.(18)
`Sunder-PlassmanandBerl(17)
`Parkkinenetal.(9)
`Zanenetal.(16)
`JacobsandAlexander(15)
`Milman(14)
`Kooistraetal.(5)
`Sekiguchietal.(13)
`Huisman(12)
`McIntoshetal.(11)
`CoxandKing(1)
`
`Comparative
`
`Irondegradationkinetics
`
`Noiron
`Oraliron
`Ironsucrose
`Ironsaccharate
`Ironsucrose
`Ferricgluconate
`
`ID
`Ironsucrose
`Ferricgluconate
`
`ID
`
`NTBI
`
`OversaturationofTf
`
`iron;ascorbateandincubationtimeincrease%detection
`
`FSGC⬎IDINFeD.Detects2–7%INFeD,7–33%FSGCasserum
`
`Invitro
`
`Seligmanetal.(10)
`
`Comparative
`
`Ironassayinterference
`
`Note
`
`Model
`
`Author
`
`IronAgentClass
`
`Effect
`
`Table1.EvidenceforbioactivityofIVironagentsinvivoandinvitro:Reviewoftheliteraturea
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`
`

`
`J Am Soc Nephrol 15: S107–S111, 2004
`
`Manifestations of Labile Iron
`
`S109
`
`strated after exposure to IV iron agents. However, the con-
`centration of iron agent needed to demonstrate cell toxicity
`in vitro is far higher than can be achieved in patients after IV
`iron administration.
`
`Relationship between Labile Iron and the
`Chemistry of IV Iron Agents
`Results of comparative studies of labile iron activity asso-
`ciated with IV iron agents consistently show an inverse rela-
`tionship between labile iron and molecular weight of the iron-
`carbohydrate compound. Whether the examined manifestation
`is interference with serum iron assay, rate of iron degradation,
`direct donation of iron to Tf, generation of oxidant stress, or
`alteration of intracellular iron homeostasis, the magnitude of
`the labile iron effect is greatest in iron-carbohydrate com-
`pounds of lowest molecular weight and least in those of the
`highest weight.
`Recent imaging and direct measurement of the core radius of
`iron-carbohydrate compounds provide a potential explanation
`(43). If, as proposed, labile iron reflects the ionic iron that is
`first released from IV iron agents, then the point of release
`likely would be the surface of the iron-oxyhydroxide core. The
`focus of attention, therefore, should be the total surface area
`available for iron release.
`Because all agents share the same core chemistry, the rate of
`iron release per unit surface area likely would be similar among
`agents (differing, perhaps, only by the strength of the carbo-
`hydrate ligand-core iron bond). However, for the same total
`amount of core iron, surface area available for iron release
`increases dramatically as core radius decreases. In short, a
`collection of many small spheres exposes a greater total surface
`area than does a collection of an equal mass of fewer, larger
`spheres.
`That the relationship between surface area and core radius is
`not linear explains why small core radius differences between
`agents of small molecular weight are as significant as large
`core radius differences between agents of high molecular
`weight. This is simple mathematics. Because surface area is a
`function of the product of 4␲ and the square of the radius,
`Surface area ⫽ 4␲r2, and volume is a function of the cube of
`the radius, Volume ⫽ 4/3␲r3, then the ratio of surface area to
`volume is a function of the product of the constant 3 and
`reciprocal of the radius: Surface Area:Volume Ratio ⫽ 3r⫺1.
`Thus, as the radius increases, surface area to volume ratio
`decreases first abruptly, then more gradually (Figure 1). Be-
`cause large iron-oxyhydroxide cores such as those in iron
`dextran tend to assume an ellipsoidal (football or cigar-like)
`rather than spherical shape, the effective core radius is more
`difficult to estimate, but the same general relationships apply.
`
`Clinical Implications of Labile Iron
`Given the reassuring evidence of safety of IV iron in clinical
`practice, do any of the broad range of findings on labile iron in
`vitro and in vivo have implications for IV iron administration
`in patients? This question returns attention to previous specu-
`lation that the presence in an iron-carbohydrate compound of a
`
`IN,intravenous;HD,hemodialysis;Tf,transferrin;NTBI,non–Tf-boundiron;ID,irondextran;SFGC,sodiumferricgluconatecomplex;IS,ironsucrose;IP,ironpolymaltose;
`
`BDI,bleomycin-detectableiron.
`
`100mgIVeverywkdecreasedoxidantstress,TNF-␣;increasedIL-4
`Noeffectat20and100mgIVonMDAandredcelldeformability
`Transientoxygen-radicalmediatedeffectonvasodilation
`AdvancedoxidativeproteinproductsinHDpatients
`TransientBDIwhenTSAT⬎80%
`Oxidizedproteinsriseafter125mgbutnot62.5mgIVover1h
`SFGCdisruptsratlivermitochondriabyoxidantmechanism
`F2-isoprostanesincreasemodestlyafter700mgIVover60min
`
`Invivo
`Invivo
`Invivo
`Invivo
`Invivo
`Invivo
`Invitro
`Invivo
`InvivoMacrophageNO2inratsafterIViron:SFGC⬎IS⬎IDDexf⬎IP
`Invitro
`Invitro
`
`Lipidperoxidation:ID⬎SFGC⬎IS.
`Labileiron:SFGC⬎IS⬎IP
`
`Salahudeenetal.(38)
`Legssyeretal.(37)
`Zageretal.(31)
`Espositoetal.(20)
`
`Weissetal.(42)
`Cavdaretal.(41)
`Rooyakersetal.(18)
`Druekeetal.(40)
`Parkinnenetal.(9)
`Michelisetal.(39)
`FerricgluconateMasinietal.(29,30)
`ID
`
`Ironsucrose
`
`Comparative
`
`Oxidantstressandcatalyticiron
`
`SerumofpatientsafterISsupportedStaphepidermidisgrowthif
`Nostudies
`
`Invitro
`
`Parkkinenetal.(9)
`
`Ironsucrose
`Ferricgluconate
`
`TSAT⬎80%,effecttransient
`
`bacteriostasisandopsonizationofE.colibyserumisalsolower.
`InvitroMothersgivenIVirondextranduringpregnancyshowlowerTIBC;
`
`Websteretal.(36)
`
`ID
`
`Bacterialgrowthenhancement
`
`Note
`
`Model
`
`Author
`
`IronAgentClass
`
`Effect
`
`Table1.Continued
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`Journal of the American Society of Nephrology
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`J Am Soc Nephrol 15: S107–S111, 2004
`
`in the back or chest, and hypotension that characterizes free
`iron reactions closely resembles the effect of giving too much
`of any IV iron agent too fast. Thus, although there is no direct
`evidence of free iron in any IV iron agent, free-iron–like
`reactions account for many of the serious adverse drug events
`listed in Table 1 in “Safety of Intravenous Iron in Clinical
`Practice: Implications of Anemia Management Protocols” in
`this supplement.
`If labile iron can cause a free-iron–like reaction and free-
`iron–like reactions are dose limiting, then, by extension, the
`size of the labile iron fraction may be dose limiting, and, if so,
`then the maximum tolerated dose and rate of administration
`would be inversely related to labile iron fraction and would
`follow the sequence ID⬎IS⬎SFGC. This proposed effect of
`labile iron explains the relationship between dose size, rate of
`infusion, and rate of adverse drug events observed in Table 1
`in “Safety of Intravenous Iron in Clinical Practice: Implications
`of Anemia Management Protocols,” fits the observed differ-
`ences between IV iron agents in maximum tolerated single
`dose and rate of infusion, predicts that agents of larger overall
`molecular weight likely will be associated with greater safety
`at high doses and rapid injection rates, explains why patients
`who weigh ⬍50 kg are more likely to experience adverse
`reactions than larger patients given the same dose (44), con-
`firms the observation that Tf saturation is more likely to occur
`in patients with low total iron-binding capacity (and therefore
`lower unbound iron binding capacity) (17), and suggests that
`labile iron provides the pathogenetic basis for dose-limiting
`and infusion rate–limiting acute IV iron toxicity (10 – 42)(43).
`
`References
`1. Cox JSG, King RE: Valency investigations of iron dextran (Im-
`feron). Nature 207: 1202–1203, 1965
`2. Hatton RC, Portales IT, Finlay A, Ross EA: Removal of iron
`dextran by hemodialysis: An in vitro study. Am J Kidney Dis 26:
`327–330, 1995
`3. Manuel MA, Stewart WK, Clair Neill GD, Hutchinson F: Loss of
`iron-dextran through cuprophane membrane of a disposable coil
`dialyser. Nephron 9: 94 –98, 1972
`4. Calvar C, Mata D, Alonso C, Ramos B, Lopez dN: Intravenous
`administration of iron gluconate during haemodialysis. Nephrol
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`Figure 1. Relationship between core radius and surface area to volume
`ratio. Core radii from Kudasheva et al. (43). Iron dextran core radius
`is an effective estimate given ellipsoidal configuration of the core.
`
`small biologically active iron fraction could provoke a free-
`iron–like reaction in patients if sufficient agent were adminis-
`tered too rapidly. The labile iron fraction is indeed small but
`larger than originally estimated. Moreover, the size of the
`fraction is not uniform among agents. As expected, the labile
`iron fraction follows the sequence SFGC⬎IS⬎ID INFeD⬎ID
`Dexferrum, varying inversely with core radius and overall
`molecular weight (Figure 2).
`To explore the possibility that labile iron release from iron-
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`mum tolerated dose of free iron would have been 8 mg or less.
`Remarkably, the complex of gastrointestinal complaints, pain
`
`Figure 2. Percentage of iron donation to transferrin by iron agent
`tested. The fraction of iron agent available for donation is inversely
`related to the molecular weight of the patient. Adapted from reference
`8.
`
`Pharmacosmos A/S v. Luitpold Ex. Pharmaceuticals, Inc., IPR2015-01490
`
`Luitpold Pharmaceuticals, Inc., Ex. 2049, P. 6
`
`

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`J Am Soc Nephrol 15: S107–S111, 2004
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