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A Comprehensive Vision for Intravenous Iron Therapy

Daniel W. Coyne, MD

Commonly used iron indices, such as serum ferritin and transferrin saturation (TSAT), have limitedutility in patients with chronic kidney disease. Both dialysis and nondialysis patients may have normal tohigh serum ferritin levels and little or no iron available for erythropoiesis. Inflammation can result inincreased serum ferritin level and low TSAT and restrict the ability to mobilize iron stores. Managementof anemia in patients with chronic kidney disease requires recognizing that not only decreasederythropoietin production, but also decreased iron availability, can lead to anemia. The Dialysis Patients’Response to IV Iron with Elevated Ferritin (DRIVE) trial showed the efficacy of intravenous (IV) iron inanemic hemodialysis patients with serum ferritin levels of 500 to 1,200 ng/mL and TSAT of 25% or lessreceiving adequate erythropoiesis-stimulating agent doses. Withholding iron from these patientsresulted in worsening iron-restricted erythropoiesis. To improve anemia management in patientsreceiving hemodialysis and being treated with ESAs, clinicians should consider the benefits of IV iron.Am J Kidney Dis 52(S1):S14-S20. © 2008 by the National Kidney Foundation, Inc.

INDEX WORDS: Intravenous iron; erythropoiesis-stimulating agent; serum ferritin; anemia of chronickidney disease.

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nflammation has an important role in the patho-genesis of the anemia of chronic kidney dis-

ase (CKD). It generally is accepted that patientsith CKD are likely to develop anemia as a conse-uence of their impaired kidney function as a resultf inadequate endogenous erythropoietin produc-ion. Viewed in this fashion, it is not surprising thatdministration of erythropoiesis-stimulating agentsESAs) to stimulate red blood cell (RBC) produc-ion has been a cornerstone of treatment. However,ndividuals with CKD often have inflammation,nd the various pathways through which inflamma-ion can contribute to the anemia of CKD andmpact on iron homeostasis should be considered.

Hepcidin, a serum protein produced mainly byhe liver, is a key regulator of iron mobilizationnd absorption.1-4 Research suggests that in-reased hepcidin levels may contribute signifi-antly to the anemia of CKD.1-4 To protect theody from iron overload, in iron-replete individu-ls under normal physiological circumstances,lasma hepcidin concentrations will increase,

From the Washington University School of Medicine, Stouis, MO.This article was published as part of a supplement spon-

ored by an educational grant from Watson Pharmaceuti-als.

Address correspondence to Daniel W. Coyne, MD, Wash-ngton University School of Medicine, 600 Euclid Ave,ampus Box 8129, St Louis, MO 63110. E-mail:coyne@im.wustl.edu© 2008 by the National Kidney Foundation, Inc.0272-6386/08/5206-0103$34.00/0

sdoi:10.1053/j.ajkd.2008.09.003

American Journal of Kidney Disea14

estricting iron absorption from the gastrointesti-al tract and inhibiting the release of iron fromhe reticuloendothelial (RE) system.3,4 Con-ersely, in a state of iron deficiency, plasmaepcidin levels decrease dramatically, allowinghe intestine to absorb dietary iron and enhancingelease of iron from RE stores, thereby maintain-ng appropriate transferrin saturation (TSAT) lev-ls.3,4 However, hepcidin is an acute-phase reac-ant and levels are increased in patients withnflammatory states, including the anemia ofKD.1,2 Patients with CKD with increased hep-idin levels may absorb less iron in the long termnd release stored iron less efficiently.2 There-ore, the action of hepcidin in patients withnflammation can interfere with the ability toobilize the iron necessary for effective RBC

roduction. Treating anemia in patients with CKDhrough only ESA administration is managingnly a single part of the equation. A betterpproach would be to weigh the impact of notnly diminished erythropoietin production, butlso the action of increased hepcidin expressionaused by inflammation, which leads to lessvailable iron for erythropoiesis. In addition, thenemia treatment paradigm should be directed atiscovering and treating the mechanism trigger-ng the inflammatory process.

INFLAMMATION AND LIMITATIONS OFIRON INDICES

Inflammation affects 2 laboratory tests widelysed to assess iron status and guide iron therapy:

erum ferritin and TSAT. Both indices are acute-

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A Vision for IV Iron Therapy S15

hase reactants, which limit their utility for diag-osing iron deficiency.4,5 Serum ferritin is anndirect measure of body iron stores. It containsittle or no iron, unlike tissue ferritin, whicherves as the major iron storage protein. Serumerritin originates from the leakage or secretionf tissue ferritin, thus merely reflecting themount of ferritin in the tissue. Serum ferritinevel, which increases as iron stores increase,ay also be increased by inflammation, malnutri-

ion, and infection despite limited or absent stor-ge iron.

TSAT is a measure of the amount of ironirculating in the body and available for erythro-oiesis. Iron circulates tightly bound by trans-errin protein, which shuttles iron from storageites in the RE system to the erythroid marrow.uring inflammatory states and malnutrition,SAT may decrease. TSAT is also subject toiurnal variation and can vary with meals.6

Patients with CKD receiving ESAs often showow TSATs combined with normal or high serumerritin levels, suggesting iron-restricted erythro-oiesis.3,4,7-11 In patients receiving ESAs, if theate of erythropoiesis outpaces the rate at whichransferrin can replenish circulating iron withron released from storage, iron-restricted eryth-opoiesis develops.6-8 A low TSAT can indicateron-restricted erythropoiesis.4,10 Increased se-um ferritin levels and low TSATs, in conjunc-ion with reduced hemoglobin (Hb) levels andncreased ESA doses, may also be a sign of annflammation-mediated process that restricts/educes the release of iron from RE storage toransferrin.7

QUESTIONS RAISED BY SERUM FERRITINAND TSAT GUIDELINES

The National Kidney Foundation 2006 Kidneyisease Outcomes Quality Initiative (KDOQI)linical Practice Guidelines and Clinical Prac-

ice Recommendations for Anemia in Chronicidney Disease recommend maintaining serum

erritin, TSAT, and reticulocyte Hb content (CHr;direct measure of iron status at the level of the

eticulocyte) at greater than certain lower limits.7

he practice recommendations suggest that irontores are adequate if TSAT is 20% or greater,Hr is 29 pg/cell or greater, and serum ferritin is

00 ng/mL or greater for patients on hemodialy- t

is therapy or 100 ng/mL or greater for all otheratients with CKD.7

The KDOQI recommendations state that theres insufficient evidence to recommend routinentravenous (IV) iron administration when serumerritin levels exceed 500 ng/mL.7 The cautiousse of IV iron at greater serum ferritin levels maye caused by the concern that accumulation ofxcessive iron in tissues, such as the heart, liver,nd pancreas (as observed in patients with hemo-hromatosis), can be harmful.6 However, mostron accumulation in patients on hemodialysisherapy is found in the RE cells, with very littleamage in the parenchymal cell.6 KDOQI ad-ises that when encountering greater serum fer-itin levels, clinicians should evaluate a patient’slinical status, Hb level, ESA dose and respon-iveness, and levels of other iron indices, such asSAT, before making iron treatment decisions.7

hese recommendations are based on the opin-ons of the work group because of the lack ofublished data at the time.7 They neither proposen upper serum ferritin level at which to uni-ormly refrain from administering IV iron norirect clinicians to withhold IV iron when serumerritin level is 500 ng/mL or greater. Neverthe-ess, these recommendations have promptedome clinicians to use a serum ferritin level of00 ng/mL as a reflexive stop point for IV ironherapy.

The recommendations have also given rise toeveral questions about how to appropriatelyanage anemia in patients with CKD receivingSAs. For example, does a serum ferritin level of00 ng/mL in patients with CKD receiving hemo-ialysis or 100 ng/mL in other patients withKD correctly reflect adequate iron stores? Doesserum ferritin level of 500 ng/mL really indi-

ate no need for iron? How should cliniciansanage anemia in patients in whom iron indices

re discordant; ie, increased serum ferritin levelnd low TSAT?

EXAMINING DATA FOR SERUM FERRITIN

The first step in contending with some of theseuestions is to realize that, as stated by the KDOQIork Group, the guidance for serum ferritin levels

reater than 500 ng/mL is predicated on an inad-quacy of data.7 There were limitations to thetudies suggesting no benefit to IV iron in patientsith serum ferritin levels greater than 500 ng/mL

hat were published before the 2006 KDOQI rec-

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Daniel W. CoyneS16

mmendations were released. For example, toetermine the treatment success rate whenerum ferritin level exceeds 500 ng/mL, a 2004ublication12 assessed 4 studies conducted be-ween 1996 and 2001.10,13-15 These 4 studiesompared the sensitivities and specificities ofarious serum ferritin levels and investigated theesponse of hemodialysis patients to a 500- to,000-mg dose of IV iron (saccharated ferricxide in 1 study, iron dextran in the other 3).esponse was defined as a specific increase inb level, hematocrit, or reticulocyte count or aecrease in ESA dose during a prespecified peri-d.10,13-15 Each study found no significant rela-ionship between pretreatment serum ferritin levelnd the efficacy of IV iron.10,13-15 Despite this,ome interpreted these data as showing that IVron therapy was increasingly less efficacious aserum ferritin levels approached 300 ng/mL andltogether unsuccessful when serum ferritin levelas 500 ng/mL or greater.12 However, these 4

tudies had few or no patients with serum ferritinevels greater than 500 ng/mL,10,13-15 and in 2tudies, the response rate in the 300- to 500-g/mL serum ferritin range was at least 50%ased on the numbers of patients and sensitivitynalysis results for serum ferritin (Fig 1).10,13

hus, although flawed, these studies indicatedhat serum ferritin level was a poor predictor ofV iron needs and a serum ferritin level of 500g/mL had no strong discriminative value.

INCREASED SERUM FERRITIN AND EVIDENCEOF NEED FOR IRON

Data have shown that patients with CKD and

Fishbane 1996 (5-pt HctLin 2001 (1.0 g/dL Hb InCombined Data in 100 n

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o high serum ferritin levels and still requireron.4,16-18 In a 2006 study, Gotloib et al18 con-ucted sternal bone marrow biopsy and mea-ured RBC parameters in 47 patients with CKDho were not receiving ESA therapy and inhom the mean pretreatment serum ferritin level

235 � 54.3 ng/mL) was adequate by KDOQIecommendations.18 Patients had a mean TSATf 13.5% � 4.1% and Hb levels less than 12/dL (mean pretreatment Hb, 10.16 � 1.32). Irontaining on bone marrow biopsy showed that 46f the 47 patients had no evidence of iron in theirone marrow, indicating that they were severelyron deficient. After receiving 250 mg of IV ironsodium ferric gluconate) twice a month for 3onths, mean Hb levels increased significantly

y 1.80 � 1.72 g (P � 0.01) to 11.96 � 1.52/dL, and 53% of patients reached an Hb levelf 12 g/dL or greater. Mean TSAT increased to2% � 1.72%, and serum ferritin level increasedo 275 � 92 ng/mL.18 The outcomes suggestedhat anemia in these patients was not a result ofrythropoietin insufficiency, but of iron defi-iency. The investigators concluded that ironeficiency is a more common cause of anemia inondialysis patients with CKD than currentlyecognized, and correcting it with IV iron canelp patients achieve an Hb level of 12 g/dLithout ESA therapy.18 The investigators alsoiscussed the possibility that an inflammatorytate may have triggered hepcidin-mediated ironlockade in these patients.18 There is a strongikelihood that many patients with CKD haveuch conditions as inflammation or infection that

se or 10% ESA Decrease)

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Figure 1. The relationshipof pretreatment serum ferritinto likelihood of a successful re-sponse to intravenous iron inhemodialysis patients. Data arefrom the sensitivity and speci-ficity reported by Lin et al10 andFishbane et al.13 The blue linecombines the data from thosestudies. Hb in g/dL may be con-verted to g/L by multiplying by10. Ferritin levels expressed inng/mL and �g/L are equivalent.

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A Vision for IV Iron Therapy S17

evels and may be bypassed successfully by IVron administration.

Another 2-year observational study at a cen-er of approximately 200 hemodialysis patientsuggests that increasing the average serumerritin level through regular IV iron adminis-ration reduced iron-restricted erythropoiesisnd improved response to ESA therapy.19 TheV iron (iron sucrose) administration protocolas adjusted in 3 phases, with an average of 53g/wk in phase 1, increased to an average of

7 mg/wk in phase 2, and settled at an average1 mg/wk in phase 3. During the 3 phases ofhe study, median ESA dose decreased from36 to 72 U/kg/wk as median serum ferritinevel increased from 188 to 480 ng/mL, whileedian Hb level was sustained at 11.3 to 11.8

/dL.19 When the average serum ferritin wasbout 500 ng/mL after increased IV iron usesimilar to the average serum ferritin of the USKD population20), ESA doses and the percent-ge of hypochromic RBCs were greatly re-uced. The study concluded that a serum fer-itin level in the range of 350 to 650 ng/mLecreased ESA requirements and addressedpparent iron-restricted erythropoiesis in thisopulation.19

Other studies found that administering IV irono patients receiving hemodialysis significantlyecreased ESA requirements. ESA doses de-reased by 33% to 70% through IV iron adminis-ration in 4 different studies (Table 1).21-24 Twof these studies also reported cost savings througheduced ESA use despite the cost of IV iron.22,24

he long-term management of IV iron at allerum ferritin target levels has not been tested in

Table 1. Reduced ESA Doses Achieved

Study No. of Patients Iron D

ishbane et al21 20 200 mg/wk*epandj et al22 50 50 mg/wk*under-Plassmann et al23 52 100 mg/HD seaylor et al24 12 125 mg/wk‡aylor et al24 34 31.25-62.5 mg

Note: Values expressed as mean � SEM (Fishbane), meAbbreviations: ESA, erythropoiesis-stimulating agent; HD*Iron dextran.†Iron saccharate.‡Sodium ferric gluconate.

andomized trials. l

DRIVE: RANDOMIZED CONTROLLEDEVIDENCE OF IV IRON EFFICACY IN HIGH

SERUM FERRITIN AND LOW TSAT

Although the publications cited undermine theotion that serum ferritin level is an effectivearker of iron status in patients with CKD, the

tudies can be criticized as observational studies,onrandomized trials, or small trials lackingroper controls. Combined, they lack the abilityo sufficiently test the clinical validity of a particu-ar serum ferritin or TSAT value.

To address these criticisms of prior studies andvaluate the clinical value of a serum ferritinevel of 800 ng/mL, the 6-week, open-label,andomized Dialysis Patients’ Response to IVron with Elevated Ferritin (DRIVE) trial waserformed.17 DRIVE examined the efficacy ofV iron (sodium ferric gluconate) in improvingnemia in patients on hemodialysis therapy re-eiving ESA doses of 22,500 U/wk or greaterith an Hb level of 11 g/dL or less, serum ferritin

evel of 500 to 1,200 ng/mL, and TSAT of 25%r less. Patients were randomly assigned to re-eive IV iron (1 g administered as 125-mg dosesver 8 consecutive hemodialysis sessions; n �8) or no IV iron (control; n � 66). At theeginning of week 1, both groups received a5% increase in ESA dose, which was then heldonstant for the next 6 weeks.17

DRIVE showed that IV iron was efficacious inmproving anemia in this patient population.

ean Hb levels increased by a significantlyreater amount (1.6 g/dL) in the IV iron grouphan in the control group (1.1 g/dL; P � 0.028or the difference between groups).17 Patients inhe IV iron group were also significantly more

Intravenous Iron: Results of 4 Studies

Baseline Mean ESA Dose Change in ESA Dose (%)

7,100 � 571 U/treatment �4696 � 59 U/kg/wk �35217 � 179 U/kg/wk �709,000 U/wk �336,000 U/wk �33

D (Sepandj, Sunder-Plassmann), and median (Taylor).odialysis.

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nd the IV iron group responded significantlyore rapidly than the no-iron group.17

In DRIVE, withholding IV iron from controlatients resulted in a steady and significant de-rease in CHr (Fig 2).17 CHr will decrease if notnough iron is available to support the process ofBC production stimulated by ESA therapy. Inontrast to the control group, CHr levels of theV iron group increased significantly during theeeks of iron administration (Fig 2). These re-

ults suggest that treating a serum ferritin level of00 ng/mL as a stop point for IV iron therapyill result in worsening iron-restricted erythropoi-sis in some patients.17

DRIVE: INABILITY OF IRON MARKERS TOPREDICT IV IRON RESPONSE

The DRIVE outcomes address whether levelsf the iron indices recommended by KDOQI touide IV iron administration can predict a re-ponse to IV iron.16,17 Patients in DRIVE weretratified by baseline serum ferritin level: 500 to00 ng/mL or greater than 800 ng/mL.17 Annalysis of the rate of responders for each serumerritin stratum showed that the likelihood ofesponding was similar in both strata (Fig 3).17

here was no significant difference between theerum ferritin strata in change in Hb level orercentage of responders.16,17 The similar re-ponse rates and Hb level changes between the 2erum ferritin strata challenge the view that lev-ls greater than 500 ng/mL or greater than 800g/mL indicate iron sufficiency.Although the KDOQI recommendations ad-

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arget of IV iron therapy,7 DRIVE found thatatients were just as likely to respond to IV ironhether TSAT was 19% to 25% compared with

ess than 19%.16,17 In patients with TSATs of9% or less, the responder rate and mean changen Hb level in the IV iron group and controlroup were similar to results seen in patientsith TSATs of 19% to 25% (Fig 4; data on file,atson Pharmaceuticals, Morristown, NJ).16,17

hese DRIVE results show that neither TSATor serum ferritin level is a good predictor ofesponse to IV iron in this patient population.

Another KDOQI-recommended iron markerested in DRIVE was CHr. Although KDOQIecommends maintaining a CHr of 29 pg/cell orreater as a target of iron therapy,7 patients inRIVE with a baseline CHr of 31.2 pg/cell orreater were 5.3 times (95% confidence interval,.78 to 15.83) more likely to respond (defined as2-g/dL increase in Hb level) to IV iron than

atients with lower CHr levels.16 These resultsaise the question of whether the KDOQI recom-endation of greater than 29 pg/cell should be

evisited.16,17

CONCLUSION

Confronting the anemia of CKD requires aomprehensive vision that recognizes that inflam-ation and other factors may affect patients’

bility to mobilize iron and that many patientsith CKD, both on and off dialysis therapy, canave normal to high serum ferritin levels andittle or no iron.4,16-18 The DRIVE trial showedhe efficacy of IV iron in anemic hemodialysis

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Figure 2. Changes in weeklyreticulocyte hemoglobin con-tent (CHr) in the ferric glu-conate and control groupsduring the Dialysis Patients’Response to IV Iron with El-evated Ferritin trial.17 Valuesare � SE. Ferric gluconategroup versus control group,P � 0.011. Control group base-line versus week 6, P � 0.001.Abbreviation: LOCF, last obser-vation carried forward. Re-printed with permission fromCoyne et al.17

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A Vision for IV Iron Therapy S19

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Figure 3. Change in hemoglobin (Hb)16 levels and percentage of patients achieving a clinically significant Hb response,17

efined as at least a 2-g/dL increase in Hb level, stratified by serum ferritin level (500 to 800 or 801 to 1,200 ng/mL) in theerric gluconate and control groups during the Dialysis Patients’ Response to IV Iron with Elevated Ferritin trial.17 Rates ofesponders were similar for each strata, and there was no difference between strata in change in Hb levels. Hb in g/dL may be

onverted to g/L by multiplying by 10. Ferritin levels expressed in ng/mL and �g/L are equivalent.

TSAT <19%

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Figure 4. Change in hemoglobin (Hb) levels and percentage of patients achieving a clinically significant Hb response,efined as at least a 2-g/dL increase in Hb level, stratified by transferrin saturation (TSAT; �19% or 19% to 25%) in the ferricluconate and control groups during the Dialysis Patients’ Response to IV Iron with Elevated Ferritin trial.17 Data for rate ofesponse for the less-than-19% TSAT stratum and change in Hb level for both TSAT strata are from data on file, Watson

16

harmaceuticals, Morristown, NJ. Remaining data are from Singh et al. Rates of responders and changes in Hb levelsere similar for each strata.16,17 Hb in g/dL may be converted to g/L by multiplying by 10.

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g/mL and TSATs of 25% or less receivingdequate ESA doses, and withholding iron fromhese patients resulted in worsening iron-re-tricted erythropoiesis.17 The DRIVE outcomesontradict the theory that a serum ferritin level of00 ng/mL is an effective cutoff point for IV iron.It is important to remember that anemia of

KD may be a product of not only decreasedrythropoietin production, but also decreased ironvailability, and both lead to impaired erythropoi-sis. Therefore, to improve anemia managementn patients receiving hemodialysis and beingreated with ESAs, clinicians should consider theenefits of IV iron.

ACKNOWLEDGEMENTSThe author acknowledges the assistance of Regina Kelly

n preparation of this manuscript.Support: None.Financial Disclosure: Within the past 3 years, Dr Coyne

eports having served as a consultant for AMAG Pharmaceu-icals Inc, which is developing an IV iron replacementherapeutic for the treatment of iron deficiency anemia inatients with CKD; Watson Pharmaceuticals, which marketsn injectable sodium ferric gluconate compound; and Roche,hich markets an ESA. He has served as a speaker foratson and Amgen Inc, which markets an ESA. Within this

eriod, Dr Coyne has also received research funding fromMAG Pharmaceuticals Inc, Amgen Inc, Roche, and Watsonharmaceuticals.

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