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EDITORIAL

Epidemic of Iron Overload in Dialysis Population Causedby Intravenous Iron Products: A Plea for Moderation

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End-stage renal disease is associated with anemia, which iscaused by reduced production of the renal hormone eryth-ropoietin; shortened erythrocyte life span caused by uremictoxins and oxidative stress, which are constant features ofuremia;1 impaired iron availability due to inflammation-riven production of hepcidin, which by blocking ferropor-in inhibits intestinal absorption and release of iron fromissue stores;2 occult blood loss due to uremic platelet dys-unction; and iatrogenic factors.

Common use of blood transfusion to treat anemia beforehe introduction of recombinant erythropoietin was associ-ted with a high incidence of iron overload in patients onialysis. Introduction of recombinant erythropoietin morehan 2 decades ago nearly obviated the need for bloodransfusion in this population. Because of recurrent lossf blood in hemodialysis circuits, blood samples takenor laboratory tests, mobilization of iron stores with re-ombinant erythropoietin therapy, and impaired intestinalron absorption, patients on dialysis readily develop ironeficiency, which necessitates intravenous (IV) ironupplementation.2

Although judicious use of IV iron is indispensible foranemia treatment in patients on hemodialysis, its indiscrim-inate use can have serious consequences. Excessive use ofIV iron intensifies chronic kidney disease-associated oxida-tive stress and inflammation,3-7 promotes endothelial dys-function and cardiovascular disease,8-10 compromises im-

une system,11,12 increases the risk of infections byenhancing microbial growth and virulence and compromis-ing host defense,13-15 and impairs insulin production andeightens insulin resistance.16 Many of these effects are

mediated by iron-catalyzed conversion of endogenous hy-drogen peroxide to hydroxyl radical (.OH), which is themost reactive and cytotoxic free radical known (H2O2�Fe2�¡.OH�OH�� Fe3�).

Although ferritin is a sensitive indicator of body ironstore, as an acute phase reactant its plasma concentration

Funding: None.Conflicts of Interest: None.Authorship: The author is solely responsible for the content of this

Imanuscript.

0002-9343/$ -see front matter © 2012 Elsevier Inc. All rights reserved.http://dx.doi.org/10.1016/j.amjmed.2012.02.009

increases in systemic inflammation independently of bodyiron stores. According to the accepted guidelines, IV ironproducts can be used in patients on dialysis with ferritinvalues as high as 500 �g/L.17 Some authors have suggestedhat IV iron may be administered safely in patients witherritin levels as high as 1200 �g/L.18 This is based on thessumption that elevation of ferritin in such patients may beue to inflammation as opposed to iron overload. Althoughhis explanation is true, it does not justify the use of IV ironn patients with severe inflammation. This is because bymplifying oxidative stress, IV iron can intensify the ad-erse effects of inflammation.

Generally, it is believed that the high prevalence of ironverload among patients on dialysis in the pre-recombinantrythropoietin era was due to blood transfusion. However,n an elegant prospective study published in the currentssue of the Journal, Rostoker et al19 found iron overload in

84% of a cohort of 119 stable patients on hemodialysis whowere treated with recombinant erythropoietin and IV ironpreparations in compliance with the accepted guidelines.The magnitude of hepatic iron load in more than 30% oftheir patients approached that found in hemochromatosis.The results of this study confirmed those of 2 earlier inves-tigations20,21 that showed iron overload in 70% of patients

ith end-stage renal disease, the majority of whom (70%)ad serum ferritin values less than 500 �g/L.20 They further

showed that ferritin values exceeding 340 �g/L were asso-iated with iron overload. These observations provide com-elling evidence that the currently accepted guidelines forse of IV iron products fail to protect against iron overload.

Recent implementation of the bundling reimbursementolicy for dialysis treatment has dramatically increased these of IV iron by for-profit dialysis facilities in an attempto lower their cost by limiting recombinant erythropoietinequirement. In many instances, IV iron is administeredoutinely with insufficient attention to the body iron storesr presence of inflammation. If continued, this trend canulminate in an epidemic of severe iron overload in theialysis population. It is of note that compared with thentestinal absorption of 1 to 2 mg/d in the course of 3 meals,

V infusion of large quantities (100-1000 mg) of iron within

952 The American Journal of Medicine, Vol 125, No 10, October 2012

a few minutes represents an enormous biological challengeto which the body is not accustomed. In fact, administrationof these products raises the non-transferrin-bound, catalyt-ically active iron and intensifies oxidative stress and inflam-mation in patients on dialysis.4-7 Via trapping and expan-sion of iron pool in macrophages, elevation of hepcidin,which is commonly present in patients on dialysis,22

renders them particularly vulnerable to the adverse ef-fects of IV iron. This is in contrast with the slow pace ofiron retention and organ damage (evolving over a periodof 3-4 decades) in hemochromatosis, which is marked byhepcidin deficiency.23

The currently accepted guidelines fail to protect patientson dialysis against iron overload. Therefore, reassessmentand modification of these guidelines and adoption of indi-vidualized care principle are urgently needed.

Nosratola D. Vaziri, MD, MACPDivision of Nephrology and Hypertension

Departments of Medicine and Physiology and BiophysicsUniversity of California, Irvine

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J Am Soc Nephrol. 2007;18:382-393.3. Lim CS, Vaziri ND. The effects of iron dextran on the oxidative stress

in cardiovascular tissues of rats with chronic renal failure. Kidney Int.2004;65:1802-1809.

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17. KDOQI National Kidney Foundation. ll. Clinical practice guidelinesand clinical practice recommendations for anemia in chronic kidneydisease in adults. Am J Kidney Dis. 2006;47:Sl6-S85.

18. Coyne DW, Kapoian T, Suki W, Singh AK, Moran JE, Dahl NV,DRIVE Study Group. Ferric gluconate is highly efficacious in anemichemodialysis patients with high serum ferritin and low transferrinsaturation: results of the Dialysis Patients’ Response to IV Iron withElevated Ferritin (DRIVE) Study. J Am Soc Nephrol. 2007;18:975-984.

19. Rostoker G, Griuncelli M, Loridon C, et al. Hemodialysis-associatedhemosiderosis in the era of erythropoiesis-stimulating agents: A MRIstudy. Am J Med. 2012;125:991-999.

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21. Ferrari P, Kulkarni H, Harrison C, St Pierre TG, Olynyk JK. Serumiron markers are inadequate for guiding iron repletion in chronickidney disease. Clin J Am Soc Nephrol. 2011;6:77-83.

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