A111erican
`Journal of
`Kidney
`Diseases
`
`The Official Journal of the
`National Kidney Foundation
`
`Editor-in-Chief
`Saulo Klahr, MD
`
`Consulting Editors
`Robert G. Luke, MD
`George A. Porter, MD
`
`Assistant Editors
`James A. Delmez, MD
`Kevin J. Martin, MD
`George F. Schreiner, MD
`
`Associate Editors
`Adrian I. Katz, MD
`William G. Couser, MD
`M. Roy First, MD
`Bryan D. Myers, MD
`Raymond Hakim, MD
`Giuseppe Remuzzi, MD
`Michael Kashgarian, MD
`Norman J. Siegel, MD
`
`Hannah E. Abboud
`Paul A. Abraham
`Lawrence Agodoa
`Robert J. Alpern
`Charles E. Alpers
`Sharon Anderson
`Raymond Ardaillou
`Jose A. L. Arruda
`Robert C. Atkins
`Howard A. Austin
`Ellis D. Avner
`Morrell M. Avram
`Daniel C. Batlle
`William M. Bennett
`Jonas Bergstrom
`Tomas Berl
`Daniel G. Bichet
`Vittorio Bonomini
`Wayne A. Border
`Peter C. Brazy
`Daniel Brennan
`Josephine P. Briggs
`Giulio A. Cinotti
`Frederic L. Coe
`John J. Curtis
`Giuseppe D' Amico
`Thomas 0. Daniel
`Connie L. Davis
`Natale G. De Santo
`Thomas D. DuBose, Jr
`Lance D. Dworkin
`Garabed Eknoyan
`Ronald J. Falk
`Agnes Fogo
`
`Editorial Board
`Eli A. Friedman
`Patricia A. Gabow
`John H. Galla
`Kenneth D. Gardner, Jr
`Robert Gaston
`Stanley Goldfarb
`L. Lee Hamm
`Jean L. Holley
`Alan R. Hull
`Iekuni Ichikawa
`Bertram L. Kasiske
`George A. Kaysen
`William F. Keane
`Donald E. Kohan
`Stephen M . Korbet
`Rajiv Kumar
`Kiyoshi Kurokawa
`Andrew S. Levey
`Nathan W. Levin
`Edmund J. Lewis
`Victoria S. Lim
`Stuart L. Linas
`Marshall D. Lindheimer
`Hartmut H. Malluche
`Shaul G. Massry
`S. Michael Mauer
`William M. McClellan
`Dawn S. Milliner
`William E. Mitch
`Bruce A. Molitoris
`Aubrey R. Morrison
`Cynthia C. Nast
`Karl A. Nath
`Karl D. Nolph
`
`Klaus Olgaard
`William F. Owen, Jr
`Tom F. Parker, III
`Beth Piraino
`Friedrich K. Port
`Venkateswara Rao
`Andrew J. Rees
`Helmut G. Rennke
`Richard A. Rettig
`Eberhard Ritz
`Claudio Ronco
`Pierre Ronco
`Brad H. Rovin
`David J. Salant
`Isidro B. Salusky
`Nestor Schor
`Steve J. Schwab
`Sudhir V. Shah
`Richard A. Sherman
`Eduardo Slatopolsky
`Gary E. Striker
`Manikkam Suthanthiran
`Robert D. Toto
`Fernando Valderrabano
`Flavio G. Vincenti
`John Walls
`J. Joseph Wal she
`David G. Warnock
`Roger C. Wiggins
`James F. Winchester
`David Windus
`Marsha Wolfson
`Fuad N. Ziyadeh
`
`

`

`NF The Official Journal of the
`
`National Kidney Foundation
`
`Am.erican
`Journal of
`Kidney
`Diseases
`
`. . ..
`
`I
`
`American Journal of Kidney Diseases (lSSf':/ 0272-6386) is published monthly by W.B. Saunders Company. Corporate
`and Editorial Offices: The Curtis Center, Independence Square West, Philadelphia, PA 19106-3399. Accounting and
`Circulation Offices: 6277 Sea Harbor Dr, Orlando, FL 32887. Periodicals postage paid at Orlando, FL 32862, and
`additional mailing offices. POSTMASTER: "SCehci address changes to American Journal of Kidney Diseases (ISSN 0272-
`6386), W.B. Saunders Company, Periodicals Department, 6277 Sea Harbor Dr, Orlando, FL 32887-4800.
`Editorial correspondence should be addressed to Saulo Klahr, MD, Editor-in-Chief, AJKD, Department of Medicine,
`Jewish Hospital at Washington University Medical Center, 216 S Kingshighway, St Louis, MO 63110.
`Business correspondence (subscriptions, change of address) should be addressed to the Publisher, W .B. Saunders
`Company, Periodicals Department, 6277 Sea Harbor Dr, Orlando, FL 32887-4800.
`Change of address notices, including both the old and new addresses of the subscriber, should be sent at least one
`month in advance.
`Customer Service: 1-800-654-2452.
`Yearly subscription rates: United States and possessions: individual, $206.00; institution, $347.00; single issue, $33.00.
`All other countries: individual, $360.00; institution, $395.00; single issue, $33.00. For all areas outside the United States
`and possessions, there is no additional charge for surface delivery. For air mail delivery, add $48.00. Student and resident:
`United States and possessions, and Canada, $132.00; all other countries, $360.00. To receive student/resident rate, orders
`must be accompanied by name of affiliated institution, date of term, and the signature of program/residency coordinator
`on institution letterhead. Orders will be billed at individual rate until proof of status is received. Single issues, both
`current and back, exist in limited quantities and are offered for sale subject to availability. Current prices are in effect
`for back volumes and back issues. Back issues sold in conjunction with a subscription are on a prorated basis. / 995
`bound volume price: $95.00; foreign customers, please add $15 .00 for postage. To purchase a 1995 bound volume,
`customer must be a subscriber for 1995. Cumulative Index (1983-1989) price: $95.00; foreign customers, please add
`$2.25 for surface delivery, or $8.00 for air mail delivery. Prices are subject to change without notice. Checks should be
`made payable to W.B. Saunders Company and sent to American Journal of Kidney Diseases, W .B. Saunders Company,
`Periodicals Department, PO Box 628239, Orlando, FL 32862-8239.
`Agents for the United Kingdom, Ireland, and Europe: Harcourt Brace & Company Ltd, 24-28 Oval Rd, London
`NWl 7DX, England. Agents for Australia and New Zealand: Harcourt Brace & Company Australia, 30-52 Smidmore St
`(Locked Bag 16), Marrickville, NSW 2204, Australia. Agents for Japan: Harcourt Brace Japan, Inc, lchibancho Central
`Bldg., 22-1 Ichibancho, Chiyoda-Ku, Tokyo 102, Japan.
`Copyright © 1996, National Kidney Foundation. All rights reserved. No part of this publication may be reproduced or
`transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information
`storage and retrieval system, without permission in writing from the publisher. Printed in the United States of America.
`Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed
`to Journal Permissions Department, W .B. Saunders Company, Orlando, FL 32887. Telephone number 1-407-345-2500.
`The appearance of the code at the bottom of the first page of an article in this journal indicates the copyright owner's
`consent that copies of the article may be made for personal or internal use, or for the personal or internal use of specific
`clients. This consent is given on the condition, however, that the copier pay the stated per-copy fee through the Copyright
`Clearance Center, Inc. (222 Rosewood Dr, Danvers, MA 01923) for copying beyond that permitted by Sections 107 or
`108 of the US Copyright Law. This consent does not extend to other kinds of copying, such as copying for general
`distribution, for advertising or promotional purposes, for creating new collective works, or for resale. Absence of the
`code indicates that the material may not be processed through the Copyright Clearance Center, Inc.
`Ad...ertising representative: Cunningham Associates, 180 Old Tappan Rd, Old Tappan, NJ 07675. Telephone 1-201-
`767-4170; fax 1-201-767-8065.
`The ideas and opinions expressed in the American Journal of Kidney Diseases do not necessarily reflect those of the
`National Kidney Foundation, the Editor, or the Publisher. Publication of an advertisement or other product mention in
`the American Journal of Kidney Diseases should not be construed as an endorsement of the product or the manufacturer' s
`claims. Readers are encouraged to contact the manufacturer with any questions about the features or limitations of the
`products mentioned. The National Kidney Foundation and the Publisher do not assume any responsibility for any injury
`and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The
`reader is advised to check the appropriate medical literature and the product information currently provided by the
`manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or
`contraindications. It is the responsibility of the treating physician or other health care professional, relying on independent
`experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient.
`
`W.B. Saunders Company
`
`Philadelphia, PA
`
`A Division of Harcourt Brace & Company
`
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`The Safety of Intravenous Iron Dextran in Hemodialysis Patients
`
`Steven Fishbane, MD, Virgiliu-Dan Ungureanu, MD, John K. Maesaka, MD,
`Charles J. Kaupke, MD, Victoria Lim, MD, and Jay Wish, MD
`
`• The treatment of anemia in hemodialysis patients is frequently hindered by the presence of suboptimal iron
`stores. Intravenous iron dextran is in common use to maintain iron stores in this population, but there are little
`published data regarding the incidence and type of adverse events. The purpose of this study was to evaluate
`the safety of this medication. Charts from four hemodialysis centers of all 573 patients treated with intravenous
`iron dextran (INFeD; Schein Pharmaceutical, Inc, Florham Park, NJ) between July 1, 1993, and June 30, 1995, were
`studied. Twenty-seven patients (4.7%) had adverse reactions that were related to iron dextran. Four patients
`(0.7%) had reactions classified as serious (one cardiac arrest; three others required hospitalization). Ten patients
`(1.7%) had reactions classified as anaphylactoid. No patients died or developed permanent disability as a result
`of reactions. The most common adverse reactions included itching (1.5% of patients) and dyspnea or wheezing
`(1.5%); others included chest pain (1.0%), nausea (0.5%%), hypotension (0.5%), swelling (0.5%), dyspepsia (0.5%),
`diarrhea (0.5%), skin flushing (0.3%}, headache (0.3%), cardiac arrest (0.2%), and myalgias (0.2%). Five of all the
`reactions occurred during a test dose; four of these were anaphylactoid. Several factors were studied as possible
`predictors of adverse reactions. A positive history of drug allergy (odds ratio, 2.4; P = 0.03) and history of multiple
`drug allergy (odds ratio, 5.5; P = 0.0004) were significant predictors of reactions. In summary, we found serious
`adverse reactions to be uncommon in hemodialysis patients treated with intravenous iron dextran. Future prospec(cid:173)
`tive studies will help confirm this finding.
`© 1996 by the National Kidney Foundation, Inc.
`
`INDEX WORDS: Hemodialysis; anemia; iron deficiency; iron dextran.
`
`E FFECTIVE treatment of the anemia of end(cid:173)
`
`stage renal disease has been possible in
`most hemodialysis patients since the introduction
`of recombinant human erythropoietin. 1 In many
`patients, however, therapy is hindered by the
`presence of inadequate iron stores, making it dif(cid:173)
`ficult to achieve therapeutic goals. 2 Most hemodi(cid:173)
`alysis patients are prescribed oral iron supple(cid:173)
`ments in an attempt to achieve a positive iron
`balance. When chronic oral iron therapy fails to
`maintain adequate iron stores, intravenous iron
`dextran is indicated.2 Intravenous iron dextran
`leads to a rapid improvement in erythropoiesis
`in hemodialysis patients with iron deficiency. 3
`There is wide variability, however, in practice
`patterns regarding the use of this medication.
`Some nephrologists have avoided prescribing it
`due to reports of serious allergic reactions, such
`as anaphylaxis. The incidence of such reactions
`is unclear, especially among hemodialysis pa(cid:173)
`tients. A large study performed in a nonuremic
`population found three immediate, serious reac(cid:173)
`tions among 2,099 iron dextran injections (0.1 % )
`in 481 patients (0.6%) . Less severe reactions
`occurred with 12% of injections, more com(cid:173)
`monly with doses of greater than 250 mg.4 Be(cid:173)
`cause there is a paucity of published data regard(cid:173)
`ing the safety of intravenous iron dextran in
`hemodialysis patients, the purpose of our analy(cid:173)
`sis was to attempt to define the incidence, type,
`
`and predictors of adverse reactions in this popu(cid:173)
`lation.
`
`MATERIALS AND METHODS
`
`Patient records from four dialysis centers were reviewed
`in retrospect to obtain data for this study. The four centers
`were the Winthrop-University Hospital, the Center for Dial(cid:173)
`ysis Care (Cleveland, OH), the University of Califomia-Ir(cid:173)
`vine Dialysis Center, and the University of Iowa Dialysis
`Center. The same protocol was used by each center. Every
`hemodialysis patient treated with intravenous iron dextran
`(INFeD; Schein Pharmaceutical, Inc, Florham Park, NJ) be(cid:173)
`tween July I, 1993, and June 30, 1995, was included for
`analysis; no patient was excluded. If a patient received more
`than one course of treatment with intravenous iron dextran,
`then only the first course was included. If a patient receiving
`multiple courses had a reaction with any course, then that
`was the one course selected for inclusion in the study.
`The charts of patients treated with intravenous iron dextran
`
`From the Department of Medicine, Winthrop-University
`Hospital, Mineola, NY; Division of Nephrology, University
`of California-Irvine, Irvine, CA; Division of Nephrology, Uni(cid:173)
`versity of Iowa, Iowa City, IA ; and Division of Nephrology,
`Case Western Reserve University, Cleveland, OH.
`Received March 15, 1996; accepted in revised form June
`18, 1996.
`Supported by an unrestricted educational grant from
`Schein Pharmaceutical, Inc, Florham Park, NJ.
`Address reprint requests to Steven Fishbane, MD, 222 Sta(cid:173)
`tion Plaza North, Suite 510, Mineola, NY 11501.
`© 1996 by the National Kidney Foundation, Inc.
`0272-6386/96/2804-0007$3.00/0
`
`American Journal of Kidney Diseases, Vol 28, No 4 (October), 1996: pp 529-534
`
`529
`
`

`

`530
`
`FISHBANE ET AL
`
`Table 1. Patient Characteristics
`
`Site (no. of patients)
`New York
`Ohio
`Iowa
`California
`Men: women (%)
`Age (yr)
`Ethnicity (%)
`African-American
`White
`Hispanic
`Asian
`Native American
`Other
`History of diabetes
`
`132
`264
`23
`154
`49:51
`48.6 ±: 4.2
`
`44
`39
`8
`3
`
`5
`30
`
`were reviewed for the presence of any adverse event possibly
`related to the medication. Every note entered into the patient' s
`chart and the dialysis record by physicians and nurses for
`each day of administration and the subsequent week was
`noted. Any new symptom or sign that developed within this
`period was considered a possible reaction. The initial data(cid:173)
`base included the date of administration of iron dextran and
`the patient's age, ethnicity, sex, complete medical history,
`allergies, and history of alcohol abuse.
`For a patient in whom a reaction occurred, the type of
`reaction, onset, and duration were recorded. The actions taken
`as a result of the reaction were noted, including the use of
`specific medications or other interventions. An adverse event
`was coded as a serious reaction if the patient died, was at
`immediate risk for death, or required hospital care, or if a
`perrnanent disability resulted. Immediate risk for death in(cid:173)
`cluded factors such as hypotension, severe dyspnea, cardiac
`arrhythmias, and evidence of airway obstruction. The assess(cid:173)
`ment of the seriousness of the reaction was made in tandem
`by the individual site coordinator and medical principal inves(cid:173)
`tigator. Reactions were defined as anaphylactoid if there was
`any dyspnea, wheezing, hypotension, urticaria, or angio(cid:173)
`edema. The central study coordinator (S.F.) reviewed the
`appropriateness of determinations; no changes from the origi(cid:173)
`nal assessments were required.
`The probability that an adverse reaction was actually
`caused by the administration of the intravenous iron dextran
`was rated as certain, probable, possible, or unrelated by the
`site investigator. Factors used in making this determination
`included biologic plausibility, temporal relationship, and the
`presence or absence of other obvious explanations for the
`reaction. If it was not possible to make this determination,
`then no probability was assigned. Reactions scored as unre(cid:173)
`lated were reanalyzed by the central coordinator (S.F.), and
`if he concurred that there was no relationship, that reaction
`was excluded from final analysis.
`
`Statistical Analysis
`The incidence of adverse reactions was calculated as a
`percentage of the total number of patients treated. Some stud-
`
`ies have calculated incidence based on total number of drug
`administrations. The latter approach was not used based on
`the rationale that it understates the reaction rate. Since pa(cid:173)
`tients who do not develop reactions usually are treated for a
`course of 10 drug administrations, whereas patients who de(cid:173)
`velop reactions have truncated courses, incidence calculations
`based on administration number underestimate the occurrence
`rate of reactions.
`Potential predictors of adverse reactions were studied using
`Fisher's exact test. Results are reported as mean ±: SD. Statis(cid:173)
`tical significance was defined as P < 0.05.
`
`RESULTS
`Five hundred seventy-three patients were
`treated with intravenous iron dextran between
`July 1, 1993, and June 30, 1995, at the four sites
`(New York, 132; Ohio, 264; Iowa, 23; and Cali(cid:173)
`fornia, 154). Table 1 lists patient characteristics.
`Men comprised 49% of the combined study pop(cid:173)
`ulation. The mean age was 48.6 ± 4.2 years;
`44% of patients were African-American, 39%
`were white, 8% were Hispanic, 3% were Asian,
`I% were Native American, and 5% were other
`ethnicities. Diabetic patients comprised 30% of
`the study patients.
`Thirty adverse reactions occurred (5.2% of pa(cid:173)
`tients treated) (Tables 2 and 3). There was no
`statistically significant difference in the incidence
`of reactions detected per study site. Three reac(cid:173)
`tions were found to be unrelated (as defined in
`Materials and Methods) to intravenous iron dex(cid:173)
`tran; these were excluded from further analysis.
`The likelihood that adverse reactions were re(cid:173)
`lated to the administration of the intravenous iron
`dextran was reported as probable (see definition
`in Materials and Methods) or certain in 70%
`cases; in 30% of cases the reaction was believed
`to be possibly related to the medication.
`Four reactions (0.7% of patients treated) were
`defined as serious; in one patient a cardiac arrest
`
`Table 2. Adverse Reaction by Study Site
`
`Site
`
`Severe
`All
`Reactions Reactions
`
`Total
`Anaphylactoid
`Reactions
`
`California (n = 154)
`Iowa (n = 23)
`New York (n = 132)
`Ohio (n = 264)
`Total (n = 573)
`
`9
`1
`4
`16
`
`0
`
`2
`
`3
`
`5
`
`30 (5.2%) 4 (0.7%) 10(1 .7%)
`
`

`

`IRON DEXTRAN IN HEMODIAL YSIS
`
`531
`
`Table 3. Adverse Reactions
`
`Total no. of patients
`No. of adverse reactions
`Reactions unrelated to iron dextran
`Adverse reactions attributable to iron
`dextran
`Types of reactions (%)
`Dyspnea or wheezing
`Itching
`Chest pain
`Nausea
`Hypotension
`Swelling
`Diarrhea
`Dyspepsia
`Skin flushing
`Headache
`Cardiac arrest
`Myalgias
`
`573
`30 (5.2%)
`3
`
`27 (4.7%)
`
`1.5
`1.5
`1.0
`0.5
`0.5
`0.5
`0.5
`0.5
`0.3
`0.3
`0.2
`0.2
`
`temporally related to treatment with iron dextran
`led to hospitalization, as did three other cases of
`patients who experienced dyspnea, hypotension,
`or chest pain. The patient with cardiac arrest was
`a 52-year-old African-American man with a pre(cid:173)
`vious history of diabetes mellitus, hypertension,
`myocardial infarctions, and congestive heart fail(cid:173)
`ure. There was no previous history of drug al(cid:173)
`lergy, and the patient was not currently taking
`any other medications that could have precipi(cid:173)
`tated or exacerbated this reaction. Chest pain de(cid:173)
`veloped during the test dose administration (25
`mg), and cardiac arrest occurred within minutes.
`The patient was resuscitated with advanced car(cid:173)
`diac life support, and was admitted for observa(cid:173)
`tion. No evidence was found for myocardial in(cid:173)
`farction, and the patient was discharged shortly
`thereafter. No patient in this study died as a result
`of treatment and no patient developed permanent
`disability. Ten ( 1.7%) reactions (including all
`four of the serious reactions) met the criteria for
`anaphylactoid reactions as defined above. Seven
`of these IO patients were treated with antihista(cid:173)
`mines or steroids and two with epinephrine as a
`result of the reaction. In 22 cases (3.8%), the
`adverse reaction led to permanent discontinuance
`of the medication. In five patients, treatment with
`iron dextran was successfully reinstituted. No pa(cid:173)
`tient who had a reaction classified as anaphylac(cid:173)
`toid was rechallenged with the drug.
`Types of reactions noted included itching
`
`(1.5% of patients), dyspnea or wheezing (1.5 %),
`chest pain (1.0%), nausea (0.5%%), hypotension
`(0.5%), swelling (0.5%), dyspepsia (0.5%), diar(cid:173)
`rhea (0.5%), skin flushing (0.3%), headache
`(0.3% ), cardiac arrest (0.2% ), and myalgias
`(0.2% ). More than one symptom was described
`by 45% of patients who experienced an adverse
`event.
`Of all reactions, only five occurred with the
`initial test dose of iron dextran. Four of these
`reactions were classified as anaphylactoid. Dur(cid:173)
`ing one 25-mg test dose, a patient had a cardiac
`arrest as described above. A second patient de(cid:173)
`veloped itching within 30 minutes of a 25-mg
`test dose. A third patient experienced nausea and
`dyspnea with a 50-mg test dose. The fourth pa(cid:173)
`tient received a 10-mg test dose and developed
`back pain and dyspnea. A fifth patient developed
`chest pain, dyspnea, and hypotension after a 25-
`mg test dose; this patient previously had an aller(cid:173)
`gic reaction to iron dextran prior to this rechal(cid:173)
`lenge. Iron dextran was permanently discon(cid:173)
`tinued in all five of these patients.
`Several variables were analyzed as possible
`predictors of adverse reactions. These included
`age, sex, history of drug allergy, history of pul(cid:173)
`monary disease, cardiovascular disease, or cur(cid:173)
`rent use of alcohol. The only variable that was
`found to be predictive of the development of an
`adverse event was a history of drug allergy (not
`including allergy to iron dextran) (odds ratio, 2.4;
`P = 0.03): nine of 27 reactions occurred in pa(cid:173)
`tients with a history of drug allergy. In patients
`with a history of multiple drug allergies (re(cid:173)
`corded allergy to more than one drug), there was
`a significantly increased risk of a reaction to iron
`dextran (odds ratio, 5.5; P = 0.0004): six of 27
`reactions occurred in patients with multiple drug
`allergies. The negative predictive value of an ab(cid:173)
`sent history of drug allergy was 96% (only 4%
`of patients with no history of drug allergies de(cid:173)
`veloped a reaction to iron dextran). When ana(cid:173)
`phylactoid reactions were analyzed separately, a
`history of drug allergy was again a statistically
`significant predictor (odds ratio, 3.9; P = 0.04).
`Interestingly, three of IO anaphylactoid reactions
`occurred in patients with a history of multiple
`drug allergies. In patients with multiple drug al(cid:173)
`lergies the odds ratio for an anaphylactoid reac(cid:173)
`tion was 4.9 (P = 0.046).
`
`

`

`532
`
`FISHBANE ET AL
`
`DISCUSSION
`
`The development and introduction into clinical
`use of recombinant human erythropoietin have
`made it possible to successfully treat the anemia
`of end-stage renal disease in the majority of pa(cid:173)
`tients.1 Therapy is often suboptimal, however,
`due to the development of inadequate iron stores.
`In hemodialysis patients, this occurs for a variety
`of reasons, including blood retention in the dial(cid:173)
`ysis lines and filter, poor intestinal absorption of
`iron,5 gastrointestinal bleeding, blood loss during
`surgical procedures, and frequent blood drawing
`for laboratory testing.2 Once iron stores become
`inadequate, it is difficult to achieve therapeutic
`goals for hemoglobin and hematocrit, and resis(cid:173)
`tance to recombinant human erythropoietin leads
`to a need for high doses. Oral iron supplements
`are frequently used in an attempt to achieve posi(cid:173)
`tive iron balance. Such therapy is often ineffec(cid:173)
`tive6 due to limited patient compliance as a result
`of gastrointestinal side effects and to poor intesti(cid:173)
`nal absorption of iron in hemodialysis patients.5
`In addition, oral iron is not effective in the treat(cid:173)
`ment of frank iron deficiency in this population.
`In this setting, intravenous iron dextran is gener(cid:173)
`ally agreed to be the treatment of choice to rees(cid:173)
`tablish iron stores. 2 Intravenous iron results in
`replenishment of depleted iron stores, with a
`7 The typi(cid:173)
`rapid improvement in erythropoiesis. 3
`•
`cal treatment regimen consists of 10 doses of
`I 00 mg of iron dextran injected during sequential
`hemodialysis treatments.
`Nephrologists vary widely in their utilization
`of intravenous iron dextran. Many have been un(cid:173)
`comfortable prescribing this therapeutic agent
`because of reports of severe allergic reactions.
`Reactions due to dextran were first noted during
`its use as a volume expander prior to 1950. Iron
`dextran, which became available in 1952, also
`has been associated with allergic reactions.4 The
`iron dextran complex is comprised of 165,000-d
`microspherules with a diameter of 5 nm. The
`center, or core, of each sphere is composed of
`iron in the ferric state complexed to oxyhydrox(cid:173)
`ide (FeOOH). 8 This is surrounded by a stellate
`pattern of dextran chains that project out to the
`sphere's surface. The dextran chains are syn(cid:173)
`thetic glucose polymers of approximately 5,000
`d molecular weight.9 After intravenous injection,
`
`iron dextran is removed from plasma by the retic(cid:173)
`uloendothelial system after a half-life in plasma
`of 1 to 3 days. 10 Serum ferritin levels increase
`within 2 weeks,3 probably due to rapid intracellu(cid:173)
`lar processing of iron dextran within the reticulo(cid:173)
`endothelial system. 11
`The mechanism of allergy to iron dextran is
`not known, but because of the rapidity of onset
`it is likely due to a direct effect on mast cells and
`basophils leading to their degranulation. There
`is little evidence in the literature to support an
`immunoglobulin E- or immune complex-medi-
`112
`ated process. In a recent study, Novey et a
`found evidence for direct basophil degranulation
`as the etiology for an anaphylaxis-like reaction
`in a patient treated with iron dextran. There was
`no evidence to support an irnrnunoglobulin E(cid:173)
`mediated event. Some episodes of hypotension
`occurring immediately after iron dextran admin(cid:173)
`istration may be attributable not to allergy, but
`to free divalent iron dissociated from the parent
`complex. In a study in cats, Cos and King found
`the risk of hypotension to be in direct proportion
`dd".
`13 I
`n a 1t1on
`to the quantity of free iron present.
`to serious immediate reactions, other types of
`adverse reactions may occur with intravenous
`iron dextran administration. Local reactions,
`such as pain in the injected vein, have been asso(cid:173)
`ciated with injection rates of greater then 100
`mg/min. 4 Less severe reactions, which are often
`delayed for 4 to 48 hours after the administration,
`can include symptoms such as arthralgias, myal(cid:173)
`gias, fever, headaches, and lymphadenopathy.
`The risk of these reactions may be related to the
`total dose of iron dextran administered. 4
`The actual incidence and type of reactions due
`to iron dextran in hemodialysis patients have
`been difficult to ascertain due to a dearth of pub(cid:173)
`lished data using current formulations of the
`agent. Anaphylactic-type reactions in a general
`population have been estimated to occur in ap(cid:173)
`proximately 0.1 % of administrations.4 Less se(cid:173)
`vere reactions probably occur with greater fre(cid:173)
`quency. The purpose of our current study was to
`define the incidence and type of adverse reactions
`related to intravenous iron dextran administration
`in hemodialysis patients.
`We found adverse events to occur in 5.2%
`of hemodialysis patients treated with courses of
`intravenous iron dextran. In general, reactions
`
`

`

`IRON DEXTRAN IN HEMODIAL YSIS
`
`533
`
`tended to be mild and self-limited in nature. Four
`patients (0. 7%) had reactions classified as seri(cid:173)
`ous. Six other patients (10 patients total, 1.7%)
`had at least some symptoms consistent with ana(cid:173)
`phylactoid-type reactions (any dyspnea, wheez(cid:173)
`ing, hypotension, urticaria, or angioedema). It is
`reassuring that the incidence of this type of reac(cid:173)
`tion was low and that no death or disability re(cid:173)
`sulted. Nonetheless, in facilities that use intrave(cid:173)
`nous iron dextran frequently, some symptoms of
`this type will occasionally be encountered. In
`addition, anaphylaxis may occur in hemodialysis
`patients for other reasons, such as exposure to
`ethylene oxide, other leachable compounds,
`polyacrylonitrile membranes, or other medica(cid:173)
`tions. 14 Therefore, it is important that appropriate
`therapeutic agents, such as epinephrine, oxygen,
`diphenhydrarnine, and hydrocortisone, be readily
`available.
`One previous, large review of the safety of
`intravenous iron dextran by Hamstra et al4 in(cid:173)
`volved 481 nonurernic patients treated with rela(cid:173)
`tively high doses (majority, 250 mg or 500 mg
`per injection). Their reported incidence of imme(cid:173)
`diate, serious reactions was almost identical to
`our finding: 0.6% of patients treated. Two clear
`differences between our study results were that
`Hamstra et al found a moderate number of local
`reactions, such as burning during the infusion,
`and a 1 % risk of the delayed onset of severe
`myalgias and arthralgias. In our study there were
`no reactions of either type. This was almost un(cid:173)
`doubtedly due to rapid infusions of large doses
`of iron dextran in the study of Hamstra et al. 4
`Most of their patients received between 500 and
`2,500 mg in a single administration. Our four
`centers primarily used lower doses (100 mg per
`treatment was the most common) and when
`larger doses were used, they were infused slowly.
`We found the presence of a previous history
`of drug allergy to be predictive of adverse reac(cid:173)
`tions to intravenous iron dextran. Interestingly,
`in patients with a history of multiple drug allergy
`the risk of a reaction was markedly increased.
`We also found a history of previous drug allergy
`or multiple drug allergies to be significant pre(cid:173)
`dictors of anaphylactoid-type reactions. This as(cid:173)
`sociation is intuitive, but does not necessarily
`follow from knowledge about anaphylaxis. There
`clearly are individuals who are highly atopic
`
`(tendency for allergic manifestations, such as
`asthma, urticaria, rhinitis, and eczematous der(cid:173)
`matitis). There does not, however, appear to be
`an increased incidence of anaphylaxis (eg, peni(cid:173)
`cillin-related) in such highly allergic individuals.
`It is therefore unclear why patients with histories
`of multiple drug allergy would have a higher rate
`of anaphylactoid reactions to iron dextran.
`A test dose of 25 mg of iron dextran is com(cid:173)
`monly recommended before a full treatment
`course is initiated. The theory behind this prac(cid:173)
`tice is inherently sound: to attempt to identify
`patients who are allergic with a minimal dose
`and close observation. It is unclear, however,
`whether the practice actually yields helpful clini(cid:173)
`cal information. Of 27 reactions studied, only
`five of our patients reacted during the initial test
`dose. Importantly, however, 40% of all anaphy(cid:173)
`lactoid-type reactions occurred with the test dose.
`Given this fact, it would be sound clinical prac(cid:173)
`tice to continue to use the test dose prior to a
`therapeutic course of iron dextran. Since the test
`dose is administered with close monitoring, this
`is the optimal setting for identifying anaphylac(cid:173)
`toid reactions. However, it is clear from our re(cid:173)
`sults that anaphylactoid reactions may also occur
`with doses subsequent to the initial test dose.
`Future study would therefore be helpful to exam(cid:173)
`ine practical issues, such as how frequently a test
`dose should be repeated.
`The retrospective study design we used may
`limit the ability to generalize our findings. We
`have made every effort to ensure the complete(cid:173)
`ness and accuracy of the study data. Nonetheless,
`it is possible that the incidence of reactions may
`be understated due to incompleteness of the med(cid:173)
`ical records used to derive information. We feel
`confident, however, that no serious reactions
`were missed for the following reasons