Nephrol Dial Transplant (1992) 7: 35-39
`© 1992 European Dialysis and Transplant Association-European
`Renal Association
`
`Nephroloqy
`Dialysis
`Transplantation
`
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`
`Original Article
`
`Dextran Antibodies, Complement Conversion and Circulating Immune
`Complexes After Intravenous Iron Dextran Therapy in Dialysed
`Patients
`Laura W. Fleming1, W. K. Stewart1 and D. Parratt2
`Departments of 'Medicine and 2Medical Microbiology, University of Dundee, Ninewells Hospital and Medical School,
`Dundee, Scotland, UK
`
`Abstract. Serum immune complexes, plasma dextran
`antibodies and percentage conversion of complement
`have been measured in 20 dialysed patients before and
`after an intravenous infusion of iron dextran providing
`600 mg elemental iron. Complement conversion was
`unmeasurable and there were no changes in circulating
`immune complexes. The presence of dextran antibodies
`in nine patients before the infusion was not related to
`prior exposure to iron dextran. They became undetec-
`table in these patients within hours after the infusion,
`reappearing 1 month later in three. Two of three
`patients reporting mild aches and shivers on the day
`following the infusion had no detectable dextran anti-
`bodies. An adverse reaction involving inflamed joints
`occurred 1-2 days after a second infusion given to one of
`the patients studied above. The parameters under study
`were again measured and did not appear to relate to the
`reaction.
`The presence of dextran antibodies does not preclude
`the giving of iron dextran to patients on dialysis, and the
`immune complex and complement systems remain
`undisturbed by iron dextran infusions.
`
`Key words: Iron dextran; Dialysis; Immune complexes;
`Dextran antibodies; Complement
`
`Introduction
`
`Intravenous iron dextran has been used in our dialysis
`unit since 1972 to ameliorate the iron deficiency com-
`ponent of the multifactorial anaemia of patients on
`maintenance hameodialysis [1, 2]. With the advent of
`recombinant erythropoietin treatment the oral iron
`used by many other units may be insufficient [3] and
`therefore the efficacy and safety of intravenous iron
`therapy in these patients warrant reconsideration.
`Acute adverse reactions, mainly after total dose
`infusions containing 1-2 g elemental iron or more have
`been reported [4-9]. A type I hypersensitivity mechan-
`ism involving the complexing of a specific IgE antibody
`to the dextran moiety has been suggested [10]. None of
`the published reports on adverse reactions refers to
`patients on dialysis. We have investigated in detail 20
`patients on dialysis beginning a course of intravenous
`iron dextran treatment over the course of 1 year and
`measured circulating immune complexes, concentra-
`tions of dextran antibodies, and percentage conversion
`of complement to look for evidence of a type III
`immune complex reaction.
`
`Patients and Methods
`
`Correspondence and offprint requests to: Laura W. Fleming, Depart-
`ment of Medicine, Ninewells Hospital and Medical School, Dundee,
`DD1 9SY, Scotland, U.K.
`
`The investigation was approved by the Tayside Health
`Board Ethical Committee. Nineteen patients on main-
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`L. W. Fleming et al
`36
`Table 1. Circulating dextran antibodies in 20 dialysed patients before and after the first infusion of a course of iron dextran infusions and, where
`indicated, 1 month after the 9th infusion
`
`M49
`
`F442
`
`M43
`
`512
`512
`256
`128
`
`00000
`
`32
`
`2
`
`64
`64
`64
`64
`
`000004
`
`-
`
`32
`32
`32
`32
`
`0000
`
`64
`128
`
`16
`
`Sample time
`
`n 103
`
`Plasma
`
`dextran
`
`antibodies
`
`M25
`
`M54
`
`M53
`
`(reciprocal titre) in
`1ft TflHiVtrln^le fi/itV1
`roKI* titrpc
`i H^mnncti
`1 QU1C II LI CS
`F22
`F19
`M24
`F47
`
`riuuiiio
`
`mil
`
`4--2 --0-0- 0
`
`4--2 --0-0- 2
`
`2--2 --0-0- -
`
`0222 00000- 0
`
`2400 000000 -
`
`4844 000000 -
`
`0000 00002- 2
`
`0000 000000 0
`
`n=4
`2n=3
`NEn=3
`
`Before iron dextran
`7 days (predialysis)
`7 days (postdialysis)
`5 days (predialysis)
`0
`(predialysis)
`After iron dextran1
`6 h (postdialysis)
`9 h (postdialysis)
`24 h (between)
`48/56 h (predialysis)
`7 days (predialysis)
`1 month (predialysis)
`After 9th infusion
`1 month (predialysis)
`
`1 Time since beginning infusin; 2 patient developed on inflammatory arthropathy after her second infusion. 3 Individuals with no demonstrable
`titres at any time: M15, M21, M23, M32, M45, M66, F20, F23, F54, F54.
`Underlining indicates the six patients who had received iron dextran previously.
`NE, not estimated.
`
`tenance haemodialysis (HD) and one on continuous
`ambulatory peritoneal dialysis (CAPD) entered the
`study (12 males and 8 females aged between 16 and 66
`years). The duration of dialysis treatment varied
`between 4 and 162 months. Six patients had received
`intravenous iron therapy in the past, 3-8 years pre-
`viously. Patients are designated in this report by sex (M
`or F) and age in years. Infusions of iron dextran BP
`(Imferon, Fisons, UK) were given intravenously during
`the course of a dialysis. The iron dextran (12 ml
`containing 600 mg elemental iron) was added to 500 ml
`of 0.9% saline solution and infused slowly over a 4-h
`period into the predialyser blood line. A similar time
`interval was taken to deliver the infusion intravenously
`to the patient on CAPD. No patients received oral iron.
`Blood samples were taken prior to the first infusion of
`a course of nine monthly infusions and during the week
`following the first infusion at the times listed in Table 1,
`with a final predialysis sample one month later. Immune
`complexes were measured in serum and all other para-
`meters in plasma. Circulating IgG immune complexes
`were measured by a modification of the method of
`Casali et al [11]. Dextran antibodies were assayed
`utilising passive haemagglutination of dextran-coated
`sheep red blood cells and the percentage conversion of
`complement by two-dimensional immune electrophore-
`sis. Total iron concentrations in plasma were measured
`by the ICSH recommended method [12].
`Seven patients did not complete the full course of nine
`infusions - three reached normal haemoglobin con-
`
`centrations after fewer than four infusions, one patient
`left the area, two patients showed no haemoglobin
`response after two and six infusions respectively, and
`one had a delayed reaction to the second infusion,
`described in Results. In the 13 patients completing the
`course of nine infusions, dextran antibodies were mea-
`sured again 1 month after the final (9th) infusion.
`
`Results
`
`Prior to the first infusion, total iron concentration in
`plasma (Fig. 1) ranged between 6 and 24 ymo\l\ in all
`but one patient, who maintained concentrations at 37
`jmiol/1. Six and nine hours after the beginning of the
`infusion (2 and 5 h respectively after the end of the
`infusion) peak plasma iron concentrations ranged
`between 1570 and 3580 yano\l\, with the majority having
`values between 2600 and 2800 ^mol/1. Thereafter total
`iron concentrations decreased steadily. One week later,
`plasma iron concentrations had returned to normal
`baseline values in eight patients, and in 12 were between
`46 and 208 /anol/1. After 1 month, all patients had
`returned to baseline (Fig. 1).
`Abnormal circulating immune complex concentra-
`tions (26 to 53 fig equivalents of aggregated globulin/ml)
`were detected in only one patient (M25) and did not
`differ before and after the infusion. This patient had a
`protracted subacute infective endocarditis due to
`Staphylococcus aureus. During the previous year his
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`Immune Complexes and Iron Dextran
`
`37
`
`3000 -i
`
`2000-
`
`1 0 0 0J
`
`Plasma
`Total Iron
`/imol/1
`
`8 0-
`
`4 0-
`
`normal
`range
`
`0J
`
`(n-12)
`
`(n-8)
`
`9 24 48
`hours
`
`or¥
`
`Iron
`Dextran
`600 mo
`
`Fig. 1. Plasma total iron concentration (mean ± SEM) in 20 dialysed
`patients before and after an infusion of iron dextran.
`
`circulating immune complexes ranged from 48 to 129
`/ig/ml (reference range <16 /ig/ml). All other patients
`had values below 10 /ig/ml in all samples. Complement
`conversion was not detected in any patient, either
`before or after the infusion.
`Prior to the first infusion, dextran antibodies (Fig. 2)
`were detected in nine patients. Six of these were in the
`group of 14 who had not previously received iron
`dextran and three were in the group of six who had
`received iron dextran in the past (3-8 years previously).
`Of the nine with detectable antibodies, five had low
`reciprocal antibody titres (2-4). The three highest recip-
`rocal titres, (32-512) were seen in patients who had
`never before received iron dextran. The patient with the
`highest concentrations ate a ha'llal diet. In the month
`following the infusion, dextran antibodies (Table 1)
`remained absent in all patients without prior antibodies,
`except in the patient with circulating immune complexes
`(M25) in whom a low reciprocal antibody titre of 2 was
`detectable 7 days after the infusion (see also Fig. 2). In
`the nine patients who had antibodies before the
`infusion, the antibodies disappeared from the plasma
`6 h after the infusion and were not detectable at 7 days,
`except in one patient (M49) (see also Fig. 2). In this
`patient dextran antibodies were even higher at 1 month
`and in two of the other paitents with elevated antibody
`titres prior to the infusion, antibodies were detectable
`again at 1 month (Table 1). Dextran antibodies were
`
`Reciprocal
`Titre of
`Dextran
`Antibodies
`
`1024-1
`
`258-
`
`64-
`
`16-
`
`4-
`
`r
`
`Nona
`
`3 -8 years
`previously
`Iron dextran therapy in the past
`
`Fig. 2. Reciprocal titres of dextran antibodies in the plasma of 20
`dialysed patients before the first infusion of a course of iron dextran
`infusions: • patient with circulating immune complexes; O, •
`antibodies present 1 week after the first infusion; * patient who
`developed an inflammatory reaction after the second infusion. The
`arrows indicate the three patients reporting flu-like symptoms 48 h
`after the first infusion.
`
`measured again 1 month after the ninth infusion in 13
`patients. The percentage with dextran antibodies
`present was similar 1 month after the ninth infusion (7 of
`13 patients) to that found before the first infusion (9 of
`20 patients), but the patients differed, with antibodies
`present in three with no previous antibodies and absent
`in two with previous antibodies.
`Detailed questionnaires about symptoms were indi-
`vidually discussed with all patients in the study and this
`elicited three descriptions of mild muscle aches or flu-
`like symptoms occurring 24-48 h after the iron dextran
`infusion. The patients describing such symptoms are
`indicated in Fig. 2.
`
`Arthropathy Incident
`
`A transient inflammatory arthropathy developed, not
`during this investigation, but following the routine
`second infusion given to patient F44 in this study. On
`notification of the reaction, the opportunity was taken
`to measure our investigative parameters as the reaction
`waned. Before and after the first infusion her results had
`been unremarkable - circulating immune complexes
`remained normal (<10 ///ml), percentage conversion of
`complement remained nil, and the only feature of note
`was the high dextran antibody reciprocal titre (64) prior
`to the first infusion. One month after her first infusion,
`when the second (clinically routine) infusion became
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`38
`due, small concentrations of antibody (reciprocal titre
`of 4) were detectable again. Around 30 h after the
`second infusion the patient developed hot, painful
`joints, developing along the left side and then the right,
`which lasted for 24-36 h and then began to wane,
`disappearing by the 4th day after the infusion. Samples
`taken from 48 h to 35 days after the second infusion
`showed no dextran antibodies, no complement conver-
`sion, and no change in circulating immune complexes.
`After 9 months, the patient volunteered to have a
`third infusion. Only 200 mg was infused and a similar
`inflammatory
`reaction occurred, although
`it was
`reduced in extent. Again, there was no change in
`immune complexes or complement conversion, the low
`antibody titre disappeared and was detectable again 3
`months later.
`
`Discussion
`
`Plasma Iron Concentrations
`
`Increased circulating iron after the iron dextran infusion
`was transient, with baseline levels restored by 7 days in
`40% of the patients. In the absence of discernible ill-
`effects the circulating iron was apparently complexed to
`dextran during the time the total iron concentrations
`exceeded the saturation capacity of transferrin. The
`patient with the delayed adverse reaction to her second
`infusion (F44) did not differ from the others in her peak
`total iron or in her rate of decrease in iron concentra-
`tions. There was no indication that the presence or
`absence of dextran antibodies before the infusion had
`any effect on the rate of decrease of iron concentrations.
`
`Dextran Antibodies and Reactions
`
`Although oral dextrans are poorly absorbed, circulating
`dextran antibodies can be formed in response to the
`presence of small quantities of dietary or bacterially
`produced polysaccharides irrespective of previous par-
`enteral dextran therapy [13]. In our study dextran
`antibodies were present in 45-55% of the patients. In
`Sweden and Germany, prevalence of circulating dex-
`tran antibodies is between 63% and 74% [14]. It has
`been suggested that those with high circulating dextran
`antibodies may be more liable to severe adverse
`reactions to dextran infusions given for plasma volume
`expansion [13]. Severe anaphylactoid-type adverse
`reactions to dextrans, in the first few minutes after
`receiving the infusion, have been described as IgG-
`mediated immune complex reactions (type III) [15, 16]
`and require emergency treatment with adrenaline and/
`or corttcosteroids. Hedin et al [14] have pointed out that
`
`L. W. Fleming et al
`
`if increased titres of dextran antibodies were the sole
`trigger factor for dextran-induced adverse reactions, the
`incidence of reactions would be 1000 times greater than
`that seen. This suggests the presence of some additional
`trigger factor(s), or the absence of a protective factor(s),
`before an adverse reaction can occur.
`
`Iron Dextran and Reactions
`
`Mild feverish reactions following parenteral administra-
`tion have been described on the data sheets of many
`preparations, appear to be non-specific, and do not
`recur on repeated administration. The three reports of
`mild symptoms in this study were considered to fall into
`this category. Two of the three had no dextran anti-
`bodies, and all continued with subsequent infusions,
`without any recurrence of symptoms. The majority of
`reported definite reactions to intravenous iron dextran
`in patients without renal failure appear to be of the
`delayed type [4, 6, 9]. The most common adverse
`feature is arthralgia of varying degree, as seen in our
`patient. Patients with rheumatoid arthritis seem particu-
`larly prone to an infusion-related episodic exacerbation
`of synovial pain and inflammation [5] but our patient
`had not complained of any joint pains prior to this
`episode. The mechanism of the delayed reaction involv-
`ing arthropathy is unclear. In most reports arthropathy
`has developed a day or two after the first exposure to
`parenteral iron dextran, in contrast to our patient in
`whom the second exposure precipitated the reaction,
`suggesting hypersensitivity.
`Arthropathy after iron dextran infusions in rheuma-
`toid arthritis patients has been associated pathogeneti-
`cally with lipid peroxidation disturbances induced by
`the iron component of the iron dextran [5]. This
`pathogenesis would not involve immune complexes. We
`could not detect any involvement of immune complexes
`other than the disappearance of dextran antibodies, if
`present, after an iron dextran infusion in all patients.
`Baseline dextran antibodies in our patient were no
`higher than in the others without adverse reactions.
`Whatever the source of those dextran antibodies, they
`cross-reacted with the dextran of the iron dextran in
`everyone.
`There was no indication in our study, therefore, that
`the prior presence of antibodies, even at increased
`concentrations, predisposed to reactions to iron dex-
`tran. No patients developed symptoms of an immediate
`reaction as described [15] for dextran infusions. This is
`seen very rarely with iron dextran preparations [4, 5, 8,
`10]. None of the published reports of delayed or
`immediate reactions refers to patients on haemodialy-
`sis, although the manufacturer has received a few
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`39
`
`References
`
`1. Stewart WK, Fleming LW, Shepherd AMM. Haemoglobin and
`serum iron responses to periodic intravenous iror.-dextran
`infusions during maintenance haemodialysis. Sephron 1976; 17:
`121-130
`2. Fleming LW, Saleem AKN. Goodall HB. Stewart WK. Bone
`marrow iron and plasma ferritin in dialysed patients given
`intravenous iron-dextran. Clin Lab Haematol 1984; 6: 23-32
`3. MacDougaU IC, Hutton RD, Cavill I, Coles GA, Williams JD.
`Poor response to treatment of renal anaemia with erythropoietin
`corrected by iron given intravenously. Br MedJ 1989; 299: 157—
`158
`4. Hamstra RD, Block MH, Schocket AL. Intravenous iron-dextran
`in clincial medicine. JAMA 1980; 243: 1726-1731
`5. Blake DR, Lunec J, Ahern M, Ring EFJ, Broadfield J, Gutter-
`idge JMC. Effect of intravenous iron-dextran on rheumatoid
`synovitis. Ann Rheum Dis 1985; 44: 183-188
`6. Woodman J, Shaw RJ, Shipman AJ, Edwards AM. A surveil-
`lance programme on a long-established product. Imferon (iron-
`dextran BP). Pharmaceutical Med 1987; 1: 289-296
`7. Altman LC, Petersen PE. Successful prevention of an anaphylac-
`toid reaction to iron-dextran. Ann Intern Med 1988: 346-347
`8. Auerbach M, Witt D, Toler W, Frerstein M, Lerner RG, Ballard
`H. Clinical use of the total dose intravenous infusion of iron-
`dextran. J Lab Clin Med 1988; 111: 566-570
`9. Kaisi M, Ngwalle EWK, Runyoro DE, Rogers J. Evaluation of
`tolerance of and response to iron-dextran (ImfeonR) adminis-
`tered by total dose infusion to pregnant women with iron
`deficiency anaemia. Int J Gynaecol Obstet 1988; 26: 235-243
`10. Sweeney MJ, Klotz LR, Kay CS, Steinfield LA, Klotz SD.
`Imferon hypersensitivity reaction - demonstration of a high
`molecular weight dextran specific IgE. Ann Allergy 1980; 44: 47-
`48
`11. Casali P, Bossus A, Carpentier NA, Lambert PH. Solid-phase
`enzyme immunoassay or radioimmunoassay for the detection of
`immune complexes based on their recognition by conglutin :
`conglutinin-binding test. A comparative study with l2!I-labelled
`Clq binding and Raji cell RIA tests. Clin Exp Immunol 1977; 29:
`342-354
`12. International Committee for Standardisation in Haematology
`(Iron Panel). Recommendations for measurements of serum iron
`in human blood. Br J Haematol 1978; 38: 291-294
`13. Editorial. Users reminded about adverse reactions to dextran.
`FDA Drug Bull 1983; 13: 23-24
`14. Hedin H, Richter W, Ring J. Dextran-induced anaphylactoid
`reactions in man. Im Arch Allergy Appl Immunol 1976; 52: 145—
`159
`15. Ljungstrom KG, Renck H, Strandberg K, Hedin H, Richter W,
`Widerlov E. Adverse reactions to dextran in Sweden 1970-1979.
`Ada Chir Scand 1983; 149: 253-262
`16. Ljungstrom KG, Revenas B, Smedegard G, Hedin H, Richter W,
`Saldeen T. Histopathological lung changes in immune complex
`mediated anaphylactic shock in humans elicited by dextran.
`Forensic Sci Inl 1988; 38: 251-258
`17. Van Wyck DB. Iron management during recombinant human
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`
`Received for publication 9.10.90
`Accepted in revised form 12.5.91
`
`Immune Complexes and Iron Dextran
`reports. Our own total experience of iron dextran
`infusions between 1972 and 1990 amounts to 1433
`weekly infusions providing 200 mg iron and 772 monthly
`infusions providing 500 or 600 ir.g iron given to 113
`patients on dialysis treatment. Apart from mild feverish
`symptoms (<10 instances), the only adverse reaction
`seen in 18 years has been the single arthropathy episode
`described above, which is a much lower incidence than
`that reported for iron dextran given to iron-deficient
`patients with anaemia of other aetiologies.
`
`Conclusions
`
`This investigation demonstrates that infusions of iron
`dextran providing 600 mg of elemental iron in patients
`on dialysis do not produce measurable changes in
`circulating immune complexes or conversion of comple-
`ment in either the absence or presence of a delayed
`adverse reaction. Further, the presence prior to the
`infusion of antibodies to dextran was not associated with
`adverse reactions and there was no increase in the
`prevalence of dextran antibodies in treated patients
`after a 9-month course of iron dextran infusions. The
`presence of circulating antibodies, therefore, does not
`preclude treatment with iron dextran.
`Van Wyck [17] recommends the use of oral iron
`during erythropoietin therapy and advises that intraven-
`ous iron should only be used when oral iron is failing or
`a more rapid response is required. However, one study
`of iron incorporation into red cells has demonstrated
`that intravenous iron is better utilised than oral iron
`[18]. Since erythropoietin costs are so high there is
`justification for using intravenous iron in many if not all
`patients,
`in order
`to utilise erythropoietin
`fully.
`Adoption of this regimen may be inhibited by fears of
`adverse reactions or of iron overload. It is hoped that
`the information provided in this paper will go some way
`towards alleviating doubts about the use of iron dextran
`in dialysed patients.
`
`Acknowledgements. The authors acknowledge with thanks the expert
`technical assistance of Mr G. Shepherd and the financial and technical
`support of Fisons Pharmaceuticals (UK).
`
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