the renal consult
`
`http://www.kidney-international.org
`
`© 2006 International Society of Nephrology
`
`Refractory anemia in a patient with allergy
`to intravenous iron drugs
`S Fishbane 1
`
`1Winthrop University Hospital, Mineola, New York, USA
`
`CASE PRESENTATION
`A 48-year-old woman was admitted to our dialysis
`center for hemodialysis treatments. She had been on
`hemodialysis for 2 years at another facility, with end-stage
`renal disease believed to be due to diabetes mellitus.
`The past medical history was also remarkable for
`atherosclerotic vascular disease with coronary angioplasty
`and stenting performed the previous year. In addition, the
`patient had hypothyroidism, hypertension, and peripheral
`neuropathy. Medications included oral administration of
`losartan, metoprolol, aspirin, and ferrous sulfate. Insulin
`was self-administered and the dialysis facility treated with
`intravenous epoetin alfa and paricalcitol. There was no
`history of heavy alcohol consumption, smoking, or drug
`use. Review of systems was notable for occasional
`dyspnea, particularly with ambulation, fatigue and
`daytime sleepiness, constipation, and intermittent pain in
`both feet. Physical exam revealed a slightly obese woman
`with blood pressure 148/71 mm Hg, pulse 68, normal
`head, ears, eyes, nose, throat, and neck, lungs clear, heart
`with regular rhythm and no extra sounds, abdomen soft
`with normal bowel sounds, rectal exam was deferred,
`extremities had trace peripheral edema, and pulses were
`marginally diminished.
`A major focus of the patient's dialysis evaluation was
`on her anemia treatment. She had been persistently
`hyporesponsive to epoetin, with hemoglobin rarely
`above 11 g/dl (target range 11-12 g/dl} (Table 1 ); most
`measurements in the previous year had been between
`9.5 and 10.5 g/dl. The weekly epoetin alfa dose had
`progressively been increased; most recently, it was
`54000 U. Iron testing had consistently indicated moderate
`to severe iron deficiency. The most recent test had been
`performed 5-6 weeks earlier, transferrin saturation was
`
`Correspondence: Dr S Fishbane, Winthrop University Hospital, 200 Old
`Country Road Suite 135, Mineola, New York 11501, USA.
`E-mail: sfishbane@metrorenal.com
`
`Kidney International (2006) 69, 1910-1913. doi:10.1038/sj.ki.5001536;
`published online 19 April 2006
`
`Received 26 January 2006; revised 23 February 2006; accepted 28
`February 2006; published online 19 April 2006
`
`6.2% (target > 20%), serum ferritin was 38 ng/ml (target
`> 100 ng/ml), and reticulocyte hemoglobin content was
`26.2 pg (target > 29 pg). Other potential causes of epoetin
`alfa resistance had been studied, C-reactive protein (CRP)
`was normal, parathyroid hormone (PTH) levels had varied,
`and were never severely elevated. There was no obvious
`infection or inflammation present, serum levels of folic
`acid and vitamin B12 were normal, and no evidence of
`hemolysis was found.
`The patient's iron deficiency had been treated in the
`past with intravenous iron dextran. However, during an
`administration 2 years prior she experienced severe back
`pain and hypotension and had a sensation of choking.
`Systolic blood pressure fell by approximately 55 mm Hg,
`and resuscitative treatments were administered. The
`patient was hospitalized briefly, but no long-term
`disability resulted. Because of persistent iron deficiency,
`the patient's physicians decided to reattempt intravenous
`iron treatment 4 months later. However, on the first
`administration of 100 mg iron sucrose, systolic blood
`pressure fell from 144 to 95 mm Hg over 30 min and the
`patient noted the presence of a sensation of unpleasant
`warmth and flushing. The dialysis treatment was
`continued and symptoms resolved. It was decided that the
`patient was likely allergic to all intravenous iron, and that
`treatment with oral iron should be used instead. Ferrous
`sulfate, 325 mg, was prescribed to be taken thrice daily.
`The most recent laboratory tests were notable for
`hemoglobin of 9.1 g/dl while treated with 18 000 U of
`epoetin alfa intravenously thrice weekly. Fatigue and
`dyspnea remained persistent symptoms. All readily
`definable causes for the patient's resistant anemia had
`been explored and excluded, except for iron deficiency.
`An extensive evaluation for occult bleeding as a source of
`iron deficiency yielded no diagnosis. Consequently, the
`clinicians were faced with difficult decisions as to the
`further management of her iron deficiency anemia.
`
`1910
`
`Kidney International (2006) 69, 1910-1913
`
`

`

`S Fishbane et al.: Allergy to intravenous iron drugs
`
`the renal consult
`
`Table 1 I
`
`Hemoglobin
`(g/dl)
`
`Erythropoietin Serum ferritin
`dose (u/w)
`(mg/di)
`
`Transferrin
`saturation
`(%)
`
`10.3
`11 .1
`10.2
`9.9
`9.4
`10
`10.5
`10.1
`9.9
`9.6
`10.2
`
`36000
`36000
`42000
`42000
`48000
`48000
`48000
`48000
`48000
`48000
`54000
`
`66
`
`50
`
`21
`
`38
`
`10.2
`
`8.5
`
`14.7
`
`6.2
`
`Date
`
`11/03
`12/03
`1/04
`2/04
`3/04
`4/04
`5/04
`6/04
`7/04
`8/04
`9/04
`
`DISCUSSION
`Iron deficiency occurs frequently in hemodialysis patients.
`is excessive blood loss related to
`The primary reason
`retention in dialysis lines and filters, blood testing, and
`surgical and accidental bleeding. 1 In normal adults, less than
`1-2 mg of iron is lost from the body per day, a fraction of the
`body's iron stores. In contrast, hemodialysis patients may lose
`3-10 mg/ day. Furthermore, during recombinant human
`erythropoietin therapy iron demand increases in parallel
`with accelerated erythropoiesis. 1 As a result of reduced iron
`supply and increased demand, the majority of hemodialysis
`patients require treatment with intravenous iron.
`The nephrologist caring for the patient considered a
`number of therapeutic options for refractory anemia owing
`to iron deficiency in a patient with hypersensitivity to
`intravenous iron treatment. The therapeutic goals would be
`to improve the hemoglobin level and reduce symptoms
`referable
`to anemia. Four options were weighed
`(1)
`continued progressive increase in epoetin dose, (2) transfu(cid:173)
`sion of erythrocytes, (3) intensified oral iron treatment, and
`( 4) challenge with the only form of intravenous iron that she
`had not been previously
`treated with, sodium ferric
`gluconate.
`increase in epoetin dosing would be a
`Progressive
`potentially useful,
`if somewhat
`inelegant approach
`to
`refractory anemia owing to severe iron deficiency. The
`patient was already receiving 54 000 U of epoetin alfa weekly,
`a very high dose. Whether further increases in dose in the
`setting of severe iron deficiency would lead to an improved
`hemoglobin level is unclear. It is certainly an expensive
`approach; the weekly cost at 54 000 U was probably already
`over $600. In this case, the clinicians did decide to increase
`the epoetin dose, but a 22% increment led to only a small and
`transient increase in hemoglobin level.
`A decision was made to attempt intensified oral iron
`therapy. Previous studies,
`including
`three randomized
`controlled trials have not demonstrated efficacy for oral iron
`treatment in hemodialysis patients. z-4 However, like many
`studies, these reports provided little data as to response
`heterogeneity. Therefore,
`the possibility could not be
`
`excluded that a small subgroup of patients might exist who
`could benefit from treatment. With this reasoning, a trial of
`closely monitored oral iron therapy was initiated. The patient
`was given a 3-month course of oral iron with supplemental
`ascorbic acid to improve iron absorption, with careful
`attention to education and compliance. Ferrous sulfate was
`prescribed, 325 mg four times daily. Unfortunately, it did not
`result in improvement in iron indices or hemoglobin level.
`Whether to challenge with intravenous sodium ferric
`gluconate ( or rechallenge with either of the two iron agents
`previously used) was considered. Because of the previous
`hypotensive hypersensitivity reactions, the decision hinged
`on balancing the potential benefit of improved hemoglobin
`and a reduction in fatigue and dyspnea against the risk of
`another hypersensitivity reaction. In the United States, three
`forms of intravenous iron are available, iron dextran, sodium
`ferric gluconate, and iron sucrose. While any of these drugs
`can cause immediate hypersensitivity, the reactions have been
`most extensively reported and studied with iron dextran.
`Iron dextran is composed of a dense core of iron surrounded
`by dextran polymers of various size and branch structure.
`The dextran component's first clinical use was as an injectable
`colloid solution for expansion of intravascular volume. While
`clinically effective, severe anaphylactic reactions were occa(cid:173)
`sionally noted.5 With the inclusion of dextran in the iron
`dextran compound, anaphylactic reactions continued to be
`observed.
`The etiology of intravenous iron-associated hypersensiti(cid:173)
`vity is incompletely understood. Two pathogenic pathways
`appear to play a role, with the relative contribution varying in
`different patients and with different intravenous iron drugs.
`The first is an anaphylactoid-type reaction, with mast cell
`release of histamine and other mediators. This process has
`been difficult to document as histamine release tends to be
`transient, short-lived, and difficult to measure. In contrast, a
`more stable molecule released from mast cells, tryptase, can
`be measured in serum and is a useful marker of recent
`anaphylaxis.6 In one report, two cases of apparent intrave(cid:173)
`nous iron allergy were confirmed as mast cell mediated by a
`doubling of serum tryptase levels.7
`A second mechanism for intravenous iron-associated
`hypersensitivity is increased vascular reactivity owing to the
`release of free, unbound iron into the bloodstream. After
`intravenous injection of iron, an ideal iron drug would tightly
`bind iron, carrying it directly to cells of the reticuloendo(cid:173)
`thelial system for processing. In reality, iron drugs tend to be
`somewhat 'leaky' with some of their iron load being released
`immediately into the circulation. 8'9 If there are adequate
`amounts of unbound transferrin in circulation, then the
`released iron is quickly buffered. Occasionally, however, the
`amount of transferrin may be insufficient, and the excess iron
`circulates as bioactive, free labile iron.9- 11 In this state, iron
`increases oxidative stress, and may cause hypotension and
`other typical symptoms of hypersensitivity.
`A dichotomous view of intravenous iron hypersensitivity
`is that iron dextran reactions are mast cell mediated, owing to
`
`Kidney International (2006) 69, 1910-1913
`
`1911
`
`

`

`the renal consult
`
`S Fishbane et al.: Allergy to intravenous iron drugs
`
`allergy to dextran, whereas non-dextran iron reactions are
`caused by free labile iron. The argument for iron dextran is
`driven by the large number of early reports of dextran(cid:173)
`associated anaphylaxis.5 In fact, the observation that the rate
`of hypersensitivity is high both for dextran colloid and iron
`dextran suggests that the common component, dextran,
`might be the antigenic link. However, if allergy to dextran
`was the only etiologic factor, then hypersensitivity should
`not occur with non-dextran forms of intravenous iron.
`This is not the case, reactions do occur with the non-dextran
`iron drugs, but they are generally less frequent and of a
`milder intensity than with iron dextran. However, the similar
`clinical manifestations (hypotension, flushing) and the
`existence of at least occasional cross-reactivity between iron
`dextran and non-dextran irons suggest that there is some
`intertwining of causal pathways. A more complete under(cid:173)
`standing of these processes could serve as a foundation for
`design of iron drugs that are even safer than the current
`generation of agents.
`Most studies of hypersensitivity reactions with intra(cid:173)
`venous iron drugs have used data derived from chart or
`database review. This methodology is probably far from
`optimal for determining the actual rate of reactions or for
`comparisons between different
`iron drugs. The most
`is
`that symptoms of iron
`important
`limiting factor
`hypersensitivity reactions overlap greatly with intradialytic
`symptoms that occur frequently during hemodialysis treat(cid:173)
`ments. This makes retrospective determination of causality
`next to impossible. Database reviews are further limited by
`the infrequency of reactions and substantial and inconsistent
`under reporting. An ideal study would involve direct
`observation of patients after injection with iron. One
`published study, authored by Michael et al., included over
`2500 hemodialysis patients, with direct, blinded, observation,
`comparing reaction rates between sodium ferric gluconate
`and placebo. One severe reaction (0.04%) with sodium ferric
`gluconate was observed, a rate not statistically greater than
`that for placebo.12 Other studies have relied on review of
`patient charts or analyses of databases. Fishbane et al. 13 and
`Hamstra et al.14 found the rate of severe reaction with iron
`dextran to be 0.6--0.7%. Walters and Van Wyck15 studied the
`database of a large dialysis provider to identify severe
`episodes of iron-<lextran-induced anaphylaxis. They found
`seven events out of 48 509 patients treated, all occurring with
`the first dose of drug. Bailie et al. 16 used the US Food and
`Drug Administration's Freedom of Information (FOi)
`surveillance database to estimate rates of severe reactions
`with iron drugs. The rate of reactions was found to be higher
`with iron dextran than the non-dextran forms of iron,
`although non-dextran irons did have rare severe reactions
`associated with their use. Chertow et al. 17 used similar
`methodology, and found the rate oflife-threatening reactions
`to be less than 1 per million for non-dextran iron drugs and
`3.3-11.3 per million for iron dextrans. The low rate of
`reactions reported in this and other database reviews,
`compared to the almost thousand fold greater incidence
`
`with chart reviews, undoubtedly reflects the lack of sensitivity
`of indirect data sources.
`The patient in this report had previously experienced
`hypersensitivity reactions with iron dextran and iron sucrose.
`In deciding on whether to treat this patient with yet another
`form of intravenous iron, knowledge about cross-reactivity of
`hypersensitivity between the different iron drugs is critical. In
`the study noted above by Michael et al. 143 of enrolled
`subjects had a previous history of iron dextran allergy. These
`patients received single, blinded doses of sodium ferric
`gluconate and placebo. Treatment with sodium ferric
`gluconate resulted in three suspected allergic reactions
`(2.1%) compared to one (0.7%) with placebo. Patients with
`history of iron dextran allergy had a seven fold increased rate
`of reactions (all types, not just suspected allergy) to both
`sodium ferric gluconate and placebo. 18 These results indicate
`a relatively low rate of cross-reactivity between iron dextran
`and sodium ferric gluconate, and a degree of idiosyncrasy
`that defies easy explanation. It is unclear why even placebo
`exposure resulted in such a high rate of reactions in patients
`previously sensitive to iron dextran. Cross-reactivity has also
`been studied with iron sucrose. Van Wyck et al.19 studied iron
`sucrose in 23 patients with previous reactions to iron
`dextran, and found no serious reactions.
`It could reasonably be concluded that non-dextran iron
`drugs can be administered safely to most patients previously
`sensitive to iron dextran, particularly when the reaction was
`not severe. However, when a patient has experienced a severe
`reaction with iron dextran, rechallenge with iron sucrose or
`sodium ferric gluconate must be undertaken with particular
`care. The likelihood of a reaction may be low, but the
`potential severity of a reaction mandates that the expected
`benefits must be substantial and clearly defined. In the case
`under Discussion, the direct benefit to the patient would be
`amelioration of the fatigue and dyspnea that she had
`experienced. These symptoms had restricted the patient's
`activities, and degraded her quality of life. Therefore,
`assuming a certain amount of treatment-associated risk
`might have been acceptable.
`One last option to consider before intravenous iron
`treatment was that of blood transfusion. Blood transfusion
`would effectively increase hemoglobin level and supply some
`iron, but with minor risks for immune activation and
`infection. Each ml of packed red cells contains 1 mg of iron,
`in a typical unit approximately 180 mg of iron would be
`supplied.
`
`FOLLOW-UP
`The nephrologist discussed the relative merits and risks of
`transfusion and intravenous iron with the patient. A decision
`was jointly made to treat with blood transfusions as needed
`to maintain hemoglobin > 11 g/dl. It was agreed that if the
`transfusion requirements were persistent, that rechallenge
`with intravenous iron would be reconsidered. The patient
`received two units of packed red cells at this point, and was
`transfused twice more in the ensuing 7 months (6 U total).
`
`1912
`
`Kidney International (2006) 69, 1910-1913
`
`

`

`S Fishbane et al.: Allergy to intravenous iron drugs
`
`the renal consult
`
`Most hemoglobin measures were greater than 10.5 g/dl, and
`the patient noted a significant reduction in fatigue and
`dyspnea. Interestingly, in the subsequent 5 months, no
`transfusions were required.
`In conclusion, this case was notable for highlighting
`several clinical decision points that may arise during epoetin
`therapy. Treatment hyporesponse requires an evaluation for a
`number of potential causes that can degrade responsiveness,
`rather than continually increasing the epoetin dose. In this
`case, while the cause of diminished response was a common
`one, iron deficiency, the treatment options were limited by
`sensitivity to intravenous iron. As in any area of medicine,
`when the remaining treatment options are less than optimal,
`shared decision-making yields the greatest understanding
`and outcomes. The decision to rely on blood transfusion to
`supplement epoetin treatment was something of a throwback
`to the pre-erythropoietin era. While certainly not optimal,
`the results in this case were satisfactory.
`
`REFERENCES
`1. Van Wyck DB. Iron deficiency in patients with dialysis-associated anemia
`during erythropoietin replacement therapy: strategies for assessment
`and management. Semin Nephrol 1989; 9(Suppl 2): 21-24.
`2. Markowitz GS, Kahn GA, Feingold RE et al. An evaluation of the
`effectiveness of oral iron therapy in hemodialysis patients
`receiving recombinant human erythropoietin. Clin Nephrol 1997; 48:
`3~0.
`3. Fudin R, Jaichenko J, Shostak A et al. Correction of uremic iron deficiency
`anemia in hemodialyzed patients: a prospective study. Nephron 1998; 79:
`299-305.
`4. Macdougall IC, Tucker B, Thompson J et al. A randomized controlled
`study of iron supplementation in patients treated with erythropoietin.
`Kidney Int 1996; 50: 1694-1699.
`5. Bailey G, Strub RL, Klein RC, Salvaggio J. Dextran-induced anaphylaxis.
`JAMA 1967; 200: 889-891 .
`
`6. Schwartz LB, Yunginger JW, Miller J et al. Time course of appearance and
`disappearance of human mast cell tryptase in the circulation after
`anaphylaxis. J Clin Invest 1989; 83: 1551-1555.
`7. Coyne DW, Adkinson NF, Nissenson AR, et al., Ferlecit Investigators.
`Sodium ferric gluconate complex in hemodialysis patients. II. Adverse
`reactions in iron dextran-sensitive and dextran-tolerant patients. Kidney
`Int 2003; 63: 217-224.
`8. Kooistra MP, Kersting 5, Gosriwatana I et al. Nontransferrin-bound iron in
`the plasma of haemodialysis patients after intravenous iron saccharate
`infusion. Eur J Clin Invest 2002; 32(Suppl 1 ): 36-41 .
`9. Leehey DJ, Palubiak DJ, Chebrolu 5, Agarwal R. Sodium ferric gluconate
`causes oxidative stress but not acute renal injury in patients with chronic
`kidney disease: a pilot study. Nephrol Dial Transplant 2005; 20: 135-140.
`10. Rooyakkers TM, Stroes ES, Kooistra MP et al. Ferric saccharate induces
`oxygen radical stress and endothelial dysfunction in vivo. Eur J Clin Invest
`2002; 32(Suppl 1): 9-16.
`11 . Lim PS, Wei YH, Yu YL, Kho B. Enhanced oxidative stress in haemodialysis
`patients receiving intravenous iron therapy. Nephrol Dial Transplant 1999;
`14: 2680-2687.
`12. Michael B, Coyne DW, Fish bane S, et al., Ferrlecit Publication Committee.
`Sodium ferric gluconate complex in hemodialysis patients: adverse
`reactions compared to placebo and iron dextran. Kidney Int 2002; 61 :
`1830-1839.
`13. Fishbane 5, Ungureanu VD, Maesaka JK et al. The safety of intravenous
`iron dextran in hemodialysis patients. Am J Kidney Dis 1996; 28: 529-534.
`14. Hamstra RD, Block MH, Schocket AL. Intravenous iron dextran in clinical
`medicine. JAMA 1980; 243: 1726-1731.
`15. Walters BA, Van Wyck DB. Benchmarking iron dextran sensitivity:
`reactions requiring resuscitative medication in incident and prevalent
`patients. Nephrol Dial Transplant 2005; 20: 1438-1442.
`16. Bailie GR, Clark JA, Lane CE, Lane PL. Hypersensitivity reactions and
`deaths associated with intravenous iron preparations. Nephrol Dial
`Transplant 2005; 20: 1443-1449.
`17. Chertow GM, Mason PD, Vaage-Nilsen 0, Ahlmen J. Update on adverse
`drug events associated with parenteral iron. Nephrol Dial Transplant 2006;
`21 : 378-382.
`18. Coyne DW, Adkinson NF, Nissenson AR, et ol., Ferlecit Investigators.
`Sodium ferric gluconate complex in hemodialysis patients. II. Adverse
`reactions in iron dextran-sensitive and dextran-tolerant patients. Kidney
`Int 2003; 63: 217-224.
`19. Van Wyck DB, Cavallo G, Spinowitz BS et al. Safety and efficacy of iron
`sucrose in patients sensitive to iron dextran: North American clinical trial.
`Am J Kidney Dis 2000; 36: 88-97.
`
`Kidney International (2006) 69, 1910-1913
`
`1913
`
`