Original Paper
`
`Nephron 2002;92:316–323
`
`Accepted: December 12, 2001
`
`Experience with the Use of an Iron Polymaltose
`(Dextrin) Complex Given by Single Total Dose
`Infusion to Stable Chronic Haemodialysis
`Patients
`
`Roal van Zyl-Smit Janet A. Halkett
`
`Department of Medicine, University of Cape Town, South Africa
`
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`Key Words
`Intravenous iron W Total dose infusion W Haemodialysis W
`Iron polymaltose W Iron dextrin
`
`Abstract
`Background: Many studies of anaemia in patients on
`chronic haemodialysis have noted a high prevalence of
`iron deficiency despite oral iron supplementation. Our
`study examined the effect of intravenous iron given as
`bolus replacement. As the majority of these patients
`were not receiving concurrent recombinant human
`erythropoietin (rhEPO) it allowed an analysis of the safe-
`ty and efficacy of intravenous iron as a single agent.
`Methods: All patients with a haemoglobin level of less
`than 10 g/dl and considered iron deficient by the finding
`of a percentage transferrin saturation of less than 20%
`were given intravenous iron in the form of iron polymal-
`tose (dextrin) by total dose infusion (TDI). The dose was
`calculated from tables supplied by the manufacturers.
`Patients with serum ferritin levels in excess of 225 ng/ml
`were excluded. Results: In our unit, 62 out of 80 (77%)
`patients were considered iron deficient and received IV
`iron. Ten (10%) were considered to be in iron balance
`
`and 8 (10%) had biochemistry suggesting iron overload.
`None of the patients receiving iron experienced any
`adverse reactions. At three months a rise in haemoglo-
`bin level of at least 1 g/dl was noted in 53% of patients.
`The response was less in the remainder, but only 2
`showed no response. Conclusions: Low levels of iron
`deficiency are often unrecognized in chronic haemodial-
`ysis patients on conventional therapy including oral iron
`supplementation. In such patients, the use of total dose
`infusion of iron polymaltose (dextrin) is a safe and effec-
`tive method of raising haemoglobin levels. Substantial
`improvements may be achieved without the concurrent
`use of rhEPO.
`
`Copyright © 2002 S. Karger AG, Basel
`
`Introduction
`
`Anaemia is almost always present in patients with
`severe chronic renal failure [1]. Its assessment and man-
`agement becomes more complex once chronic haemodial-
`ysis (HD) is initiated. Factors such as inadequate dialysis,
`defective utilization of iron sequestered in body iron
`stores, poor absorption of dietary iron, gastrointestinal
`
`ABC
`Fax + 41 61 306 12 34
`E-Mail karger@karger.ch
`www.karger.com
`
`© 2002 S. Karger AG, Basel
`0028–2766/02/0922–0316$18.50/0
`
`Accessible online at:
`www.karger.com/journals/nef
`
`R. van Zyl-Smit
`Renal Unit E13
`Groote Schuur Hospital
`Observatory, 7935 (South Africa)
`Tel. +27 21 448 2349, Fax +27 21 404 3318, E-Mail vzsmit@curie.uct.ac.za
`
`IPR2019-01142
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`Petitioner Ex. 1004 - Page 1
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`

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`blood and dialysis-related blood loss [2, 3], aluminum tox-
`icity [4], bone marrow fibrosis, vitamin and iron deficien-
`cy have been implicated.
`With inadequate dialysis, anaemia requiring repeated
`blood transfusions may develop and in the past has
`resulted in iron overload in up to 25% of cases [1]. With
`modern dialysis and adequate attention to all reversible
`causes of anaemia, patients on chronic HD should have
`haemoglobin levels of at least 8 g/dl and with the addition-
`al use of recombinant erythropoietin (rhEPO), normal
`haemoglobin levels may be obtained [5]. With intensive
`rhEPO therapy, insufficient iron both in the form of inad-
`equate stores or ‘functional iron deficiency’ may become
`the major limiting factor in achieving optimal haemoglo-
`bin levels [6]. With functional iron deficiency biologic
`availability of iron is reduced despite the presence of ade-
`quate storage iron. It may be demonstrated clinically by a
`response to IV iron in some patients with ferritin levels as
`high as 1,000 ng/ml [5, 6].
`In our unit the use of rhEPO is severely limited
`because of financial restrictions. We were therefore able
`to examine the response to and safety of total dose iron
`infusion of an iron dextrin preparation given to a group of
`iron deficient patients not receiving concurrent rhEPO.
`
`Patients and Methods
`
`Iron deficiency was defined by transferrin (Tf) saturation levels of
`less than 20%, in the presence of a serum ferritin level of less than
`225 ng/ml. The following were routinely measured: serum iron (SI),
`total iron binding capacity (TIBC), mean cell volume (MCV), mean
`cell haemoglobin (MCH), plasma albumin, calcium, inorganic phos-
`phate, alkaline phosphatase and, if hyperparathyroidism was sus-
`pected, serum parathyroid (PTH) levels. As a measure of dialysis effi-
`cacy, a urea reduction ratio (URR) was done and expressed as a per-
`centage. All blood samples were taken immediately before dialysis.
`
`Patients
`Of 80 patients, 62 (77%) were defined as being ‘iron deficient’
`with the remainder having either normal or elevated iron levels. The
`62 iron deficient patients were given intravenous iron by TDI and
`included in the study on efficacy and safety. During the study, 26
`patients were excluded from the efficacy analysis for the following
`reasons: patients receiving renal transplants (4); blood transfusions
`given during follow-up (6); medical dialysis problems (4); rhEPO
`commenced as part of another study (6); death (1); incomplete data
`(2) and iron not given according to the protocol (3). None of the
`patients entered into the safety analysis were excluded.
`The response to iron was studied in 36 patients including two
`patients who received rhEPO at a constant dose for the duration of
`the study, called the study group (SG). Patients who experienced a
`rise in haemoglobin, by the end of the study period, in excess of 1 g/dl
`were designated as the responder group (RG) and the remainder as
`
`the non-responder group (NRG). The SG consisted of 12 males and
`24 females with a mean age of 40 years (range 20–61 years), mean
`duration on dialysis before the study was 27 months (range 1–127
`months), mean number of units of blood given before the study was 6
`(range 0–43 units), mean urea reduction ratio for the group was 67%
`(range 48–84%), mean serum albumin was 41 g/l (range 32–48 g/l),
`mean serum alkaline phosphatase 126 u/l (range 37–993 u/l) (normal
`range 30–115 u/l).
`On completion of each dialysis session, patients routinely re-
`ceived vitamin C, folic acid, vitamin B complex, vitamin B12 and
`200 mg of iron as oral ferrous sulphate. Calcium carbonate was the
`preferred phosphate binder except where elevated calcium levels
`necessitated the use of aluminum hydroxide (17 patients). Twenty
`two patients were taking 1-alpha hydroxy vitamin D3 to elevate
`serum calcium and suppress parathyroid hormone secretion. Nine
`patients had previously undergone parathyroidectomies for tertiary
`hyperparathyroidism. Fifteen patients had radiologic evidence of
`renal osteodystrophy. PTH levels ranged from 5 to 1,000 pg/ml,
`mean 400 pg/ml (normal range 12–72 pg/ml).
`
`Laboratory Methods
`SI was determined by an automated system (BM/Hitachi System
`704). TIBC was done by saturating transferrin binding sites with iron
`added to plasma. Excess unbound iron is then removed and plasma
`iron is measured by the assay for SI as described above. Serum ferri-
`tin was assayed using an immunoturbidometirc method in an auto-
`mated system (Tina-quant®, Boehringer Mannheim). All tests were
`done at the start of the study and thereafter on a monthly basis. Urea
`Reduction Ratios (URR) were done three-monthly, using the formu-
`la:
`
`URR = Pre-Post/Pre ! 100%
`(where Pre = urea level at commencement of dialysis and Post = urea
`level 10 min after completion of dialysis).
`
`Treatment Regimen
`Patients were treated with an iron polymaltose (dextrin) prepara-
`tion (Ferrimed®, Vifor International Inc., Switzerland). The dose
`required was calculated according to body mass and haemoglobin
`concentration using a table supplied by the manufacturer and was
`given as a total dose infusion (TDI). The dosage required ranged
`from 18 to 64 ml (900–3,200 mg of iron) and was diluted in 500 ml of
`normal saline and infused over a 4-hour period during a dialysis ses-
`sion.
`
`Clinical Monitoring for Adverse Reactions
`Blood pressure and pulse were measured hourly during the 4-hour
`dialysis period and temperature at commencement and at the end of
`the 4-hour infusion. Patients were told to report any symptoms that
`developed during or after the infusion period or between dialysis ses-
`sions.
`
`Statistics
`Data are reported as mean B SD, graphs are mean B 1 SE.
`Hypotheses about differences between means were analyzed using a
`paired t test (significance: p ! 0.05).
`
`Total Dose Iron Infusion in Haemodialysis
`Patients
`
`Nephron 2002;92:316–323
`
`317
`
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`Fig. 1. Response in haemoglobin after total
`dose infusion (means B SE). [ = Whole
`study group (SG), n = 36; d = response
`group (RG), n = 19; ! = non-response group
`(NRG), n = 17. * p ! 0.05 baseline versus
`month after infusion; ** p ! 0.001 baseline
`versus month after infusion.
`
`Fig. 2. Response in mean cell volume
`(MCV) after total dose infusion (means B
`SE). [ = Whole study group (SG), n = 36;
`d = response group (RG), n = 19; ! = non-
`response group (NRG), n = 17. * p ! 0.05
`baseline versus month after infusion; ** p !
`0.001 baseline versus month after infusion.
`
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`Results
`
`The Effect of Iron Infusion on Haemoglobin
`Concentration
`Three months after the total dose infusion in the SG,
`n = 36, 19 patients (53%) had experienced a rise in hae-
`moglobin of at least 1 g/dl and were defined as the RG.
`The remaining 17 (47%) formed the NRG (fig. 1).
`Only two patients of the entire study group failed to
`show at least some rise in haemoglobin, one remained
`
`unchanged and the other had a drop in haemoglobin of
`1 g/dl. Twelve patients attained haemoglobin levels of
`greater than 10 g/dl.
`
`The Effect of Iron Infusion on Mean Cell Volumes,
`Mean Cell Haemoglobin, Transferrin Saturation and
`Serum Ferritin (fig. 2–5)
`Rises in MCV ranged from a minimum of 4 fl (in-
`cluded are some patients with starting MCV of as high as
`92 fl) to a maximum rise of 16 fl. Changes in MCH were
`
`318
`
`Nephron 2002;92:316–323
`
`van Zyl-Smit/Halkett
`
`IPR2019-01142
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`

`

`Fig. 3. Response in mean cell haemoglobin
`(MCH) after total dose infusion (means B
`1 SE). [ = Whole study group (SG), n = 36;
`d = response group (RG), n = 19; ! = non-
`response group (NRG), n = 17. * p ! 0.05
`baseline versus month after infusion; ** p !
`0.001 baseline versus month after infusion.
`
`Fig. 4. Response in transferrin saturation
`after total dose infusion (means B 1 SE). [ =
`Whole study group (SG), n = 36; d =
`response group (RG), n = 19; ! = non-
`response group (NRG), n = 17. * p ! 0.05
`baseline versus month after infusion; ** p !
`0.001 baseline versus month after infusion.
`
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`similar to those seen with the MCV. By 6 months Tf satu-
`ration had dropped to below 20% in 13 patients and ferri-
`tin to below 225 ng/ml in 15.
`In order to determine if factors were present which
`might affect the magnitude of the response, RG was fur-
`ther subdivided into RG1 (12 patients), a group with a
`haemoglobin rise of at least 2 g/dl and group RG2 (7
`patients) with a haemoglobin rise of at least 3 g/dl (ta-
`
`ble 1). Besides the rise in haemoglobin, other differences
`were small and confined to a slightly higher starting hae-
`moglobin and MCV in the NRG. Indices of iron balance
`were similar. A comparison of baseline parameters was
`also made (table 2). By comparison to the NRG, the RG
`had fewer units of transfused blood (3.1 vs. 8.6), had high-
`er serum albumin levels (42.5 vs. 39.7 g/l) and slightly less
`efficient dialysis as reflected by a lower URR.
`
`Total Dose Iron Infusion in Haemodialysis
`Patients
`
`Nephron 2002;92:316–323
`
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`

`Fig. 5. Response in serum ferritin after total
`dose infusion (means B 1 SE). [ = Whole
`study group (SG), n = 36; d = response
`group (RG), n = 19; ! = non-response group
`(NRG), n = 17. * p ! 0.05 baseline versus
`month after infusion; ** p ! 0.001 baseline
`versus month after infusion.
`
`Table 1. Response to intravenous iron
`
`RG
`n = 19
`
`6.9 (1.3)
`8.2 (1.0)
`9.1 (1.5)
`9.5 (1.5)
`8.8 (1.5)
`
`79 (9.5)
`84 (6.9)
`87 (7.2)
`87 (7.4)
`86 (10.2)
`
`27.3 (2.7)
`29.1 (2.3)
`29.9 (2.8)
`30.1 (2.6)
`28.6 (2.3)
`
`Haemoglobin (Bl)
`Month 1
`Month 2
`Month 3
`Month 6
`
`MCV (Bl)
`Month 1
`Month 2
`Month 3
`Month 6
`
`MCH (Bl)
`Month 1
`Month 2
`Month 3
`Month 6
`
`Transferrin sat (Bl)
`Month 1
`Month 2
`Month 3
`Month 6
`
`12.2 (4.4)
`37.4 (21.4)
`30.5 (15.8)
`24.7 (7.6)
`20.3 (8.7)
`
`RG1
`n = 121
`
`6.4 (1.2)
`8.0 (1.1)
`9.0 (1.8)
`9.6 (1.8)
`9.0 (1.7)
`
`77 (10)
`83 (6.5)
`86 (7.0)
`86 (6.8)
`84 (9.8)
`
`26.9 (2.3)
`26.0 (2.2)
`29.1 (2.5)
`29.9 (2.2)
`29.4 (2.0)
`
`12 (4.3)
`37 (22.7)
`34 (17.5)
`25 (6.3)
`19 (8.9)
`
`RG2
`n = 7
`
`6.2 (1.2)
`8.4 (1.1)
`9.6 (2.2)
`10 (2.1)
`8.9 (2.0)
`
`76 (13)
`82 (7.9)
`86 (9.1)
`85 (8.3)
`84 (11.7)
`
`27.0 (1.2)
`29.2 (1.4)
`29.3 (1.9)
`29.7 (2.3)
`30.0 (1.1)
`
`11 (4.1)
`31 (12.8)
`31 (4.2)
`24 (4.1)
`20 (10.7)
`
`NRG
`n = 17
`
`7.7 (1.5)
`7.9 (1.7)
`8.2 (2.0)
`7.7 (1.6)
`7.3 (1.9)
`
`81 (6.8)
`85 (6.3)
`89 (4.9)
`90 (5.9)
`87 (4.0)
`
`28.3 (2.5)
`28.8 (2.2)
`30.3 (2.5)
`30.7 (2.5)
`29.0 (2.8)
`
`13 (5.4)
`35 (19)
`30 (9.5)
`26 (10)
`21 (7.4)
`
`TG
`n = 55
`
`6.9 (1.3)
`8.1 (1.3)
`8.9 (1.8)
`9.0 (1.7)
`8.4 (1.7)
`
`78.8 (9.2)
`83.8 (6.8)
`87.3 (6.7)
`87.5 (6.9)
`85.6 (8.4)
`
`27.5 (2.4)
`29.0 (2.1)
`29.8 (2.5)
`30.2 (2.4)
`29.1 (2.2)
`
`12.3 (4.6)
`35.8 (19.8)
`31.2 (12.7)
`25.1 (7.6)
`20.2 (8.6)
`
`Serum ferritin (Bl)
`Month 1
`Month 2
`Month 3
`Month 6
`
`63 (60)
`1,069 (481)
`712 (477)
`606 (451)
`521 (664)
`
`74 (69)
`1,099 (534)
`838 (518)
`688 (527)
`819 (1,013)
`
`71 (73)
`750 (429)
`713 (404)
`927 (647)
`250 (332)
`
`69 (61)
`72 (52)
`1,320 (1,581) 1,113 (826)
`690 (452)
`733 (469)
`651 (641)
`679 (551)
`408 (342)
`517 (598)
`
`RG = Responding group; RG1 = mean haemoglobin response of 12 g/dl; RG2 = mean
`haemoglobin response of 13 g/dl; NRG = mean haemoglobin rise of !1 g/dl; TG = total
`group; Bl = baseline. Data are mean (SD).
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`320
`
`Nephron 2002;92:316–323
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`van Zyl-Smit/Halkett
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`Table 2. Comparison of baseline
`parameters between different response
`groups
`
`RG
`n = 19
`
`6.9 (1.3)
`[4.2–8.7]
`79 (9.4)
`[53–93]
`27 (2.7)
`[24–33]
`12 (4.4)
`[6–20]
`63 (61)
`[10–208]
`
`13 (68%)
`6 (32%)
`
`RG1
`n = 12
`
`6.3 (1.2)
`[4.2–79]
`78 (10.3)
`[53–93]
`26.9 (2.3)
`[24–31]
`12 (4.3)
`[6–20]
`75 (69.3)
`[10–208]
`
`9 (69%)
`4 (31%)
`
`RG2
`n = 7
`
`6.2 (1.2)
`[4.7–7.4]
`76 (13.2)
`[53–93]
`27 (1.2)
`[26–28]
`11 (4.1)
`[6–16]
`71 (73.4)
`[10–208]
`
`6 (86%)
`1 (14%)
`
`NRG
`n = 17
`
`7.6 (1.5)
`[5–11]
`81 (6.8)
`[70–92]
`28.3 (2.5)
`[23–32]
`13 (5.4)
`[6–20]
`72 (52.4)
`[9–204]
`
`11 (65%)
`6 (35%)
`
`33 (1–127)
`8.6 (0–43)
`118 (37–727)
`39.7 (32–47)
`70 (54–84)
`
`38.7 (1–127)
`8.8 (0–41)
`139 (37–727)
`38.9 (32–43)
`71 (54–79)
`
`60.1 (2–127)
`12.4 (0–41)
`91 (42–149)
`37.8 (32–421)
`74 (59–79)
`
`21.8 (3–53)
`3.1 (0–17)
`134 (37–993)
`42.5 (36–48)
`65 (53–79)
`
`Haemoglobin, g/dl
`
`MCV, fl
`
`MCH, pg
`
`Saturation, %
`
`Serum ferritin, ng/ml
`
`Females, n (%)
`Males, n (%)
`
`Months on dialysis
`Units of blood
`Alk phosphatase, IU
`Albumin, g/l
`Urea reduction ratio
`
`RG = Responding group; RG1 = mean haemoglobin response of 12 g/dl; RG2 = mean
`haemoglobin response of 13 g/dl; NRG = mean haemoglobin rise of !1 g/dl. Data are mean,
`mean (SD), or [range].
`
`Table 3. Prevalence of hyperparathyrodism
`
`Radiologic evidence
`of hyperparathyroid
`bone disease
`
`Alkaline phosphatase
`mean (SD)
`
`Study group (SG), n = 36
`Responder group (RS), n = 19
`Non-responders (NRG), n = 17
`
`17 (47%)
`10 (53%)
`7 (41%)
`
`126 (186)
`118 (150)
`135 (225)
`
`As marrow fibrosis related to hyperparathyroidism has
`been implicated in causing resistance to erythropoietin,
`the patients were assessed both clinically and radiological-
`ly for evidence of hyperparathyroidism. Radiologic evi-
`dence of hyperparathyroid bone disease was found in
`47% of the patients studied, but there was no significant
`difference in prevalence of either bone disease or of alka-
`line phosphatase levels between RG and NRG. Insuffi-
`cient estimations of PTH levels were done to allow for
`statistical analysis (table 3).
`Only two patients in the study group received rhEPO.
`It was given at a constant dose for the duration of the
`study. The responses of these patients fell within the range
`of the study group as a whole.
`
`Adverse Reactions
`No anaphylactoid and no delayed reactions such as
`pyrexia, arthralgia, or myalgia were seen. Hypotensive
`episodes were more difficult to assess as these occur fre-
`quently during the course of normal haemodialysis. At no
`stage did the clinicians responsible for the care of these
`patients feel that any of these episodes were related to the
`iron infusions, none of the infusions had to be stopped
`and no thrombophlebitis occurred. One patient died 19
`days after the infusion of complications unrelated to the
`infusion.
`
`Total Dose Iron Infusion in Haemodialysis
`Patients
`
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`Discussion
`
`In patients receiving rhEPO, iron deficiency is almost
`universal in those not receiving supplemental IV iron.
`With carefully supervised twice daily oral iron therapy
`sufficient iron may be absorbed to counter this tendency
`toward iron deficiency, but in practice, this is generally
`not achievable [7].
`Early studies were able to demonstrate the benefits of
`parenteral iron, given either as a total dose infusion or by
`intramuscular injection, despite the limitation imposed
`by the lack of adequate iron preparations as well as poor
`dialysis efficacy [8, 9]. Most of these studies were similar
`to our own in that patients were not receiving concomi-
`tant EPO [10, 11]. Superiority of IV over oral iron was
`also demonstrated [12].
`More recently effective IV iron preparations and better
`tests for the evaluation of iron balance have become avail-
`able, yet recent data from the USA indicate that many
`iron deficient haemodialysis patients are still receiving
`inadequate iron replacement [13].
`Our group of patients is unique as the vast majority
`were for financial reasons not being treated on rhEPO, yet
`77% were considered to be iron deficient by very conser-
`vative criteria. Of the 62 patients studied, only 8 had fea-
`tures suggesting iron overload and all had received multi-
`ple blood transfusions.
`The response to TDI was dramatic in many patients,
`even in some without overt signs of iron deficiency and
`ferritin levels well within what could be considered the
`normal range. Ferritin levels also allowed us to monitor
`iron stores following a single TDI, and indicated how bio-
`chemical signs of iron deficiency were starting to appear
`at the end of the 6-month follow-up period. At this time 7
`patients were sufficiently iron deficient to require more
`IV iron.
`Despite the fact that in all patients TDI had a uniform-
`ly positive effect on all measures of iron status, including a
`rise in the MCV, a substantial proportion failed to
`respond with a rise in haemoglobin level. We were unable
`to determine the factors responsible for the differences in
`response in our patients. Aluminum overload is a well rec-
`ognized cause of a non-responsive type of iron deficiency
`anaemia [4, 14]. Although we did not do formal studies of
`aluminum balance, overload is unlikely to have been
`responsible for the differences in response as the poorly
`responding group of patients had been on dialysis for a
`significantly shorter period which if anything, would sug-
`gest less exposure to aluminum. Differences in parathy-
`roid function could similarly not be demonstrated.
`
`‘Functional iron deficiency’ is a well recognized cause
`of erythropoietic unresponsiveness. It represents a situa-
`tion of low biologic iron availability despite the presence
`of adequate total body stores. In the presence of overt
`inflammatory or infective conditions, the diagnosis is
`obvious. However to exclude this condition in association
`with occult, low-grade and chronic conditions, tests such
`as CRP (as a marker of inflammation) or the % hypo-
`chromic red cells or transferrin receptor levels (as mea-
`sures of iron utilization) or a therapeutic challenge of IV
`iron may be required [5, 6, 15]. The dose of iron used in
`our study given as a TDI, resulted in a mean rise in ferri-
`tin levels well in excess of 1,000 ng/ml and transferrin sat-
`uration levels in excess of 30%. Such levels should have
`substantially reduced the potential effect of ‘functional
`deficiency’ in the majority of non-responding patients.
`Another reason for the differences in response might
`have been differing levels of endogenous erythropoietin in
`the two groups. The rise in MCV without a corresponding
`rise in haemoglobin noted in the NRG is consistent with
`previous observations of iron loading in the presence of
`insufficient EPO [16]. EPO levels were not available to
`test this hypothesis. The clinical use of rhEPO in two of
`the patients did not influence results as their response was
`similar to the other patients.
`Anti-dextran antibodies are largely responsible for the
`high prevalence of side effects, including anaphylaxis, to
`dextran containing compounds [17]. With compounds
`such as iron sucrose and iron gluconate, side effects seem
`to be mostly related to the rate of iron release. It has there-
`fore been suggested that for patients on haemodialysis,
`maximum single doses of these compounds should be lim-
`ited to about 300 and 125 mg respectively [18, 19]. The
`iron polymaltose (dextrin) preparation (Ferrimed) used in
`this study releases iron more slowly and allows the use of
`TDI. In this respect it is similar to the dextran containing
`compounds which also have minimal free iron related
`side effects with high doses used with TDI [17]. No
`obvious side effects were noted when doses containing
`1–4 mg of iron were used during our study.
`There is little data regarding the optimal size of TDI
`doses, dosing schedules as well as tests to define the need
`for further infusions [17]. It produces intermittent and
`marked fluctuations in total body iron stores as well as
`availability of iron to erythroid precursors. A fine balance
`needs to be maintained between body stores, best moni-
`tored by ferritin levels and ‘availability’ of iron, probably
`best monitored on a routine monthly basis by the transfer-
`rin saturation. Continuous techniques of iron administra-
`tion would maintain more constant levels but require
`
`322
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`more frequent IV administration and monitoring in order
`to avoid inadvertent iron overload [18].
`The main advantage of TDI over more frequent infu-
`sions is likely to be its ease of administration in patients
`attending clinics at infrequent intervals such as those on
`CAPD or those with iron deficiency not on dialysis [20,
`21]. A further advantage may be the rapidity by which
`‘non-responsiveness’ to iron therapy may be detected. An
`immediate clinical re-assessment as to the cause of the
`
`anaemia can then be made as well and the need for further
`TDI.
`In conclusion, TDI with iron polymaltose (dextrin) is a
`safe and effective way of correcting iron deficiency.
`Where financial restrictions preclude the use of rhEPO,
`IV iron may still be a relatively inexpensive and effective
`way to substantially improve the haemoglobin level. It
`was not possible to determine which patients would be
`likely to respond best.
`
`References
`
`1 Esbach JW: The anaemia of chronic renal fail-
`ure: Pathophysiology and the effects of recom-
`binant erythropoietin. Kidney Int 1989;35:
`134–148.
`2 Akmal M, Sawelson S, Karubian F, Gadallah
`M: The prevalence and significance of occult
`blood loss in patients with predialysis ad-
`vanced chronic renal failure, or receiving
`chronic dialytic therapy. Clin Nephrol 1994;
`42:198–202.
`3 Lindsay RM, Burton JA, King P: The measure-
`ment of dialyser blood less. Clin Nephrol 1973;
`1:24–28.
`4 Bia MJ, Schnall S, Duffy T, Hendler E, Mal-
`luche H, Solomon L: Aluminium induced
`anaemia: Pathogenesis and treatment in pa-
`tients on chronic haemodialysis. Kidney Int
`1989;36:852–858.
`5 Besarab A, Amin N, Ahsan M, Vogel SE, Zazu-
`wa G, Frinak S, Zazra JJ, Anandan JV, Gupta
`A: Optimization of epoetin therapy with intra-
`venous iron therapy in hemodialysis patients. J
`Am Soc Nephrol 2000;11:530–538.
`6 Fishbane S, Maesaka JK: Iron management in
`end stage renal disease. Am J Kidney Dis 1997;
`29:319–333.
`7 Wingard RL, Parker RA, Ismail N, Hakim
`RM: Efficacy of oral iron therapy in patients
`receiving recombinant human erythropoietin.
`Am J Kidney Dis 1995;25(3):433–439.
`
`8 von Hartitzsch B, Kerr DNS: Response to par-
`enteral iron with and without androgen therapy
`in patients undergoing regular haemodialysis.
`Nephron 1976;17:430–438.
`9 Stewart WK, Flemming LW, Shepherd AMM:
`Haemoglobin and serum iron responses to peri-
`odic intravenous iron-dextran infusions during
`maintenance haemodialysis. Nephron 1976;
`17:121–130.
`10 Silverberg DS, Blum M, Peer G, Kaplan E, Iai-
`na A: Intravenous ferric saccharate as an iron
`supplement in dialysis patients. Nephron 1996;
`72:413–417.
`11 Schustack A, Meshiaj D, Waiss Z, Gotloib L:
`Intramuscular iron replenishment and replace-
`ment combined with testosterone eneanthate
`in maintenance haemodialysis anemia: a fol-
`low-up of up to 8 years on 16 patients. Clin
`Nephrol 1985;23:303–306.
`12 Fudin R, Jaichenko J, Shostak A, Bennett M,
`Gotloib L: Correction of uraemic iron deficien-
`cy anemia in hemodialyzed patients: a prospec-
`tive study. Nephron 1998;79(3):299–305.
`13 Frankenfield D, Johnson CA, Wish JB, Rocco
`MV, Madore F, Owen WF: Anemia manage-
`ment of adult hemodialysis patients in the US:
`Results from the 1997 ESRD Core Indicators
`Project. Kidney Int 2000;57:578–589.
`14 Caramelo CA, Cannata JB, Rodeles MR, Mar-
`tin JLF, Mosquera JR, Monzu B, Outeirino J,
`Blum G, Andrea C, Lopes Farre AJ, Acuna G,
`Casado S, Hernando L: Mechanisms of alu-
`minium-induced microcytosis: Lessons from
`accidental aluminium intoxication. Kidney Int
`1995;47:64–168.
`
`15 Bovy C, Tsobo C, Crapenzano L, Rorive G,
`Beguin Y, Albert A, Paulus JM: Factors deter-
`mining the percentage of hypochromic red
`blood cells in hemodialysis patients. Kidney
`Int 1999;56:1113–1119.
`16 Glokal R, Weatherall DJ, Bunch C: Iron in-
`duced increase in red cell size in haemodialysis
`patients. Quarterly J Med 1979;XLVIII:939–
`401.
`17 Auerbach M, Winchester J, Wahab A, Ri-
`chards K, McGinley M, Hall F, Anderson J,
`Briefel G: A randomized trial of three iron dex-
`tran infusion methods for anemia in EPO-
`treated dialysis patients. Am J Kidney Dis
`1998;32:81–86.
`18 Bailie GR, Johnson CA, Mason NA: Parenteral
`iron use in the management of anemia in end-
`stage renal disease patients. Am J Kidney Dis
`2000;35(1):1–12.
`19 Nissenson AR, Lindsay RM, Swan S, Seligman
`P, Strobos J: Sodium ferric gluconate complex
`in sucrose is safe and effective in haemodialysis
`patients: North American clinical trial. Am J
`Kidney Dis 1999;33(3):471–482.
`20 Besarab A, Kaiser JW, Frinak S: A study of par-
`enteral iron regimens in hemodialysis patients.
`Am J Kidney Dis 1999;34(1):21–28.
`21 Silverberg DS, Iaina A, Peer G, Kaplan E, Levi
`BA, Frank N, Steinbruch S, Blum M: Intrave-
`nous iron supplementation for the treatment of
`the anaemia of moderate to severe chronic
`renal failure patients not receiving dialysis. Am
`J Kidney Dis 1996;27:234–238.
`
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