07-07-14;09:02
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`Phar'"macosmos AS
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`# 11/ 22
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`NEPHfCt'.J
`
`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
`
`Key Words
`Intravenous iron ·Total dose infusion • Haemodialysis.
`Iron polymaltose • 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(cid:173)
`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(cid:173)
`tose (dextrin) by total dose infusion (TOI). 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 BO (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(cid:173)
`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(cid:173)
`ysls 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(cid:173)
`tive method of raising haemoglobin levels. Substantial
`improvements may be achieved without the concurrent
`use of rhEPO.
`
`Copyright c 2002 S. Karger AG, Basel
`
`Introduction
`
`Anaemia is almost always present in patients with
`severe chronic renal failure [I]. Its assessment and man(cid:173)
`agement becomes more complex once chronic haemodial(cid:173)
`ysis (HD) is initiated. Factors such as inadequate dialysis,
`defective utilization of iron sequestered in body iron
`stores, poor absorption of dietary iron, gastrointestinal
`
`KAR.GEi\
`Fax+41613061234
`E-Mail kargcr@kargcr.ch
`www.kargcr.com
`
`© 2002 S. Karger AG, Basel
`00211-2166/02/0922-031m8.50/o
`
`Al:l:cssiblc onlinc at:
`WIVIV. kargcr.comljournalslner
`
`R. van Zyl.Smit
`Renal Unit Ell
`Groote Schuur Hospital
`ObscrvatoJY, 7935 (South Arrica)
`Tel +27 21 448 2349, Fax +27 21 <404 3318, E·Mail vzsmit@curic.uct.ac.za
`
`Pharmacosmos, Exh. 1006, p. 1
`
`

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`07-07-14;09:02
`
`Pharmacosmos AS
`
`# 12/ 22
`
`blood and dialysis-related blood loss [2, 3], aluminum tox(cid:173)
`icity [4], bone marrow fibrosis, vitamin and iron deficien(cid:173)
`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 [l]. With
`modem 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(cid:173)
`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(cid:173)
`equate stores or 'functional iron deficiency' may become
`the major limiting factor in achieving optimal haemoglo(cid:173)
`bin levels [6]. With functional iron deficiency biologic
`availability of iron is reduced despite the presence of ade(cid:173)
`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 fmancial 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 transfcrrin (TO saturation levels of
`less than 20%, in the presence of a scrum fcrritin level of less than
`225 nglml. The following were routinely measured: scrum iron (SI),
`total iron binding capacity (TIBC), mean cell volume (MCV), mean
`cell haemoglobin (MCH), plasma albumin, calcium, inorganic phos(cid:173)
`phate, alkaline phosphatase and, if hypcrparathyroidism was sus(cid:173)
`pected, serum parathyroid (PTH) levels. As a measure of dialysis effi(cid:173)
`cacy, a urea reduction ratio (URR) was done and expressed as a per(cid:173)
`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 (SO). Patients who experienced a
`rise in haemoglobin, by the end of the study period, in excess of 1 gtdl
`were designated as the responder group {RG) and the remainder as
`
`the non-responder group (NRG). The SO 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 numberofunits 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/) (range 32-48 g/)),
`mean scrum alkaline phosphatase 126 u/I (range 37-993 u/I) (normal
`range 30-11 S u/l).
`On completion of each dialysis session, patients routinely re(cid:173)
`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 I-alpha hydroxy vitamin D3 to elevate
`scrum calcium and suppress parathyroid hormone secretion. Nine
`patients had previously undergone parathyroidcctomics for tertiary
`hypcrparathyroidism. Fifteen patients had radiologic evidence of
`renal ostcodystrophy. PTH levels ranged from 5 to 1,000 pgfml,
`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 transfcrrin 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. Scrum ferri(cid:173)
`tin was assayed using an immunoturbidomctire method in an auto(cid:173)
`mated system (fina-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(cid:173)
`la:
`
`URR = Prc-Post/Pn: x 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(cid:173)
`tion (Ferrimcd®, 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 (I'DI). The dosage required ranged
`from 18 to64ml (900-3,200 mg of iron) and was diluted in 500mlof
`normal saline and infused over a 4-hour period during a dialysis ses(cid:173)
`sion.
`
`Cli11ical Mo11itori11gfor 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(cid:173)
`sions.
`
`Statistics
`Data arc reported as mean ± SD, graphs arc mean ± 1 SE.
`Hypotheses about differences between means were analyzed using a
`paired t test (significance: p < 0.05).
`
`Total Dose Iron Infusion in Hacmodialysis
`Patients
`
`Ncphron 2002;92:316-323
`
`317
`
`Pharmacosmos, Exh. 1006, p. 2
`
`

`
`07-07-14;09:02
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`Pharmacosmos AS
`
`# 13/ 22
`
`10
`
`9
`
`8
`
`7
`
`~
`
`Cll c :c
`
`.!2
`Cl
`0
`E
`G>
`Ill :c
`
`_ ... .------~····-·········-·---·--····---····-··
`
`--;c
`
`6
`
`Fig. 1. Response in haemoglobin after total
`dose infusion (means ± SE). 0 = Whole
`study group {SO), n = 36; A = response
`group (RO), n = 19; x =non-response group
`(NRG), n .. 17. • p < 0.05 baseline versus
`month after infusion; .. p < 0.001 baseline
`versus month after infusion.
`
`0
`
`1
`
`2
`
`3
`Time, months
`
`q:
`m
`E
`~
`~
`~ u
`c
`Ill
`CD
`:E
`
`BB
`
`87
`
`85
`
`83
`
`81
`
`79
`
`77
`
`75
`
`Fig. 2. Response in mean cell volume
`(MCV) after total dose infusion (means ±
`SE). 0 = Whole study group {SG), n = 36;
`A = response group (RG), n = 19; x =non(cid:173)
`response group (NRG), n = 17. • p < 0.05
`baseline versus month after infusion; •• p <
`0.00 I baseline versus month after infusion.
`
`/·"'··
`/
`...... ,"
`
`'/
`
`I
`
`I
`
`I
`
`I
`
`'
`
`0
`
`1
`
`2
`
`3
`lime, months
`
`8
`
`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(cid:173)
`moglobin of at least I 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 gldl. Twelve patients attained haemoglobin levels of
`greater than 10 gldl.
`
`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(cid:173)
`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
`
`Ncphron 2002;92:316-323
`
`van Zyl-Smit/Halkett
`
`Pharmacosmos, Exh. 1006, p. 3
`
`

`
`07-07-14;09:02
`
`Pharmacosmos AS
`
`# 14/ 22
`
`1500
`
`i 1000
`c :e "t: .e
`
`500
`
`E
`:I
`,j
`
`Fig. 3. Response in mean cell haemoglobin
`(MCH) after total dose infusion (means ±
`I SE). 0 = Whole study group (SG), n = 36;
`A = response group (RG), n = 19; x = non(cid:173)
`response group (NRG), n = 17. • p < 0.05
`baseline versus month after infusion; •• p <
`0.001 baseline versus month after infusion.
`
`0
`
`1
`
`2
`
`3
`lime, months
`
`6
`
`31
`
`~
`c
`:a
`0
`Cl
`0
`E 29
`m
`al
`.c
`=ii u
`c
`Ill m
`~
`
`27
`
`Fig. 4. Response in transfcrrin saturation
`after total dose infusion (means ± l SE). O =
`Whole study group (SG), n = 36; A =
`response group (RG), n • 19; x = non(cid:173)
`response group (NRG), n = 17. • p < 0.05
`baseline versus month after infusion; ** p <
`0.00 l baseline versus month after infusion.
`
`0
`
`1
`
`2
`
`3
`Time, months
`
`6
`
`similar to those seen with the MCV. By 6 months Tf satu(cid:173)
`ration had dropped to below 20% in 13 patients and ferri(cid:173)
`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(cid:173)
`ther subdivided into RG 1 (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 conf med to a slightly higher starting hae(cid:173)
`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(cid:173)
`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 Hacmodialysis
`Patients
`
`Ncphron 2002;92:316-323
`
`319
`
`Pharmacosmos, Exh. 1006, p. 4
`
`

`
`07-07-14;09 : 02
`
`Pharmacosmos AS
`
`# 15/ 22
`
`Fig. 5. Response in serum fcrritin after total
`dose infusion (means ± I SE). 0 = Whole
`study group (SG), n = 36; A. = response
`group (RG), n = 19; x .. 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
`
`40
`
`..,. 30
`c
`0 ... f
`::1 m 20
`c
`'E
`~ c:
`IQ F 10
`
`0
`
`2
`
`3
`llme, months
`
`6
`
`RG
`n= 19
`
`6.9 (1.3)
`8.2 (1.0)
`9.1 (1.5)
`9.5 (l.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.l (2.6)
`28.6 (2.3)
`
`Haemoglobin (Bl)
`Month 1
`Montb2
`Month 3
`Month6
`
`MCV(BI)
`Month 1
`Month2
`Montb3
`Month6
`
`MCH(Bl)
`Month 1
`Month2
`Month3
`Month 6
`
`Transfcrrin sat (Bl)
`Month I
`Month2
`Month3
`Month6
`
`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)
`
`RG1
`n=7
`
`6.2 (1.2)
`8.4 (I. I)
`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)
`
`Serum fcrritin (Bl)
`Month 1
`Month2
`Month3
`Month 6
`
`74(69)
`63 (60)
`1,069 (481) 1,099 (534)
`712 (477)
`838 (518)
`688 (527)
`606 (451)
`521 (664)
`819 (1,013)
`
`71 (73)
`750 (429)
`713 (404)
`927 (647)
`250(332)
`
`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)
`
`TG
`n=S5
`
`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)
`
`13 (5.4)
`35 (19)
`30 (9.5)
`26 (10)
`21 (7.4)
`72 (52)
`69 (61)
`1,320 (1,581) 1,113 (826)
`690 (452)
`733 (469)
`651 (641)
`679 (551)
`517 (598)
`408 (342)
`
`RG =Responding group; RG 1 =mean haemoglobin response of>2 g/dl; RG2 =mean
`haemoglobin response of>3 g/dl; NRG= mean haemoglobin rise of<l g/dl; TG =total
`group; Bl =baseline. Data are mean (SD).
`
`320
`
`Ncphron 2002;92:316-323
`
`van Zyl-SmiVHalkett
`
`Pharmacosmos, Exh. 1006, p. 5
`
`

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`07-07-14;09:02
`
`Phar-macosmos AS
`
`# 16/ 22
`
`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)
`16 (13.2)
`[53-93]
`21 (1.2)
`[26-28)
`11 (4.1)
`[6-16)
`71 (73.4)
`[10-208]
`
`6 (86%)
`1 (14%)
`
`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)
`
`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%)
`21.8 (3-53)
`3.1 (0-17)
`134 (37-993)
`42.5 (36-48)
`65 (53-79)
`
`Haemoglobin, g.ldl
`
`MCV,tl
`
`MCH,pg
`
`Saturation, %
`
`Scrum fcrritin, ng.lml
`
`Females, n (%)
`Malcs,n(%)
`
`Months on dialysis
`Units of blood
`Alk phosphatase, IU
`Albumin, gl)
`Urea reduction ratio
`
`RG =Responding group; RG1 =mean haemoglobin response of>l gfdl; RG2 =mean
`haemoglobin response of> 3 g.tdl; NRG= mean haemoglobin rise of< I gf di. Data arc mean,
`mean (SD), or [range].
`
`Table 3. Prevalence ofhypcrparathyrodism
`
`Radiologic evidence
`ofhypcrparatbyroid
`bone disease
`
`Alkaline phosphatase
`mean (SD)
`
`Study group (SG), n = 36
`Respondergroup (RS), n = 19
`Non-responders (NRG), n = 17
`
`17 (47%)
`10(53%)
`7 (41%)
`
`126 (186)
`118 (150)
`135 (225)
`
`As marrow fibrosis relateq to hyperparathyroidism has
`been implicated in causing resistance to erythropoietin,
`the patients were assessed both clinically and radiological(cid:173)
`ly for evidence of hyperparathyroidism. Radiologic evi(cid:173)
`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(cid:173)
`line phosphatase levels between RG and NRG. Insuffi(cid:173)
`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(cid:173)
`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
`
`Ncphron 2002;92:316-323
`
`321
`
`Pharmacosmos, Exh. 1006, p. 6
`
`

`
`07-07-14;09:02
`
`Pharmacosmos AS
`
`# 17/ 22
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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(cid:173)
`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(cid:173)
`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(cid:173)
`vative criteria. Of the 62 patients studied, only 8 had fea(cid:173)
`tures suggesting iron overload and all had received multi(cid:173)
`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(cid:173)
`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(cid:173)
`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(cid:173)
`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(cid:173)
`gest less exposure to aluminum. Differences in parathy(cid:173)
`roid function could similarly not be demonstrated.
`
`'Functional iron deficiency' is a well recognized cause
`of erythropoietic unresponsiveness. It represents a situa(cid:173)
`tion oflow 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(cid:173)
`chromic red cells or transferrin receptor levels (as mea(cid:173)
`sures of iron utilization) or a therapeutic challenge ofIV
`iron may be required [S, 6, 15]. The dose of iron used in
`our study given as a TDI, resulted in a mean rise in ferri(cid:173)
`tin levels well in excess of 1,000 ng/ml and transferrin sat(cid:173)
`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(cid:173)
`fore been suggested that for patients on haemodialysis,
`maximum single doses of these compounds should be lim(cid:173)
`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 def me 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 fme balance
`needs to be maintained between body stores, best moni(cid:173)
`tored by ferritin levels and 'availability' of iron, probably
`best monitored on a routine monthly basis by the transfer(cid:173)
`rin saturation. Continuous techniques of iron administra(cid:173)
`tion would maintain more constant levels but require
`
`322
`
`Ncphron 2002;92:316-323
`
`van Zyl-Smit/Halkctt
`
`Pharmacosmos, Exh. 1006, p. 7
`
`

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`07-07-14;09:02
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`Phar-macosmos AS
`
`# 18 / 22
`
`more frequent IV administration and monitoring in order
`to a void inadvertent iron over load [ 18].
`The main advantage of TDI over more frequent infu(cid:173)
`sions is likely to be its ease of administration in patients
`attending clinics at infrequent intervals such as those on
`CAPO 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
`TOI.
`In conclusion, TOI 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.
`
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`Total Dose Iron Infusion in Hacmodialysis
`Patients
`
`Ncphron 2002;92:316-323
`
`323
`
`Pharmacosmos, Exh. 1006, p. 8