Therapeutic Apheresis and Dialysis 11(3):220–226
doi: 10.1111/j.1744-9987.2007.00474.x
© 2007 International Society for Apheresis
Darbepoetin Alfa Effectively Maintains Hemoglobin
Concentrations at Extended Dose Intervals Relative to
Intravenous rHuEPO in Japanese Dialysis Patients
Tadao Akizawa,1 Shozo Koshikawa,2 Manabu Iwasaki,3
and the KRN321 A08 Study Group*
1
Showa University School of Medicine, Tokyo, 2Showa University Fujigaoka Hospital, Kanagawa,
and 3Seikei University, Tokyo, Japan
Abstract: Darbepoetin alfa (KRN321) is a novel molecule
that stimulates erythropoiesis by the same mechanism as
endogenous erythropoietin. Due to its three-fold longer
half-life and greater biological activity than recombinant
human erythropoietin (rHuEPO), KRN321 maintains an
effective hemoglobin (Hb) level at extended dose intervals
compared with rHuEPO. In this multicenter, open-label
study, 513 dialysis patients maintained on stable rHuEPO
therapy were switched to KRN321 at extended dose inter-
vals. Those receiving rHuEPO two (n = 144, 28.1%) or
three times (n = 305, 59.5%) per week were switched to
KRN321 once per week, and those receiving rHuEPO once
per week (n = 64, 12.5%) were switched to KRN321 once
every two weeks. The doses of KRN321 (10–120 mg) were
titrated to maintain Hb concentrations at 10–13 g/dL and, if
Darbepoetin alfa (KRN321) is a novel erythropoi-
etic protein that, due to its longer elimination half-life
(1) and greater in vivo biological activity (2), can be
administered less frequently than recombinant
human erythropoietin (rHuEPO). Several studies
have confirmed that KRN321 can be administered
less frequently than rHuEPO to correct and maintain
hemoglobin (Hb) in subjects with renal disease who
are either receiving or not receiving dialysis (3–10).
KRN321 has also been shown to contribute to the
maintenance of effective Hb concentrations when
administered once every three or four weeks (5). The
current study was performed to further confirm the
Received June 2006; revised August 2006.
Address correspondence and reprint requests to Dr Tadao
Akizawa, 1-5-8 Hatanodai, Shinagawa-ku , Tokyo 142-8666, Japan.
Email: akizawa@med.showa-u.ac.jp
*The members of the KRN321 A08 Study Group and their
affiliations are listed in the Appendix.
220
possible, within 11–12 g/dL for up to 52 weeks. If the Hb
concentration remained between 10.5 and 12 g/dL, conver-
sion of the dosing frequency from once per week to once
every two weeks was allowed. Hemoglobin concentrations
were maintained regardless of the dosing interval. The per-
centage of patients with Hb values within 11–12 g/dL was
23.6% at week 0, 41.3% at week 7, 46.1%-51.9% between
weeks 11 and 22 and 45.6% at week 52. KRN321 was well
tolerated and the safety profile was consistent with previ-
ous trials conducted for KRN321. KRN321, when adminis-
tered at extended dose intervals, is well tolerated and
effective Hb concentrations are attained in Japanese hemo-
dialysis patients. Key Words: Darbepoetin alfa, Dialysis,
Hemoglobin, Renal anemia, Safety.
long-term efficacy and safety of KRN321 given at
extended dose intervals in maintaining Hb concen-
trations in Japanese hemodialysis patients.
PATIENTS AND METHODS
This multicenter, open-label, single-arm study of
KRN321 involved 514 patients with end-stage renal
failure on hemodialysis. Clinically stable patients
(ⱖ20 years of age) with mean Hb concentrations of
9–12 g/dL, based on four Hb measurements during
the four-week baseline period, who had been on
hemodialysis (HD) for at least 12 weeks were
recruited from 47 dialysis institutes in Japan. The
patients had to be receiving stable rHuEPO (epoetin
alfa or beta) therapy one, two or three times per
week, for eight weeks prior to their entry into the
study. To ensure adequate iron stores to support
 Darbepoetin Alfa in Japanese HD Patients
erythropoiesis, serum ferritin was required to be
ⱖ100 ng/mL, or transferrin saturation to be ⱖ20%.
Patients were excluded if they had New York
Heart Association (NYHA) class III or IV conges-
tive heart failure, uncontrolled hypertension (defined
as predialysis diastolic blood pressure >100 mmHg
over 1/3 points of measurement during the screening/
baseline period) or had received red blood cell trans-
fusions during the baseline period. Patients with
inflammatory or infectious diseases, and pregnant or
lactating females were also excluded.
The study was conducted in accordance with the
revised Declaration of Helsinki and the study proto-
col was approved by each participating institution’s
independent Research Ethics Committee. The
patients were requested to give their informed
consent in writing before the study.
After a four-week baseline period the patients
were switched from rHuEPO to intravenous (IV)
administration of KRN321 at an extended dose inter-
val, as follows: those who were receiving rHuEPO
two or three times per week were switched to
KRN321 once per week, and those receiving
rHuEPO once per week were switched to KRN321
once every two weeks. For these patients, an approxi-
mate 200 IU rHuEPO : 1 mg KRN321 ratio was used
to determine the switching dose from rHuEPO to
KRN321 (7) (Table 1). Subsequent KRN321 doses
were titrated within the range of 10–120 mg per dose,
based on the Hb response at each investigator’s dis-
cretion. Blood samples were drawn at weekly inter-
vals to measure Hb. Iron status (serum ferritin or
transferrin saturation) was assessed at baseline and
TABLE 1. Conversion table for rHuEPO to KRN321
(1) Baseline rHuEPO dose once/week
Dose number rHuEPO KRN321(once/2 weeks)
1 750 IU 10 mg
2 1500 IU 15 mg
3 2250 IU 20 mg
4 3000 IU 30 mg
(2) Baseline rHuEPO dose two or three times/week
Dose number rHuEPO KRN321(once/week)
1 1500 IU 10 mg
2250 IU
2 3000 IU 15 mg
3 3750 IU 20 mg
4500 IU
4 5250 IU 30 mg
6000 IU
6750 IU
5 7500 IU 40 mg
8250 IU
9000 IU
KRN321, darbepoetin alfa; rHuEPO, recombinant human
erythropoietin.
© 2007 International Society for Apheresis
221
thereafter every four weeks. The patients were also
tested for the presence of antibodies to KRN321.
The dose of KRN321 was titrated to maintain the
Hb concentration within 10–13 g/dL, and if possible,
within 11–12 g/dL throughout the 52-week study
period. When the dose was changed, it was required
to switch to the next upper or lower “Dose number”.
The treatment of KRN321 was suspended when Hb
was >13 g/dL.
If Hb was successfully maintained between 10.5
and 12 g/dL three times consecutively, conversion of
the dosing frequency from once per week to once
every two weeks was allowed. The initial dosage after
changing the frequency was set to double the last
dose or 120 mg, whichever is smaller. To maintain
serum ferritin at ⱖ100 ng/mL or transferrin satura-
tion at ⱖ20%, IV iron supplementation was recom-
mended. The primary end point was the percentage
of Hb within 11–12 g/dL or 10–13 g/dL, and the sec-
ondary end point was the change in Hb concentra-
tion. Safety was assessed based on the occurrence of
adverse events.
Statistical analysis
Changes in Hb and dose are presented as mean
values and two-sided 95% confidence intervals (CIs).
All patients who received at least one dose of
KRN321 (n = 513) were included in the analysis of
safety and efficacy. All statistical analyses were per-
formed using the SAS software package (version
8.02, SAS, Cary, NC, USA). For the assessment per-
formed based on interval estimation, the two-sided
95% CI was used.
RESULTS
Five hundred and thirteen out of 514 patients
received at least one dose of KRN321 (Table 2).Their
mean age was 58.8 years (range: 21–88 years). The
most common causes of chronic kidney disease
(CKD) were chronic glomerulonephritis (56.9%)
and diabetes mellitus (18.5%). The mean Hb concen-
tration at baseline was 10.33 g/dL (range 9.00–
11.98 g/dL). Over the 52-week study period, 131
subjects discontinued the study because of adverse
events (52), requested withdrawal (28), Hb ⱖ 13 g/dL
(10), surgery and transfusion (4) and other reasons
(37), respectively. Regarding 52 patients who discon-
tinued due to adverse events, almost all the adverse
events occurred accidentally. The adverse events that
occurred more than three times were cerebral infarc-
tion (4) and hypertension (4).
Ther Apher Dial, Vol. 11, No. 3, 2007
222 T Akizawa et al.
TABLE 2. Patient baseline demographics and characteristics
Number of subjects
Number of women
Number of men
Age (years, mean ⫾ SD)
Body weight (kg, mean ⫾ SD)
Cause of renal failure
Glomerulonephritis
Diabetes
Nephrosclerosis
Polycystic kidney disease
Chronic pyelonephritis
Other
Administration route of rHuEPO
IV
SC
Baseline rHuEPO dose (IU/week, mean ⫾ SD)
Frequency of rHuEPO
Once per week
Twice per week
Three times per week
Time since first dialysis (months, mean ⫾ SD)
Baseline Hb (g/dL, mean ⫾ SD)
Serum ferritin (ng/mL, mean ⫾ SD)
Transferrin saturation (%, mean ⫾ SD)
Hb, hemoglobin; IV, intravenous; rHuEPO, recombinant human erythropoietin; SC,
subcutaneous.
Primary and secondary end points
Four hundred and fourty-nine patients were
started on KRN321 administered once a week, and 94
of those patients were successfully switched to once
every two weeks. Sixty-four patients were started on
KRN321 administered once every two weeks.
Changes in Hb concentration and weekly average
dosage are illustrated in Figure 1.
The mean Hb concentration was 10.43 g/dL at
week 0, but it increased after commencing the study
medication in a time-dependent manner reaching
ⱖ11 g/dL on week 7. The Hb concentration also
increased thereafter in a time-dependent manner
reaching a maximum of 11.53 g/dL at week 15. There-
after, the Hb concentration was kept at approxi-
mately 11 g/dL.
The percentage of patients whose Hb concentra-
tion was between 11 and 12 g/dL at week 0 was
23.6%. After the start of the study, this increased in a
time-dependent manner reaching ⱖ40% at week 7,
and was kept at approximately 50% from weeks
11–22. At the time of completion or discontinuation
of the study, it was 40.7% (Fig. 2).
The percentage of patients whose Hb concentra-
tion was between 10 and 13 g/dL at week 0 was
71.5%. After starting the study, this increased to
ⱖ80% at week 3, and reached approximately 90% at
week 9. At the time of completion or discontinuation
of the study, it was 83.4% (Fig. 3).
Ther Apher Dial, Vol. 11, No. 3, 2007
513
191 (37.2%)
322 (62.8%)
58.8 ⫾ 12.2 (range: 21–88)
54.4 ⫾ 9.4 (range: 33.2–90.4)
292 (56.9%)
95 (18.5%)
32 (6.2%)
24 (4.7%)
19 (3.7%)
51 (9.9%)
513 (100.0%)
0 (0.0%)
4435.31 ⫾ 2318.45
64 (12.5%)
144 (28.1%)
305 (59.5%)
91.2 ⫾ 80.5 (range: 3–412)
10.33 ⫾ 0.72 (range: 9.00–11.98)
211.8 ⫾ 351.2
28.50 ⫾ 12.05
Dose interval and dosage
In the 333 subjects who received KRN321 once
per week, the mean ⫾ SD Hb concentration was
10.38 ⫾ 0.78 g/dL at week 0, but increased thereafter,
reaching values above 11.0 g/dL at week 7 and
a maximum value of 11.56 ⫾ 0.91 g/dL at week
13. The mean ⫾ SD weekly dosage was 24.04 ⫾
10.36 mg/week at week 0 and reached a maximum of
30.37 ⫾ 19.42 mg/week at week 8. Thereafter, the
mean weekly dosage was kept approximately in the
range of 25–30 mg.
In the 53 subjects who continued to receive
KRN321 once every two weeks, the mean ⫾ SD Hb
concentration was 10.80 ⫾ 0.76 g/dL at week 0, but
increased thereafter, reaching above 11.0 g/dL at
week 13 and it was maintained at approximately
11 g/dL during the remainder of the treatment
period. The mean weekly dosage was 7.45 ⫾ 2.96 mg/
week at week 0, which was increased to more than
10 mg together with the increase of Hb and main-
tained at a dose ranging from 10 to 20 mg/week until
week 51.
In the 116 patients for who originally received
KRN321 once per week and were switched to once
every two weeks, the mean ⫾ SD Hb concentration
was 11.31 ⫾ 0.53 g/dL at the time of changing the
dosing frequency and was kept at approximately
11 g/dL until the end of the treatment period. The
mean weekly dosage was around 20–30 mg/week
© 2007 International Society for Apheresis
 Darbepoetin Alfa in Japanese HD Patients 223

14.0 100

13.0 90

12.0 80

KRN321 dosage (μg/week)

11.0 70
Hb concentration (g/dL)

10.0 60

9.0 50

8.0 40

7.0 30

6.0 20

5.0 10

4.0 0
0 4 8 12 16 20 24 28 32 36 40 44 48 52 Completion
(discontinuation)
Week
FIG. 1. Changes in hemoglobin concentration and weekly average dosage during the study period. (䊉) Hemoglobin (Hb) concentration
(mean ⫾ 95% CI); (䊊) KRN321 dosage (mean ⫾ SD).

throughout the study and 29.05 ⫾ 18.07 mg/week at Safety analysis

the time of completion or discontinuation of the Of the 513 patients included in the safety analysis,
study. 503 (98.1%) developed 4105 adverse events. Those
Results of efficacy were consistent regardless of events occurring with a frequency of ⱖ10% are pre-
the data set or any demographic factor. sented in Table 3.

100
90
80
Maintenance rate (% )

70
60
50
40
30
20
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 Completion
(discontinuation)
Week
FIG. 2. Changes in the maintenance rate of the hemoglobin value between 11 and 12 g/dL.

© 2007 International Society for Apheresis Ther Apher Dial, Vol. 11, No. 3, 2007
224 T Akizawa et al.

100
90
80
Maintenance rate (%)

70
60
50
40
30
20
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 Completion
(discontinuation)
Week
FIG. 3. Changes in the maintenance rate of the hemoglobin value between 10 and 13 g/dL.

Analysis of the adverse events that occurred
during treatment, including those events for which a
causal relationship to KRN321 could not be ruled
out, showed that there was no noteworthy trend in
the occurrence of any specific adverse event with
respect to demographic factors, although the inci-
dence was slightly higher in those subjects with dia-
betes. The number of occurrences for any specific
adverse event did not increase with the dose or
cumulative dose. No change was observed in the
safety profile after switching from weekly to two-
weekly administration of KRN321. As for the
Hb concentration, hypertension and increased
blood pressure were noted at a Hb concentration
ⱖ11.0 g/dL.
Regarding the fatal events for which a causal rela-
tionship with KRN321 could not be ruled out, ven-
tricular fibrillation (n = 1) and cerebral infarction
(n = 1) were noted (0.2%).
TABLE 3. Adverse events occurring in at least 10% of the
patients administered KRN321
Number of patients reporting adverse events
Nasopharyngitis
Arthralgia
Upper respiratory tract inflammation
Contusion
Arteriovenous fistula site complication
Hypertension
Diarrhea
Pain in extremities
Increased blood pressure
Procedural hypotension
KRN321, darbepoetin alfa.
Two subjects were discontinued from the study due
to an increase in the percentage of eosinophils (n = 1)
and an increase in aspartate aminotransferase levels
(n = 1). In both patients, laboratory values returned
to normal after discontinuation of the study drug.
None of the patients was positive for antibodies
against KRN321.
DISCUSSION
In this study, it was demonstrated that administra-
tion of KRN321 at a reduced dosing frequency as
compared with rHuEPO was effective in maintain-
ing the Hb level at approximately 11 g/dL in many
hemodialysis patients who had been treated with
rHuEPO. Furthermore, in those subjects who began
receiving KRN321 at a dosing frequency of once per
week, administration of KRN321 could be changed
to once every two weeks by initiating it at a doubled
dose. In this study, demographic characteristics did
not influence either the primary or secondary end
points.
In examining safety parameters, the majority of the
503 (98.1%) adverse events noted in this study had been recog-
322 (62.8%) nized in previous clinical studies of KRN321. Fatal
94 (18.3%)
91 (17.7%) adverse events for which a causal relationship with
89 (17.3%) KRN321 could not be ruled out occurred in patients
81 (15.8%) with either hypertension or a past history of
71 (13.8%)
59 (11.5%) thrombosis/infarction. As is the case with rHuEPO,
57 (11.1%) the administration of KRN321 will need to be care-
56 (10.9%) fully considered in patients with such complications.
53 (10.3%)
Previous studies have shown that KRN321 can
effectively maintain Hb concentrations when given at

Ther Apher Dial, Vol. 11, No. 3, 2007 © 2007 International Society for Apheresis
 Darbepoetin Alfa in Japanese HD Patients
extended dose intervals relative to rHuEPO (5–10).
The results of this study further confirm the results of
those trials, and demonstrate that KRN321 can effec-
tively and safely maintain Hb concentrations after
switching from rHuEPO at extended dose intervals
in Japanese patients.
The mean Hb concentration at the baseline was
10.326 g/dL in this study and it almost corresponds
with the findings of the Dialysis Outcomes and
Practice Patterns Study (DOPPS) study that
reported the average Hb concentration of Japanese
dialysis patient to be 10.1 g/dL (11). However,
approximately 35% (180/513) of the patients had a
baseline Hb concentration of <10 g/dL, suggesting
that they were suboptimally treated with rHuEPO.
The Hb range primarily recommended in the study
was set at 11–12 g/dL, referring to the National
Kidney Foundation Kidney Disease Outcome
Quality Initiative (K/DOQI) guidelines (12);
however, in this study a wider Hb range of
10–13 g/dL was chosen. This was because the
approved target Hb by epoetin treatment in Japan
was 10 g/dL, while 13 g/dL was applied since previ-
ous studies in which the same upper target was set
reported no major safety problem (6,7). Despite the
reduced frequency of administration, the mean Hb
concentration was maintained at approximately
11 g/dL, regardless of the dosing frequency of
KRN321. The guideline of anemia management, in
which a Hb level of 10–11 g/dL was recommended
for the general dialysis population, was proposed
during this study by Japanese Society for Dialysis
Therapy. This may affect the Hb values in this study.
The proposed Hb range was formally adopted by
the Japanese Guidelines later (13).
These data suggest that it is possible to maintain
the Hb concentrations recommended for Japanese
patients with renal anemia when switching from
rHuEPO to KRN321 at extended dose intervals. The
average dose to maintain the Hb concentration in
this study was 20–30 mg/week throughout the study
period, regardless of the dosing frequency of
KRN321. The dosage was similar to those reported
previously (6,7).
The safety profile of KRN321 was comparable
with that reported for rHuEPO. The adverse events
were generally consistent with those expected for a
patient population on dialysis. The safety profile of
KRN321 is the same before and after switching
from weekly to two-weekly administration. In addi-
tion, previous randomized, controlled trials have
reported similar incidence rates of adverse events
among subjects receiving KRN321 and rHuEPO
(3,4).
© 2007 International Society for Apheresis
225
CONCLUSIONS
In conclusion, the results of this 12-month study of
513 Japanese patients on hemodialysis demonstrate
that treatment of renal anemia with KRN321 at
extended dose intervals relative to rHuEPO can
effectively and safely maintain Hb concentrations.
Such findings suggest that KRN321 has the potential
to simplify the management of anemia in patients on
hemodialysis.
Acknowledgments: The authors thank Prof. E Uchida
(Showa University) and Dr Y Tsukamoto (Shuwa General
Hospital) for their advice on this study. This study was
supported by Kirin Brewery Co. Ltd.
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226 T Akizawa et al.
APPENDIX
The KRN321 A08 Study Group comprises the fol-
lowing members and institutions: H Ishida (Kitasaito
Hospital), N Itami (Nikko Kinen Hospital), S
Miyagata (Nakadori General Hospital), S Yumita
(Kojinkai Central Hospital), H Kawaguchi (IWAKI
Urological Clinic), R Aoyagi (Tyuetu kidney clinic),
A Tsuchida (TOHO Hospital), N Matsui (Tsuchiura
Kyodo General Hospital), T Sato (Sumiyoshi Clinic
Hospital), Y Kanno (Aizawa Hospital), Y Ishida
(Ikebukuro Hospital), K Oguchi (Ikegami General
Hospital, Medical Corporation of Showakai), Y
Komatsu (St. Luke’s International Hospital),
Y Chida (Nakano Clinic), K Matsuzaki (Nansou
Hospital Medical Corporation), F Takeda (Bousei
Anesaki Clinic, Medical Corporation of Showakai),
K Takao (Kisarazu Clinic, Medical Corporation of
Bouseikai), N Takagi (Bousei Kannai Clinic, Medical
Corporation of Showakai), S Takeuchi (Bousei
Fujisawa Clinic, Medical Corporation of Showakai),
H Ogura (Bousei Hiratsuka Clinic, Medical Corpo-
Ther Apher Dial, Vol. 11, No. 3, 2007
ration of Showakai), N Ishida (Seichi Clinic, Medical
Corporation of Seichikai), J Takahashi (Eda Clinic),
F Nakayama (Daini Eda Clinic), T Mineno
(Nakatsugawa Kyoritsu Clinic), Y Kawade (Kaikou-
kai Central Clinic), H Murai (Ama Kyoritsu Clinic),
H Seno (Anjyo Kyoritsu Clinic), Y Sato (Hekikai
Kyoritsu Clinic), K Horikawa (Shizuoka Kyoritsu
Clinic), R Miyazaki (Fujita Memorial Hospital),
S Okuno and T Yamakawa (Shirasagi Hospital),
S Hayashida (Tokuyama Central Hospital), N
Takasugi (Hakuai Hospital), K Fujiwara (Kure
Kyosai Hospital), M Fukushima (Kurashiki Central
Hospital), S Obayashi (Kinashi Obayashi Hospital),
T Mizuguchi (Kawashima Hospital), K Yuasa (Kochi
Takasu Hospital), S Miyake (Shimazu Hospital),
A Shiroozu (Kokura daiichi Hospital), H Higashi
(St.Mary’s Hospital), H Kumagai and K Ikeda
(Fukuoka Red Cross Hospital), S Funakoshi
(Sakuramachi Clinic), K Shinzato (SHINZATO
Nephro-Clinic), T Ikeda (Ikeda Hospital), H Otsuka
(Jiaikai Medical Foundation Imamura Bun-in Hospi-
tal), and S Yoshi (Okinawa Daiichi Hospital).
© 2007 International Society for Apheresis