Original Paper
Nephron Clin Pract 2007;105:c99–c107
DOI: 10.1159/000097985
Prospective Randomized Study Evaluating the
Efficacy of the Spherical Adsorptive Carbon
AST-120 in Chronic Kidney Disease Patients with
Moderate Decrease in Renal Function
Tatsuya Shoji a Akira Wada b Kazunori Inoue a Daisuke Hayashi a
Kodo Tomida a Yoshiyuki Furumatsu a Tetsuya Kaneko a Noriyuki Okada a
Yoshifumi Fukuhara b Enyu Imai c Yoshiharu Tsubakihara a
a
Department of Nephrology, Osaka General Medical Center, b Department of General Internal Medicine,
National Hospital Organization Osaka National Hospital, and c Department of Nephrology, Osaka University
Graduate School of Medicine, Osaka, Japan
Key Words
AST-120
Chronic kidney disease
Glomerular filtration
rate
Iothalamate clearance
Low protein diet
Spherical
adsorptive carbon
Abstract
Aims: We studied whether adding the spherical adsorptive
carbon AST-120 to conventional treatments is effective in in-
hibiting progression of chronic kidney disease (CKD) at the
stage of moderate decrease in renal function. Methods: 43
CKD patients with moderately impaired renal function indi-
cated by glomerular filtration rate (GFR) of 20–70 ml/min as
measured by non-radiolabeled iothalamate clearance meth-
od were enrolled in the study. 26 patients showing a de-
crease of GFR by 5 ml/min during a 1-year observation peri-
od were randomized to receive ongoing treatments only
(control group, 12 cases) or with AST-120 co-administered
with ongoing treatment (AST-120 group, 14 cases). The inter-
vention period was 1 year and the change in GFR was the
primary evaluation variable. Results: The mean changes of
GFR per month (
GFR) in the intervention period were not
significantly different between both groups. However, when
comparing the
GFR in the observation and intervention pe-
© 2007 S. Karger AG, Basel
1660–2110/07/1053–0099$23.50/0
Fax +41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
www.karger.com www.karger.com/nec
Received: January 11, 2006
Accepted: October 1, 2006
Published online: December 15, 2006
riods for each group, the rate of decline in GFR was signifi-
cantly retarded (p ! 0.001) in the AST-120 group while no
significant difference was observed in the control group.
Conclusion: These results suggest that co-administration of
AST-120 with conventional treatments retards decline in re-
nal function in CKD patients with moderate decrease in renal
function. Copyright © 2007 S. Karger AG, Basel
Introduction
In Japan, since starting a statistical survey of dialysis
patients in 1968, the annual increase of dialysis patients
has continued. In the report at the end of 2002, the num-
ber reached 229,538 and continued to see an upward
trend [1]. The medical cost for dialysis occupies a high
percentage of the total medical expenditure, and has be-
come a great social problem. In such a situation, methods
to stop or slow the progression during the early stage of
chronic kidney disease (CKD) have been re-recognized
and interdisciplinary treatment is being implemented
with lifestyle modification, dietary therapy and pharma-
cotherapy as the three central elements. Especially treat-
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Tatsuya Shoji
Department of Nephrology, Osaka General Medical Center
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3-1-56 Mandai-higashi, Sumiyoshi-ku, Osaka 558-8558 (Japan)
Tel. +81 6 6692 1201, Fax +81 6 6606 7000
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E-Mail tshoji-ind@umin.ac.jp

–12
Control group
AST-120 group
Fig. 1. Study design. Entry criteria*: aged
18–70 years at entry, GFR of 20–70 ml/min
at entry, and change of GFR !–5 ml/min/
year during the observation period. GFR
was measured using the modified plasma
iothalamate clearance method.
ment with angiotensin-converting enzyme inhibitor
(ACEI) and angiotensin II receptor blocker (ARB), that
have both hypotensive and renoprotective effects, has re-
cently attracted attention, and evidence validating their
efficacy has been reported by several controlled clinical
trials [2–5]. However, CKD manifests diverse pathologi-
cal conditions from the early stage, and even using the
above drugs does not completely stop the progression.
There is an increasing need for new drugs that possess
different mechanisms of action.
Although hypertension is closely associated with the
progression of renal dysfunction, uremic toxins have also
been presumed to be associated with the progression [6].
In Japan, a spherical adsorptive carbon, AST-120 (Kre-
mezin
), has been developed, which is thought to inhib-
it the progression of renal failure by adsorbing and re-
moving substances including precursors of indoxyl sul-
fate (one of the uremic toxins) from the intestine, a
mechanism of action entirely different from that of con-
ventional drugs. AST-120 was launched in 1991 and is
being used clinically as a treatment for progressive
CKD.
Even after launching, clinical data of AST-120 are
gradually being accumulated [7–11]. In most of the clini-
cal reports, the subjects corresponding to CKD stage 4
were studied, and pre- and post-intervention compari-
sons were made using the slope of the reciprocal of serum
creatinine (1/sCr) [12] as the evaluation index. There is
no report of controlled clinical trials on the efficacy of
AST-120 in stage 3 patients using glomerular filtration
rate (GFR) as the parameter of clinical evaluation. On the
other hand, reports using animal models of early stage
chronic renal failure have demonstrated that administra-
tion of AST-120 retarded the progression of renal failure
c100 Nephron Clin Pract 2007;105:c99–c107
Observation period Intervention period
Months Months
–9 –6 –3 0 3 6 9 12
Observation Observation
Observation AST-120 (6 g/day)
D D
Entry for study Eligible patients* were
randomly allocated
D D D
GFR GFR GFR
[13–18]. Hence, in the clinical setting also, a therapeutic
effect of oral AST-120 given from the early stage of CKD
is anticipated.
We conducted a prospective, randomized, multi-cen-
ter controlled study to examine the efficacy of the spher-
ical adsorptive carbon AST-120 in retarding decline of
renal function in patients with moderately reduced renal
function equivalent to stage 3 CKD, by measuring the
GFR using non-radiolabeled iothalamate.
Methods
Study Design
The study was a prospective, randomized, open-label, con-
trolled study on patients with progressive chronic renal failure,
conducted in three institutions in Osaka district. Subjects were
selected from outpatients aged from 18 to 70, diagnosed as having
chronic renal failure, and followed up at Osaka General Medical
Center, Osaka National Hospital, or Osaka University Hospital.
Figure 1 shows the study design. Patients who satisfied the provi-
sional entry criteria were observed for 12 months. Eligible patients
who satisfied the final selection criteria were randomly allocated
into two groups by the registration center using the block ran-
domization method [19]. The control group continued to take the
ongoing conventional treatments without change for another 12
months. The AST-120 group received co-administration of AST-
120 with the ongoing treatments for 12 months. The protocol of
this study was approved by the ethical committees of Osaka Pre-
fectural Hospital (currently Osaka General Medical Center), Na-
tional Hospital Organization Osaka National Hospital and Osaka
University, and the clinical study was conducted in these three
institutions. The registration center was established at the De-
partment of Nephrology of Osaka Prefectural Hospital, and ran-
domization was performed by a medical secretary who has no
conflict of interest with the study. Before conducting the study,
the investigator obtained informed consent from the subject us-
ing a written document before initiation of the study.
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 Patients
Patients aged from 18 to 70 years diagnosed with CKD, who
had GFR of 620 ml/min measured by the non-radiolabeled io-
thalamate clearance method [20], were provisionally entered.
Among them, those who showed a GFR decline of 65 ml/min
after 12 months were eligible as subjects. Patients who had intes-
tinal transit disorder, patients who were pregnant or had a pos-
sibility of being pregnant, patients showing poor dietary manage-
ment or blood pressure control or other conditions judged by the
investigator to be inappropriate for the study were excluded.
Procedures, Measurements and Outcome
The AST-120 group took AST-120 6 g/day divided into three
fractions. For both groups, dietary and blood pressure manage-
ments were conducted as routine medical care. The target of di-
etary management was protein 0.8 g/kg ideal body weight, calorie
35 kcal/kg ideal body weight and salt !7 g/day. Dietary compli-
ance was not assessed by interviews or by measurement of 24-
hour urinary excretion of urea. The target of blood pressure man-
agement was systolic blood pressure !140 mm Hg and diastolic
blood pressure !90 mm Hg. During the study period, the con-
comitant drugs and dietary therapy were in principle unchanged
with respect to type, method and dose. Dealing with dose chang-
es in blood pressure medication, including angiotensin-I-con-
verting enzyme inhibitors or angiotensin-II-receptor antagonists,
to achieve the target blood pressure were entrusted to attending
physician. Since AST-120 is an adsorbent, simultaneous drug tak-
ing with other concomitant drugs was avoided, and AST-120 was
taken after a lag of 60 min or between meals. In the case of occur-
rence of complications, incidental effects or serious adverse
events, dose reduction or discontinuation of the drug was decided
upon the judgment of the attending physician.
Serum biochemistry (creatinine, urea nitrogen, uric acid, total
protein, albumin, total cholesterol, triglycerides, glutamate pyru-
vic transaminase, lactate dehydrogenase, alkaline phosphatase,
sodium, chloride, calcium, phosphorus and magnesium), hema-
tology (white blood cell count, red blood cell count, hemoglobin,
hematocrit and platelet count), blood pressure, height and weight
were measured at the start of observation period, start of inter-
vention period and completion of interventional period. In the
case of the occurrence of adverse events in both groups, the caus-
al relation with the medications was investigated and measures
taken according to statutory regulations. The study was termi-
nated when continuation of the study was judged impossible due
to initiation of dialysis, death, aggravation of concurrent disease,
onset of other serious disease or adverse drug reaction during the
study period. A case was handled as dropout when the patient
failed to visit during the study period or upon the patient’s wish
to withdraw from the study.
The primary outcome was the mean rate of change in GFR,
and the rates before and after intervention were compared be-
tween groups. GFR was measured using the non-radiolabeled io-
thalamate clearance method [20] conducted at the start of obser-
vation period, at the start of intervention period (also completion
of observation period) and at the completion of interventional
period, for a total of 3 times at 12-month intervals. For each pa-
tient, the change in GFR (
GFR ml/min/month) was calculated
by: GFR at completion of period minus GFR at the start of period
divided by number of months. Thus a negative value indicates
decline in renal function and a positive value an improvement of
Efficacy of AST-120 in Moderate CKD
renal function. Individual
GFR for the observation and inter-
vention periods were calculated, and the mean values per group
were calculated. For individual patients, treatment was rated as
effective when ‘
GFR in observation period !
GFR in interven-
tion period’, and as ineffective when ‘
GFR in observation period
6
GFR in intervention period’. The percentage of effective cas-
es was compared between the two groups.
Two subgroup analyses were conducted. In one study, patients
were stratified according to dietary therapy into a normal protein
diet subgroup and a low protein diet subgroup (prescribed protein
intake !56 g/day), and the pre- and post-intervention changes in

GFR were compared between the AST-120 and control arms as
above. In the other study, patients were stratified according to the
mean GFR at randomization (at the start of intervention) into a
low GFR subgroup (!31.4 ml/min) and a high GFR subgroup
(631.4 ml/min).
Statistical Analysis
Main statistical analyses were conducted using the full analy-
sis set (FAS). Secondary analyses were also conducted using only
those cases that were compatible with the protocol, the per proto-
col set (PPS). Inter-group comparisons of patient background,
concomitant drugs and dietary therapy at the start of intervention
were conducted using 2 test, t test or Mann-Whitney U test de-
pending on the nature of the variable. The clinical laboratory test
values were presented as mean 8 SD, and paired t test was used
to compare pre- and post-intervention values while Mann-Whit-
ney U test was used to compare the values at the start of interven-
tion between groups. Wilcoxon matched-pairs signed-rank test
was used to compare pre- and post-intervention
GFR, and Fish-
er’s direct probability test was used to compare
GFR between
groups. A p value ! 0.05 was considered significant. The above
analyses were done using SAS
release 8.2 software (SAS Insti-
tute, Inc., Cary, N.C., USA).
Results
Forty-three patients satisfied the provisional entry cri-
teria with a GFR of 620 ml/min. After 12 months of ob-
servation, 27 patients satisfied the final entry criteria
with a decrease in GFR of 65 ml/min over 12 months,
and were subjected to randomization. Fourteen patients
were allocated to the AST-120 group and 13 patients to
the control group. One patient in the AST-120 group re-
fused to take AST-120 after randomization, and was ex-
cluded from PPS analysis. Since this patient underwent
conventional treatment for chronic renal failure, he was
included in FAS analysis. One patient in the control group
stopped visiting hospital 5 months after randomization
(reason unknown), and was excluded from both FAS and
PPS analyses (fig. 2).
There were no significant differences in patient back-
ground and concomitant therapies at baseline between
the two groups (tables 1, 2). The GFR and serum creati-
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AST-120 group (n = 14)
AST-120 group (n = 14)
1 withdrawn
(protocol violation)
Follow-up for 1 year (n = 13)
Fig. 2. Disposition of patients.
nine level at the start of intervention were 31.5 8 10.1 and
1.7 8 0.6 mg/dl, respectively, in the control group, and
31.3 8 14.1 and 2.0 8 0.8 mg/dl in the AST-120 group,
with no significant differences between groups. There
were also no differences between two groups in other
clinical laboratory test values including systolic blood
pressure, diastolic blood pressure (fig. 3), urea nitrogen,
albumin, total cholesterol and hematocrit. In the AST-
120 group, the maintenance dose of AST-120 averaged
4.8 8 1.4 g/day, and 7 patients were on a maintenance
dose of 6 g/day.
Primary Outcome
The mean
GFRs in the intervention period were not
significantly different between the AST-120 and the con-
trol groups (fig. 4). We next compared the
GFR in the
observation period with that in the intervention period
for each group. In the AST-120 group, the mean
GFR
(mean 8 SE) was –1.11 8 0.13 ml/min/month over the
observation period and +0.12 8 0.15 ml/min/month
over the intervention period, showing a significant retar-
dation (p ! 0.001) of GFR decline after intervention. On
the other hand, in the control group, the mean
GFR was
–1.33 8 0.22 ml/min/month over the observation period
and –0.34 8 0.33 ml/min/month over the intervention
period, showing no significant difference in mean
GFR
before and after intervention (fig. 4).
c102 Nephron Clin Pract 2007;105:c99–c107
Study entry (n = 43)
Eligible for study (n = 27)
Number randomized (n = 27)
Control group (n = 13)
1 withdrawn
(discontinued)
Control group (n = 12) FAS
Follow-up for 1 year (n = 12) PPS
After calculating the
GFR in the observation and in-
tervention periods for individual patients, each case was
rated as effective or ineffective by comparing the
GFR
in the intervention period with that in the observation
period as described in the Methods. The percentage of
effective cases was 100% (14/14) in the AST-120 group
and 58.3% (7/12) in the control group, and a significant
difference (p = 0.012) was observed between two
groups.
Subgroup Analysis
Subgroup analyses were conducted with the subjects
stratified by dietary therapy and mean GFR at random-
ization (at the start of intervention).
First, the subjects were stratified by prescribed dietary
protein intake of !56 g/day. Even when the patients were
divided into a subgroup of normal protein diet and a sub-
group of low protein diet, there were no significant dif-
ferences in patient background between the AST-120 and
control arms in the two subgroups (data not shown).
In the normal protein diet subgroup, decline of GFR
was significantly retarded (p = 0.016) in the intervention
period compared to the observation period in the AST-
120 group (7 cases), while no significant difference was
observed before and after intervention in the control
group (n = 7) (fig. 5). In the low protein diet group also,
decline of GFR was significantly inhibited (p = 0.016) in
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 150 150

120 120

DBP (mm Hg)

SBP (mm Hg)
90 90

60 60

30 30

Fig. 3. Systolic blood pressure (SBP) and 0 0

diastolic blood pressure (DBP) changes –12 0 12 –12 0 12 –12 0 12 –12 0 12
during the study. SBP and DBP were not Months Months
changed significantly during the study in AST-120 Control AST-120 Control
(n = 14) (n = 12) (n = 14) (n = 12)
both groups. There were no differences be-
tween two groups in SBP and DBP.

Table 2. Concomitant use of conventional medications and diet

Table 1. Baseline characteristics of the patients therapy at baseline

Characteristics AST-120 Control Total 2 test or Co-administrated drug/therapy AST-120 Control Total 2
group group t test** group group test
(n = 14) (n = 12) p (n = 14) (n = 12) p

Sex Antihypertensive drug 13 10 23 0.887

Male 11 10 21 1.000 ACE inhibitor 7 7 14 0.976
Female 3 2 5 Ca channel blocker 10 4 14 0.122
Age, years* 54.1811.2 54.5812.9 0.940** Diuretics 3 2 5 1.000
Underlying disease -Blocker 6 3 9 0.589
DM 1 1 2 0.664 Antiplatelet drug 5 9 14 0.108
CGN 9 8 17 Antihyperuricemic drug 13 7 20 0.106
PCKD 0 1 1 Antihyperlipidemic drug 10 4 14 0.122
Others 4 2 6 Calcium carbonate drug 2 0 2 0.532
Complication 12 10 22 1.000 Sodium bicarbonate drug 4 2 6 0.802
Hypertension 10 6 16 0.474 Drug change during the study 7 5 12 0.976
Hyperlipidemia 4 2 6 0.802
Hyperuricemia 2 3 5 0.848 Diet therapy*
DM 4 0 4 0.142 No 7 7 14 0.976
GFR, ml/min* 31.3814.1 31.5810.1 0.969** Yes 7 5 12
sCr, mg/dl* 2.080.8 1.780.6 0.404** Prescribed protein intake
UN, mg/dl 27.8810.1 26.389.6 0.704** 25–39 g/day 1 0 1 0.632
SBP, mm Hg 132.1817.3 124.5818.5 0.287** 40–49 g/day 2 3 5
DBP, mm Hg 80.9811.4 74.2811.0 50–56 g/day 4 2 6
0.144**
Alb, g/dl No restriction 7 7 14
3.980.4 3.880.4 0.677**
Prescribed energy intake
TC, mg/dl 200.9832.5 186.7831.1 0.275**
1,500–1,999 kcal/day 2 3 5 0.512
Ht, % 39.685.8 38.385.5 0.581**
2,000–2,250 kcal/day 5 2 7
Not prescribed 7 7 14
* Mean 8 SD. DM = Diabetes mellitus; CGN = chronic glo-
Prescribed salt intake
merulonephritis; PCKD = polycystic kidney disease; GFR = glo-
7.0 g/day 7 5 12 0.976
merular filtration rate; sCr = serum creatinine; UN = urea nitro-
No restriction 7 7 14
gen; SBP = systolic blood pressure; DBP = diastolic blood pres-
sure; Alb = albumin; TC = total cholesterol; Ht = hematocrit.
* Diet therapy was not changed during the study.
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Efficacy of AST-120 in Moderate CKD Nephron Clin Pract 2007;105:c99–c107 c103

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 1.0 1.0
p < 0.001*1 NS*1 p = 0.016*1 NS*1
0.5 0.5

GFR (ml/min/month)

GFR (ml/min/month)
0

–0.5 –0.5

–1.0 –1.0

–1.5 –1.5
NS*2 NS*2
–2.0 –2.0
NS*2 NS*2
–2.5 –2.5
rio n

rio n

rio n

rio n

ri n

rio n

rio n

rio n
pe atio

pe tio

pe atio

pe tio

pe atio

pe tio

pe atio

pe tio
d

I n od

d
en

en

en

en
rv

rv

rv
rv
rv

rv

rv

rv
se

se

se
se
te

te

te

te
Ob

Ob

Ob

Ob
In

In

In
AST-120 group (n = 14) Control group (n = 12) AST-120 group (n = 7) Control group (n = 7)

Fig. 4. AST-120 retards the decline of GFR in the analysis of all
subjects. Data are presented as mean 8 SE. *1 Wilcoxon matched-
pairs signed-rank test; *2 Wilcoxon two-sample test; NS: not sig-
nificant.
GFR = GFR at completion of period – GFR at start of
period/number of months.
Fig. 5. AST-120 retards the decline of GFR in the normal protein
diet subgroup. Data are presented as mean 8 SE. *1 Wilcoxon
matched-pairs signed-rank test; *2 Wilcoxon two-sample test; NS:
not significant.
GFR = GFR at completion of period – GFR at
start of period/number of months.

1.0 1.0
p < 0.001*1 NS*1 p = 0.016*1 p = 0.125*1
0.5 0.5

GFR (ml/min/month)

GFR (ml/min/month)

0 0

–0.5 –0.5

–1.0 –1.0

–1.5 –1.5

–2.0 NS*2 –2.0 NS*2

NS*2 NS*2
–2.5 –2.5
ri n

rio n

rio n

rio n

ri n

rio n

rio n

rio n
pe atio

pe tio

pe atio

pe tio

pe atio

pe tio

pe atio

pe tio
I n od

d
en

en

I n od

d
rv

rv

en

en
rv

rv
rv

rv
se

se

rv

rv
se

se
te

te
Ob

Ob

te

te
In

Ob

Ob

In

AST-120 group (n = 7) Control group (n = 5) AST-120 group (n = 7) Control group (n = 6)

Fig. 6. AST-120 retards the decline of GFR in the low protein diet
subgroup. Data are presented as mean 8 SE. *1 Wilcoxon matched-
pairs signed-rank test; *2 Wilcoxon two-sample test; NS: not sig-
nificant.
GFR = GFR at completion of period – GFR at start of
period/number of months.
Fig. 7. AST-120 retards the decline of GFR in the low GFR sub-
group (GFR at the start of intervention: !31.4 ml/min). Data are
presented as mean 8 SE. *1 Wilcoxon matched-pairs signed-rank
test; *2 Wilcoxon two-sample test; NS: not significant.
GFR =
GFR at completion of period – GFR at start of period/number of
months.
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 Discussion
1.0
p = 0.016*1 p = 0.625*1 We studied whether additional add-on oral AST-120
0.5 therapy to conventional treatments is effective in inhibit-
ing progression of CKD at the stage of moderate decrease

GFR (ml/min/month)

0
in renal function, and found that this therapy is useful to
–0.5
retard the progression of renal failure, irrespective of the
concurrent conventional treatment.
–1.0 In the present study, the GFR at the start of interven-
tion was 31.3 8 14.1 ml/min in the AST-120 group and
–1.5 31.5 8 10.1 ml/min in the control group. According to
NS*2
–2.0
the GFR staging in the Kidney Disease Outcome Quality
NS*2 Initiative (K/DOQI) guidelines proposed by the US Na-
–2.5 tional Kidney Foundation [21], our cases corresponded
to stage 3 of CKD defined as renal impairment with mod-
ri n

rio n

rio n

rio n
pe atio

pe tio

pe atio

pe tio
I n od

d
en

en
rv

rv

erate decrease in GFR (30–59 ml/min). In the guidelines,

rv

rv
se

se
te

te
Ob

Ob

In

AST-120 group (n = 7) Control group (n = 6)

Fig. 8. AST-120 retards the decline of GFR in the high GFR sub-
group (GFR at the start of intervention: 631.4 ml/min). Data are
presented as mean 8 SE. *1 Wilcoxon matched-pairs signed-rank
test; *2 Wilcoxon two-sample test; NS: not significant.
GFR =
GFR at completion of period – GFR at start of period/number of
months.
the intervention period compared to the observation pe-
riod in the AST-120 group (7 cases), while no significant
difference was observed before and after intervention in
the control group (n = 5) (fig. 6).
Next, the subjects were stratified by the mean GFR
(31.4 ml/min) at randomization (at the start of interven-
tion). In both low and high GFR subgroups, no signifi-
cant changes in
GFR were observed before and after
intervention in the control group, whereas the
GFR was
significantly improved after intervention compared to
the observation period in the AST-120 group (fig. 7, 8).
There were no significant differences in patient back-
ground between the AST-120 and control arms in both
the low and high GFR subgroups (data not shown).
As secondary analyses, all the above analytical items
were tested by PPS analyses, and the results were equal to
those of FAS analyses.
In the AST-120 group, there was no discontinuation
due to adverse reaction of AST-120 during the interven-
tion period.
the action plan for CKD stage 3 includes blood pressure
control targets of !125/75 for 24-hour urinary protein
excretion of 61 g, and !135/85 for !1 g. Also, ACEI, ARB
and calcium channel blocker are recommended as anti-
hypertensive agents. In the present study, we enrolled pa-
tients who showed progression of renal function impair-
ment, despite reasonable blood pressure control by con-
ventional medications including ACEI, calcium channel
blockers, diuretics and -blockers, and examined wheth-
er add-on therapy of the spherical adsorptive carbon
AST-120 achieves retardation of the progression.
When comparing the mean change in GFR per month
(
GFR) in the intervention period between two groups,
the AST-120 group was not significantly superior to the
control group, probably due to the fact that 7 of 12 cases
in the control group showed a tendency of improvement
in
GFR. The possible reason for this phenomenon may
be the study design, relatively short intervention periods,
or the small sample size. This study was add-on design to
other therapeutic interventions such as antihypertensive
medication and dietary therapy. In the control group, 7
patients (58.3%) had been taking angiotensin-I-convert-
ing enzyme inhibitors. The intervention periods were 12
months which might be short to elucidate the effect of
AST-120 to retard the progression of CKD stage 3. Next,
we compared the
GFR in the observation and interven-
tion periods for each group. In the AST-120 group, the

GFR in the observation period was –1.11 ml/min show-
ing progression of renal failure, whereas the
GFR in the
intervention period was +0.12 ml/min showing an im-
provement of GFR. These results suggest that add-on
therapy with AST120 not only retards the progression of
renal failure but may also be expected to improve the re-
nal function. Even in the comparison of the effective rate
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based on the changes in GFR in individual patients, all
the patients taking AST-120 showed a higher
GFR value
in the intervention period than in the observation period,
proving the efficacy of AST-120 intervention.
Our results suggest that AST-120 add-on therapy is ef-
fective regardless of whether low protein dietary therapy
is being implemented. We stratified the subjects by di-
etary status (low protein or normal protein) to examine
whether the efficacy of AST-120 intervention is depen-
dent on the diet. In both subgroups of low protein diet
and normal protein diet, significant improvement was
observed in the AST-120 group whereas the decline of
GFR in the control group was not retarded.
Furthermore, we stratified the subjects by GFR at ran-
domization (at the start of intervention) into low and high
GFR subgroups and compared the
GFR. While the de-
cline of GFR was significantly inhibited during the inter-
vention period compared to the observation period in the
AST-120 group, the
GFR did not change significantly in
the control group. These findings indicate that AST-120
therapy is not only effective when chronic renal failure has
advanced considerably, but is also useful at an early stage
when the renal function is relatively preserved.
In these analyses, there were no significant differences
between groups in the concomitant dietary therapy and
medications at entry, and no pre- and post-intervention-
al differences in clinical laboratory test values such as
blood pressure, lipids and anemia.
AST-120 adsorbs indole, the precursor of indoxyl sul-
fate, in the intestine to decrease the blood level and uri-
nary excretion of indoxyl sulfate, and improves the exces-
sive load of indoxyl sulfate on the residual nephrons [22–
24]. Uremic toxins such as indoxyl sulfate have been
demonstrated to be a factor for the progression of renal
failure [6]. Indoxyl sulfate promotes glomerulosclerosis
and interstitial fibrosis of the kidney, and is presumed to
be associated with metabolic disorder. In studies using
animal disease models of diabetic nephropathy and
chronic renal failure, administration of AST-120 has been
shown to retard the progression of glomerular hypertro-
phy, glomerulosclerosis, interstitial fibrosis and urinary
protein excretion [14, 18]. AST-120 may break the vicious
cycle of renal failure progression and retards the progres-
sion of renal failure by adsorbing the uremic toxins in the
body [25].
Previous reports suggest that the factors responsible
for the preservation of GFR and retardation of CKD pro-
gression by AST-120 are different from the factors related
to blood pressure and dietary protein load, but are associ-
ated with the so-called ‘circulating toxin’. In studies com-
c106 Nephron Clin Pract 2007;105:c99–c107
paring AST-120 with control using a rat model of chron-
ic renal failure with pair-feeding, AST-120 has been re-
ported to be effective in maintaining GFR under a
condition of normal protein diet as well as when main-
tained on low protein diet or administered ACEI [26, 27].
Both clinical and animal studies have demonstrated that
AST-120 inhibits the progression of renal failure without
affecting the renin-angiotensin system or protein intake
[28–31]. Administration of AST-120 to patients with non-
diabetic chronic renal failure before initiation of dialysis
has been shown to improve pulse wave velocity and in-
tima-media thickness and also inhibit atherosclerosis
[32]. A study using the adriamycin-induced nephropathy
model has suggested that administration of AST-120 mit-
igates vascular lesions [33]. Addition of AST-120 to con-
ventional treatments is also expected to achieve synergis-
tic effects in retarding CKD progression and mitigating
cardiovascular complications. A criticism of this study
may be the suggestion that influence of proteinuria was
not explored at all. Of course, the level of proteinuria is
one of the important factors that may affect the decline
of renal function. We could not examine the level of pro-
teinuria in detail enough in outpatient setting.
In the present study, we enrolled CKD patients with
moderately decreased renal function and measured the
GFR using non-radiolabeled iothalamate. Our results
suggest that the spherical adsorptive carbon AST-120 re-
tards progressive decline of renal function and may also
provide renoprotection. In addition, AST-120 possesses a
mechanism of action different from those of convention-
al therapeutic agents, and is expected to be a very impor-
tant modality in the treatment strategy for CKD. How-
ever, the number of cases in this study was limited (espe-
cially if there were less than 10 cases each in subgroup
study) and further comparative study with a larger num-
ber of cases is required to validate the present results.
169.230.243.252 - 11/30/2014 10:53:09 AM
Shoji et al.
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