VOL 47, NO 4, APRIL 2006

AJKD
ORIGINAL INVESTIGATIONS
American Journal of
Kidney Diseases

Pathogenesis and Treatment of Kidney Disease and Hypertension

A Multicenter, Randomized, Double-Blind, Placebo-Controlled,
Dose-Ranging Study of AST-120 (Kremezin) in Patients With
Moderate to Severe CKD
Gerald Schulman, MD, Rajiv Agarwal, MD, Muralidhar Acharya, MD, Tomas Berl, MD,
Samuel Blumenthal, MD, and Nelson Kopyt, DO

● Background: AST-120 (Kremezin; Kureha Chemical Industry Co Ltd, Tokyo, Japan) is an orally administered adsorbent
showing adsorption ability superior to activated charcoal for certain organic compounds known to be precursors of
substances that accumulate in patients with chronic kidney disease (CKD) and that are believed to accelerate the decline in
kidney function. AST-120 is approved in Japan for prolonging time to hemodialysis therapy and improving uremic symptoms
in patients with CKD. Methods: A multicenter, randomized, double-blind, placebo-controlled, dose-ranging study was
designed to examine the nephroprotective effects of 3 doses of AST-120 versus placebo in adult patients with moderate to
severe CKD and elevated serum indoxyl sulfate levels while following an adequate protein-intake diet. Eligible patients were
randomly assigned to 1 of 3 doses of AST-120 (0.9, 2.1, or 3.0 g) or placebo 3 times daily for 12 weeks. Results: AST-120
decreased serum indoxyl sulfate levels in a dose-dependent fashion. During the 12-week treatment period, AST-120 did not
affect serum creatinine levels or 24-hour urine creatinine appearance. Significant improvements in malaise were observed in
a dose-dependent fashion. All doses of AST-120 were well tolerated and did not adversely affect the general health status of
patients. Conclusion: Results suggest that the dose of 3 g 3 times daily is an optimal dose for the US population, and it may
be useful in the treatment of patients with CKD. Because AST-120 did not directly affect serum creatinine levels or 24-hour
urine creatinine appearance, the composite end point of doubling of serum creatinine level, transplantation, and dialysis
therapy would be appropriate for a confirmatory phase III therapeutic outcome study. Am J Kidney Dis 47:565-577.
© 2006 by the National Kidney Foundation, Inc.

INDEX WORDS: Serum indoxyl sulfate; chronic kidney disease (CKD); nephroprotective; AST-120; Kremezin
(Kureha Chemical Industry Co Ltd, Tokyo, Japan); serum creatinine; urine creatinine; uremic toxins.

T HE INCIDENCE OF end-stage renal dis-

ease in the United States has increased
annually during the past decade, a develop-
ment with important implications for indi-
vidual patients and caregivers, as well as for
society. The nephroprotective effects of capto-

From Nephrology, Vanderbilt University Medical Center,
Nashville, TN; Medicine, Indiana University, Indianapolis, IN;
Outcomes Research International Inc, Hudson, FL; Renal,
University of Colorado, Denver, CO; Nephrology, University of
Wisconsin, Milwaukee, WI; and Northeast Clinical Research
Center Inc, Allentown, PA.
Received August 3, 2005; accepted in revised form
December 12, 2005.
Originally published online as doi:10.1053/j.ajkd.2005.12.036
on February 16, 2006.
Support: This study was supported by Kureha Chemical
Industry Co, Ltd, and Sankyo Co, Ltd. Potential conflicts of
interest: None.
Presented in part at American Society of Nephrology Renal
Week 2004, St Louis, MO, October 27-November 1, 2004.
Address reprint requests to Gerald Schulman, MD, Profes-
sor of Medicine, Vanderbilt University School of Medicine,
S3223 Medical Center North, Vanderbilt University Medical
Center, Nashville, TN 37232. E-mail: gerald.schulman@
vanderbilt.edu
© 2006 by the National Kidney Foundation, Inc.
0272-6386/06/4704-0001$32.00/0
doi:10.1053/j.ajkd.2005.12.036

American Journal of Kidney Diseases, Vol 47, No 4 (April), 2006: pp 565-577 565
566
pril, an angiotension-converting enzyme (ACE)
inhibitor, were shown in a well-designed pro-
spective randomized clinical study,1 and it is
available in the United States for the treatment
of patients with type 1 diabetic nephropathy.
Ramipril, another ACE inhibitor, was shown to
slow the progression of chronic kidney disease
(CKD),2 and the nephroprotective effects of
losartan and irbesartan (angiotensin II receptor
blockers) were shown in long-term large-scale
studies.3-5 These agents now are approved for
the treatment of patients with type 2 diabetic
nephropathy.
However, even with these available treat-
ments, a substantial number of patients still
progress to end-stage renal disease. New agents
capable of altering the rate of decline in renal
function through novel pharmacological
mechanisms offer a potentially meaningful ex-
pansion in the number of treatment options. To
augment the number of treatment options cur-
rently available, new agents operating through
novel mechanisms of action are needed to slow
renal deterioration in patients with CKD.
Indoxyl sulfate is one of many putative
uremic toxins.6 Serum indoxyl sulfate levels
are increased in patients with CKD and appear
to correlate with disease progression. Adminis-
tration of indoxyl sulfate to nephrectomized
rats resulted in decreased renal function and
increased glomerular sclerosis in the remnant
kidney.7 Furthermore, indoxyl sulfate–stimu-
lated transcription of genes related to renal
fibrosis, such as transforming growth factor
␤1, tissue inhibitor of metalloproteinases 1,
and pro-␣1 collagen, was observed.8,9 Uremic
toxins, including indoxyl sulfate, may induce
free radical production by renal tubular cells
and activate nuclear factor-␬B, which, in turn,
upregulates plasminogen activator inhibitor 1
expression.10 The induction of nephrotoxicity
by indoxyl sulfate may be mediated by organic
anion transporters, such as organic anion trans-
porter types 1 and 3.11 In vivo synthesis of
indoxyl sulfate begins with enterobacterium-
mediated conversion of dietary tryptophan to
indole in the gastrointestinal tract. After en-
teric absorption, hepatic hydroxylation and sul-
fation of indole results in the formation of
indoxyl sulfate. Patients with normal renal
function have serum indoxyl sulfate levels
SCHULMAN ET AL
approaching 0 mg/dL, whereas values progres-
sively increase in patients with renal compro-
mise, generally exceeding 0.8 to 1.0 mg/dL in
those with serum creatinine levels of 3.0 mg/dL
or greater (ⱖ265 ␮mol/L).7
AST-120 (Kremezin; Kureha Chemical In-
dustry Co Ltd, Tokyo, Japan) has superior
adsorption ability for certain small-molecular-
weight organic compounds known to accumu-
late in patients with CKD. In uremic rats and
patients with CKD, oral administration of AST-
120 decreased the elevated pretreatment levels
of serum indoxyl sulfate.12,13 In Japan, it was
reported that AST-120 suppressed the increase
in serum creatinine levels, improved uremic
symptoms, and, consequently, led to the post-
ponement of dialysis therapy in a clinical
study.14 Although the mechanism of action of
AST-120 is uncertain, one possibility is that
the agent may absorb enteric indole, resulting
in a decrease in increased serum indoxyl sul-
fate levels. This does not rule out other mecha-
nisms of action because AST-120 can bind a
number of low-molecular-weight compounds
that are putative toxins. However, it is clear
that AST-120 prevented proteinuria, glomeru-
lar hypertrophy, interstitial fibrosis, and pro-
gression of renal failure disease in animals
with reduced renal mass.15,16 Thus, use of
AST-120 may abrogate profibrotic stimuli by
mechanisms that initially differ from those
entrained by ACE inhibitors or angiotensin II
receptor blockers.
In addition, important observations from ex-
perimental models of CKD showed that use of
AST-120 in conjunction with an ACE inhibitor
is associated with a greater protective effect
than either agent alone.17,18
This study evaluates the effect of 3 doses of
AST-120 (0.9, 2.1, or 3.0 g, 3 times daily)
compared with placebo on change from base-
line in serum indoxyl sulfate levels (primary
end point) as a surrogate end point for a
potential nephroprotective effect. This study
also evaluates the potential for AST-120 to
affect serum creatinine levels and urinary cre-
atinine appearance independent of its effect on
renal function (eg, as a consequence of creati-
nine adsorption by AST-120 in the gut lumen,
which would lead to decreased 24-hour urinary
creatinine excretion). Additional objectives in-
AST-120 LOWERS INDOXYL SULFATE LEVELS IN CKD
clude assessment of uremic symptoms, serum
vitamin D and K concentrations, nutritional
status, patient compliance with study-drug regi-
mens, and drug safety and tolerability.
METHODS
Patients
Patients were enrolled in this study from 29 clinical
sites in the United States. Eligible patients were 18 years
or older and had serum creatinine levels of 3.0 mg/dL or
greater (ⱖ265 ␮mol/L) and 6.0 mg/dL or less (ⱕ530
␮mol/L) and serum indoxyl sulfate levels of 0.50 mg/dL
or greater while following an adequate protein-intake
diet. They also had to have no recent (within 3 months)
evidence of spontaneous improvement in underlying CKD
and a stable blood pressure (⬍160/90 mm Hg) during the
previous 3 months. Patients were excluded from the study
if they were clinically malnourished (defined as dietary
protein intake ⬍0.6 g/kg/d, serum albumin level ⱕ2.9
g/dL [ⱕ29 g/L], or serum prealbumin level ⱕ16 mg/dL),
had a history of recent (within 6 months) accelerated or
malignant hypertension, had a history of acute nephro-
toxic or ischemic (acute tubular necrosis) kidney disease
within the past 3 months, or had uncontrolled arrhythmia
or severe cardiac disease (New York Heart Association
classes III to IV), including acute myocardial infarction,
percutaneous transluminal coronary angioplasty, cardio-
vascular accident, or transient ischemic attack, within the
past 3 months.
To assess treatment compliance, accurate records were
kept of all returned empty bottles, unused study drug, and
packaging cartons for each individual patient in the study.
The study was completed according to the guidelines of
Good Clinical Practice, conducted in full compliance with
the World Medical Assembly Declaration of Helsinki, and
approved by each site’s institutional review board. All pa-
tients provided written consent before participation in the
study.
Study Design
This was a multicenter, randomized, double-blind, pla-
cebo-controlled, parallel-group, comparative, dose-rang-
ing study designed to examine the effect of 3 doses of
AST-120 versus placebo on serum indoxyl sulfate levels
in adult patients with moderate to severe CKD and
elevated serum indoxyl sulfate levels while following an
adequate protein-intake diet.
After an initial 2- to 4-week screening period, eligible
patients were randomly assigned (stratified within each
treatment arm by type of CKD; diabetic or nondiabetic
nephropathy) to administration of 1 of 3 doses of AST-
120 (3.0, 2.1, or 0.9 g) or matching placebo 3 times daily
for 12 weeks. Total daily doses of AST-120 were 9.0, 6.3,
and 2.7 g for the 3 active-treatment groups, respectively.
Patients in the 9.0-g AST-120 treatment group were
administered 10 capsules of 300-mg active drug 3 times
daily, patients in the 6.3-g AST-120 treatment group were
administered 7 capsules of 300-mg active drug and 3
capsules of 300-mg placebo 3 times daily, patients in the
567
2.7-g AST-120 treatment group were administered 3 cap-
sules of 300-mg active drug and 7 capsules of 300-mg
placebo 3 times daily, and patients in the placebo treat-
ment group were administered 10 capsules of 300-mg
placebo 3 times daily. Study drug was administered with
meals and at least 1 hour after the administration of other
drugs. A 2-week follow-up period for safety evaluations
concluded the controlled study. Randomization sequences
were computer generated. Patients who met all eligibility
requirements were randomly assigned to 1 of the 4
treatment groups after baseline evaluations by using a
1:1:1:1 ratio.
Study Drug
AST-120 consists of black spherical carbon particles
approximately 0.2 to 0.4 mm in diameter. Active drug
used in this study was provided as a capsule containing
300 mg of AST-120. Capsules used were a size-0 maroon
opaque hard gelatin capsule without seeing through the
contents to maintain the double-blind design. Placebo
(black microcrystalline cellulose) was supplied in the
same capsules. The drug substance was provided by
Kureha Chemical Industry Co Ltd, Tokyo, Japan, and
encapsulated and bottled by Schwarz Pharma Manufactur-
ing Inc, Seymour, IN. Packaging, labeling, and distribu-
tion were handled by Xerimis Inc, Moorestown, NJ.
Criteria of Evaluation
The primary efficacy end point is change in serum
indoxyl sulfate level from baseline. Secondary efficacy
end points include changes from baseline in serum creati-
nine levels, reciprocal of serum creatinine, proteinuria,
creatinine excretion, and creatinine clearance; assess-
ments of nutritional status (urine urea nitrogen, serum
albumin, and prealbumin levels) and uremic symptoms
(malaise, nausea, anorexia, pruritus, halitosis, and neurop-
athy); and patient compliance with the study drug. For the
evaluation of safety, adverse events, clinical laboratory
assessments, and complete physical examination data
were collected. All recorded adverse events were coded
by using MedDRA version 5.1 (Northrup Grumman,
Mission Systems, Reston, VA). Treatment-emergent ad-
verse events included nonserious adverse events starting
between the first dose and last dose of study drug or those
that worsened in intensity and serious adverse events
starting between the first dose of study drug and 30 days
after the last dose of study drug. All laboratory assessments
except that of serum indoxyl sulfate were performed at a central
laboratory. Indoxyl sulfate concentration in serum was deter-
mined by means of liquid chromotography/mass spectroscopy
using tetra deuterated indoxyl sulfate as an internal standard in
CentraLabS Clinical Research Inc, East Millstone, NJ.
Statistical Analysis
The intent-to-treat population was used for the analysis of
both primary and secondary end points. The primary effi-
cacy end point is within-treatment-group change from base-
line in serum indoxyl sulfate levels. Significance of the
change from baseline after 3 months of treatment within
568
each treatment group was evaluated by using a paired t-test
and signed rank test.
For the secondary analysis of serum indoxyl sulfate lev-
els, analysis of covariance (ANCOVA) model with treat-
ment and center as factors and baseline as covariate and
Mann-Whitney test with treatment as factors were per-
formed to evaluate the significance of change from baseline
after 3 months between each AST-120 treatment group and
the placebo group.
Secondary efficacy end points were analyzed by using the
same methods as for the primary end point.
To evaluate the reciprocal of serum creatinine change rate
over time (from week 0 to end of study, excluding the
follow-up visit), linear regression was constructed for each
patient by using the actual week as an independent variable.
Slopes from individual linear regressions were summarized
by treatment groups. The analysis of variance model with
treatment and center as factors and Mann-Whitney test with
treatment as factor were performed to evaluate the signifi-
Fig 1. Patient disposition: 164 patients were randomly assigned. Patients who discontinued the study before
study drug administration, those administered study drug, and those who completed the study were disposed in
each treatment group.
SCHULMAN ET AL
cance of the slope difference between each AST-120 treat-
ment group and the placebo group.
Uremic symptoms (malaise, nausea, anorexia, pruritus, hali-
tosis, and neuropathy) were graded by patients as mild, moder-
ate, or severe. Results were summarized for each symptom
according to whether the symptom was unchanged, improved,
or aggravated at week 12 compared with baseline. Chi-square
test was used to compare changes from baseline in active-
treatment groups versus placebo.
Patients who reached a composite-outcome end point
component (doubling of serum creatinine level compared
with baseline, transplantation or dialysis therapy [initiation
of hemodialysis or peritoneal dialysis therapy or serum
creatinine ⬎8.0 mg/dL (⬎707 ␮mol/L) in patients without
diabetes or serum creatinine ⬎6.0 mg/dL (⬎530 ␮mol/L) in
patients with diabetes in postbaseline assessment], and death)
were summarized for each treatment group. Time to achieve
a composite end point component was summarized by
means of Kaplan-Meier estimates. Log rank tests were used
AST-120 LOWERS INDOXYL SULFATE LEVELS IN CKD 569

to evaluate the significance of differences between each
AST-120 treatment group and the placebo group.
RESULTS
Study Population
One hundred sixty-four patients were randomly
assigned to administration of at least 1 dose of
study drug: 41 patients (25.0%) in the 9.0-g AST-
120 treatment group, 41 patients (25.0%) in the
6.3-g AST-120 treatment group, 40 patients (24.4%)
in the 2.7-g AST-120 treatment group, and 42
patients (25.6%) in the placebo treatment group
(Fig 1). Of these 164 patients, 7 patients (4.3%)
were randomly assigned, but never administered
study drug: 2 patients (4.9%) in the 9.0-g AST-120
treatment group, 1 patient (2.4%) in the 6.3-g
AST-120 treatment group, 1 patient (2.5%) in the
2.7-g AST-120 treatment group, and 3 patients
(7.1%) in the placebo treatment group. Reasons for
7 patients discontinuing before receiving the study
drug were fractured hip and hospitalization, dia-
betic gastroparesis, transportation problems to clinic,
delayed baseline visit, myocardial infarction before
baseline visit, and withdrawal of consent because
of the number of capsules.
One hundred fifty-seven patients were admin-
istered at least 1 dose of study drug and were
included in the safety analyses. Of these, 154
patients (98.1%) were included in the intent-to-
treat population for all efficacy analyses, and 3
patients were excluded from the intent-to-treat
population because they did not have at least 1
postbaseline efficacy evaluation.
One hundred thirty-two patients (84.1%) com-
pleted the 12-week treatment phase: 33 patients
(84.6%) in the 9.0-g AST-120 treatment group, 32

Table 1. Demographic and Baseline Characteristics

Treatment Group

9.0 g AST-120 6.3 g AST-120 2.7 g AST-120 Placebo

Parameter (N ⫽ 39) (N ⫽ 40) (N ⫽ 39) (N ⫽ 39)

Age (y)
n 39 40 39 39
Mean (SD) 69.3 (13.93) 66.3 (10.24) 59.6 (13.83) 63.1 (12.94)
Median 71 66.5 59 65
Minimum, maximum 40, 88 37, 86 29, 81 25, 84
Sex
Male 30 (76.9) 22 (55.0) 30 (76.9) 25 (64.1)
Female 9 (23.1) 18 (45.0) 9 (23.1) 14 (35.9)
Race
White 30 (76.9) 29 (72.5) 24 (61.5) 22 (56.4)
Black 3 (7.7) 9 (22.5) 9 (23.1) 11 (28.2)
Asian 1 (2.6) 1 (2.5) 3 (7.7) 0 (0)
Hispanic 5 (12.8) 1 (2.5) 2 (5.1) 6 (15.4)
American Indian 0 (0) 0 (0) 1 (2.6) 0 (0)
Other 0 (0) 0 (0) 0 (0) 0 (0)
Height (cm)
n 39 39 36 38
Mean (SD) 172.2 (10.77) 170.1 (10.04) 169.6 (11.21) 170.3 (9.58)
Median 171 170.2 170.1 170.2
Minimum, maximum 147, 198 152, 185 147, 191 155, 185
Weight (kg)
n 39 40 39 39
Mean (SD) 85.6 (21.07) 93.2 (17.95) 94.6 (23.79) 94.8 (20.99)
Median 83 92.4 90.9 91.9
Minimum, maximum 44, 148 49, 134 47, 144 60, 146
Type of CKD
Diabetic nephropathy 22 (56.4) 24 (60.0) 22 (56.4) 17 (43.6)
Nondiabetic nephropathy 17 (43.6) 16 (40.0) 17 (43.6) 22 (56.4)

NOTE. Values expressed as number of patients evaluated for demographics (percent) unless indicated otherwise. N
indicates number of patients in the safety population; n indicates number of patients evaluated for demographics.
570 SCHULMAN ET AL

Fig 2. Mean changes in serum indoxyl sulfate values from baseline; mean point estimates with 95% confidence
intervals of changes in serum indoxyl sulfate levels from baseline by visit.

patients (80.0%) in the 6.3-g AST-120 treatment
group, 33 patients (84.6%) in the 2.7-g AST-120
treatment group, and 34 patients (87.2%) in the
placebo treatment group.
Patient age ranged from 25 to 88 years, with a
mean age of 64.6 years. The majority of these
patients were white (66.9%) and men (68.2%).
Average duration of therapy was 84 days. Demo-
graphic and baseline characteristics showed ho-
mogeneity between treatment groups for sex,
race, height, weight, and type of CKD (Table 1).
Efficacy Evaluations
Primary end points. Figure 2 shows mean
changes in serum indoxyl sulfate levels from
baseline for the intent-to-treat population at weeks

Table 2. Changes in Serum Indoxyl Sulfate Levels From Baseline at Week 12

Treatment Group

9.0 g AST-120 6.3 g AST-120 2.7 g AST-120 Placebo

(N ⫽ 38) (N ⫽ 39) (N ⫽ 39) (N ⫽ 38)

Baseline values (mg/dL)

Mean (SD)* 0.84 (0.407) 0.85 (0.386) 0.78 (0.332) 0.98 (0.364)
Change from baseline to week 12
n 38 39 39 38
Mean (SD) ⫺0.330 (0.298) ⫺0.171 (0.321) ⫺0.020 (0.359) ⫺0.027 (0.371)
Median ⫺0.265 ⫺0.180 ⫺0.040 ⫺0.015
Minimum, maximum ⫺0.88, 0.42 ⫺0.75, 1.07 ⫺0.85, 1.36 ⫺1.20, 0.98
95% CI for treatment difference
(AST-120 v placebo)† ⫺0.48-⫺0.18 ⫺0.32-⫺0.02 ⫺0.24-0.06
P
Paired t-test within treatment group ⬍0.001 0.002 0.726 0.655
ANCOVA model (AST-120 v placebo)† ⬍0.001 0.026 0.252

NOTE. The last nonmissing observed postbaseline value was used if a postbaseline value was missing. If a patient
terminated early, the value for week 12/early termination visit was used for each following scheduled visit(s).
Abbreviations: CI, confidence interval; N, number of patients in the intent-to-treat population; n, number of patients
evaluated for serum indoxyl sulfate levels.
*Baseline value was week 0 value or screening value if week 0 value was missing.
†Ninety-five percent CI and P for treatment difference (AST-120 versus placebo) were based on ANCOVA model with
treatment and center as factors and baseline measurement as covariate.
AST-120 LOWERS INDOXYL SULFATE LEVELS IN CKD 571

Table 3. Changes in Serum Creatinine, Reciprocal of Serum Creatinine, Creatinine Clearance,

24-Hour Urine Protein, and 24-Hour Urine Creatinine From Baseline to Week 12

Treatment Group

9.0 g AST-120 6.3 g AST-120 2.7 g AST-120 Placebo

(N ⫽ 38) (N ⫽ 39) (N ⫽ 39) (N ⫽ 38)

Serum creatinine (mg/dL)

Baseline values
Mean (SD)* 4.33 (0.867) 4.47 (0.888) 4.35 (0.965) 4.58 (1.044)
Change from baseline to week 12
N 38 39 39 38
Mean (SD) 0.10 (0.69) 0.13 (0.73) 0.20 (0.69) ⫺0.10 (0.99)
Median 0.10 0.10 0.20 0
Minimum, maximum ⫺1.4, 1.7 ⫺1.3, 1.8 ⫺1.2, 2.2 ⫺4.7, 1.6
95% CI for treatment difference
(AST-120 v placebo)† ⫺0.023-0.56 ⫺0.17-0.60 ⫺0.10-0.68
P
Paired t-test within treatment
group 0.367 0.286 0.081 0.526
ANCOVA model (AST-120 v
placebo)† 0.403 0.264 0.145
Reciprocal of serum creatinine
(␮L/mg)
Baseline values
Mean (SD)* 24,093.8 (5,199.09) 23,227.3 (4,640.76) 24,072.3 (5,047.87) 22,838.4 (4,689.67)
Change from baseline to week 12
n 38 39 39 38
Mean (SD) ⫺531.6 (4,184.7) 375.6 (4,738.6) ⫺574.7 (3,563.8) 680.6 (5,090.2)
Median ⫺665.5 ⫺443.3 ⫺847.9 0
Minimum, maximum ⫺13,492, 10,036 ⫺10,714, 15,152 ⫺8,333, 10,721 ⫺5,769, 20,346
95% CI for treatment difference
(AST-120 v placebo)† ⫺3,103.0-1,339.3 ⫺2,320.3-2,066.6 ⫺3,207.8-1,216.3
P
Paired t-test within treatment
group 0.439 0.623 0.320 0.415
ANCOVA model (AST-120 v
placebo)† 0.433 0.909 0.375
Creatinine clearance (mL/min)
Baseline values
Mean (SD)* 16.90 (6.149) 16.22 (5.922) 19.18 (5.902) 16.97 (6.394)
Change from baseline to week 12
n 30 29 32 32
Mean (SD) 0.91 (9.69) ⫺1.92 (5.10) ⫺1.80 (6.33) 0.19 (6.14)
Median ⫺0.57 ⫺1.96 ⫺2.77 ⫺0.75
Minimum, maximum ⫺8.9, 45.9 ⫺14.8, 8.2 ⫺12.3, 13.5 ⫺17.0, 12.4
95% CI for treatment difference
(AST-120 v placebo)† ⫺2.71-3.4 ⫺6.74-⫺0.36 ⫺5.14-1.51
P
Paired t-test within treatment
group 0.611 0.053 0.117 0.861
ANCOVA model (AST-120 v
placebo)† 0.803 0.030 0.281
24-Hour urine protein (mg/24 h)
Baseline values
Mean (SD)* 2,335.1 (3,241.67) 2,668.1 (2,917.56) 2,216.0 (2,653.98) 2,033.3 (2,080.46)
Change from baseline to week 12
n 29 31 36 32
Mean (SD) 224.46 (1,238.29) 8.46 (993.18) 254.58 (1,589.47) 390.79 (1,367.06)
(Continued)
572 SCHULMAN ET AL

Table 3 (Cont’d). Changes in Serum Creatinine, Reciprocal of Serum Creatinine, Creatinine Clearance,
24-Hour Urine Protein, and 24-Hour Urine Creatinine From Baseline to Week 12

Treatment Group

9.0 g AST-120 6.3 g AST-120 2.7 g AST-120 Placebo

(N ⫽ 38) (N ⫽ 39) (N ⫽ 39) (N ⫽ 38)

Median 45.00 ⫺16.00 ⫺0.60 49.00

Minimum, maximum ⫺4,011.0, 3,088.0 ⫺2,795.0, 2,943.0 ⫺3,850.0, 6,632.0 ⫺1,983.0, 5,361.0
95% CI for treatment difference
(AST-120 v placebo)† ⫺810.92-605.73 ⫺1,013.65-400.54 ⫺882.77-516.67
P
Paired t-test within treatment
group 0.337 0.624 0.343 0.116
ANCOVA model (AST-120 v
placebo)2 0.774 0.392 0.605
24-Hour urine creatinine (mg/24 h)
Baseline values
Mean (SD)* 1,167.1 (408.02) 1,196.6 (452.24) 1,352.5 (375.02) 1,303.0 (416.60)
Change from baseline to week 12
n 30 31 36 33
Mean (SD) 106.50 (744.88) ⫺119.48 (321.61) ⫺96.81 (413.62) 10.85 (436.18)
Median 32.00 ⫺101.00 ⫺128.50 ⫺31.00
Minimum, maximum ⫺750.0, 3,659.0 ⫺1,057.0, 347.0 ⫺970.0, 756.0 ⫺1,130.0, 892.0
95% CI for treatment difference
(AST-120 v placebo)† ⫺240.05-230.34 ⫺444.68-25.86 ⫺361.13-105.77
P
Paired t-test within treatment
group 0.440 0.047 0.169 0.887
ANCOVA model (AST-120 v
placebo)† 0.967 0.080 0.280

NOTE. The last nonmissing observed postbaseline value was used if a postbaseline value was missing. If a patient
terminated early, the value for week 12/early termination visit was used for each following scheduled visit(s). To convert
creatinine in mg/dL to ␮mol/L, multiply by 88.4; creatinine clearance in mL/min to mL/s, multiply by 0.01667.
Abbreviations: CI, confidence interval; N, number of patients in the intent-to-treat population; n, number of patients
evaluated for an efficacy parameter.
*Baseline value was week 0 value or screening value if week 0 value was missing.
†Ninety-five percent CI and P for treatment difference (AST-120 versus placebo) were based on ANCOVA model with
treatment and center as factors and baseline measurement as covariate.

8 and 12. For the primary analysis, mean changes
from baseline in serum indoxyl sulfate levels for
the 9.0-g and 6.3-g AST-120 treatment groups
showed statistically significant decreases at week
12 (for both active treatment groups, P ⱕ 0.002
for paired t-test within-treatment-group analy-
ses; Table 2).
For the secondary analysis, mean changes
from baseline in serum indoxyl sulfate levels for
the 9.0-g and 6.3-g AST-120 treatment groups
showed dose-related statistically significant de-
creases compared with placebo at week 12 (P ⱕ
0.03 for ANCOVA for both treatment groups).
Secondary end points. During the 12-week
study period, patients treated with AST-120
showed no consistent or dose-related changes in
serum creatinine levels, reciprocal of serum cre-
atinine, creatinine clearance, or urine protein
levels (Table 3). Mean change from baseline in
urinary creatinine excretion in the 6.3-g AST-120
treatment group showed a statistically significant
decrease (⫺119.48 mg/24 h) at week 12 for paired
t-test within-treatment-group analyses (P ⫽ 0.047).
However, this pattern was not evident in the other
dose groups.
For the uremic symptoms assessed, no changes
from baseline to week 12, except for malaise,
were observed. Changes in the uremic symptom
of malaise from baseline to week 12 are listed in
Table 4. The 9.0-g and 6.3-g AST-120 treatment
groups showed statistically significant improve-
ments in a dose-dependent fashion compared
AST-120 LOWERS INDOXYL SULFATE LEVELS IN CKD 573

Table 4. Changes in Malaise From dance with the protocol. There were no statistical
Baseline to Week 12 differences among the 4 treatment groups. In
Treatment Group addition, no patient in any of the 4 treatment
groups attained doubling of serum creatinine
9.0 g 6.3 g 2.7 g level or died.
Change AST-120 AST-120 AST-120 Placebo
For patients treated with AST-120, baseline
Improved 16 (42) 11 (28) 11 (28) 3 (8) mean values ranged from 4.15 to 4.21 g/dL (41.5
Unchanged 17 (45) 24 (62) 21 (54) 25 (66) to 42.1 g/L) for serum albumin, 31.7 to 34.0 g/dL
Aggravated 5 (13) 4 (10) 7 (18) 10 (26) for serum prealbumin, and 7.88 to 8.50 g/24 h for
P
24-hour urine nitrogen. These data, which repre-
Chi-square test v
placebo 0.002 0.028 0.066 — sent patient nutritional status, did not change
significantly after 12 weeks of treatment, except
NOTE. Values expressed as number (percent). Malaise for serum albumin (⫺0.09 g/dL; P ⫽ 0.018) and
was assessed based on a scale of 1 to 4 (1 ⫽ none, 2 ⫽ serum prealbumin levels (⫺1.67 g/dL; P ⫽ 0.040)
mild, 3 ⫽ moderate, and 4 ⫽ severe) at each visit, and
in the 6.3-g AST-120 treatment group.
changes from baseline to week 12 were presented.
There were no clinically significant changes
observed in absorption of vitamins D and K,
with placebo at week 12 (P ⫽ 0.002 and P ⫽ indicating that AST-120 treatment does not ad-
0.028, respectively). There were no significant versely affect absorption of these fat-soluble
differences in other uremic symptoms (nausea, vitamins after 12 weeks of treatment (Table 5).
anorexia, pruritus, halitosis, and neuropathy). No clinically significant changes were observed
Baseline mean blood urea nitrogen values in patient nutritional status, body weight, physi-
ranged from 61.2 to 67.0 mg/dL for patients cal examination findings, or electrocardiogram
treated with AST-120. No significant changes in tracings.
blood urea nitrogen levels from baseline to week From baseline to week 12, a total of 69.2% to
12/early termination were observed. 85.0% of patients in the 4 treatment groups were
Fourteen patients (9.1%) in the 4 treatment 90.0% or greater compliant in using the study
groups attained the composite end point; only 1 drug, assessed by means of return of empty
of these 14 patients (treated with 9.0 g of AST- bottles or unused study drug.
120) initiated hemodialysis therapy, whereas the
other 13 patients developed a serum creatinine Safety
level greater than 8.0 mg/dL (⬎707.2 mol/L) in Of 157 patients administered at least 1 dose of
patients without diabetes or greater than 6.0 study drug, 121 patients (77.1%) reported 1 or
mg/dL (⬎530.4 mol/L) in patients with diabetes more treatment-emergent adverse events. The
and were judged as initiation of dialysis in accor- overall incidence of treatment-emergent adverse

Table 5. Changes in Vitamins D and K From Baseline to Week 12

Treatment Group

Parameters 9.0 g AST-120 6.3 g AST-120 2.7 g AST-120 Placebo

Vitamin D (14-60 ng/mL)

n 24 18 20 19
Mean (SD) ⫺2.13 (19.08) 0.90 (9.32) ⫺1.84 (4.42) ⫺1.80 (6.12)
P
Paired t-test within treatment group 0.590 0.687 0.078 0.216
Vitamin K (0.13-1.19 ng/mL)
n 21 15 17 19
Mean (SD) 0.11 (0.57) ⫺0.09 (0.38) 0.18 (0.59) 0.05 (0.53)
P
Paired t-test within treatment group 0.375 0.395 0.236 0.713

NOTE. To convert vitamin D in ng/mL to nmol/L, multiply by 2.496; vitamin K in ng/mL to nmol/L, multiply by 2.22.
574 SCHULMAN ET AL

Table 6. Treatment-Related Adverse Events by System Organ Class

Treatment Group

9.0 g AST-120 6.3 g AST-120 2.7 g AST-120 Placebo

(n ⫽ 39) (n ⫽ 40) (n ⫽ 39) (n ⫽ 39)

Total no. of treatment-related adverse events 13 16 13 17

Patients with at least 1 treatment-related adverse event 9 (23.1) 11 (27.5) 5 (12.8) 9 (23.1)
Blood and lymphatic system disorders 0 (0) 0 (0) 0 (0) 1 (2.6)
Gastrointestinal disorders 7 (17.9) 11 (27.5) 3 (7.7) 6 (15.4)
Investigations 0 (0) 0 (0) 0 (0) 1 (2.6)
Metabolism and nutrition disorders 1 (2.6) 1 (2.5) 0 (0) 3 (7.7)
Nervous system disorders 0 (0) 1 (2.5) 0 (0) 0 (0)
Respiratory, thoracic, and mediastinal disorders 1 (2.6) 0 (0) 0 (0) 1 (2.6)
Skin and subcutaneous tissue disorders 1 (2.6) 0 (0) 3 (7.7) 0 (0)

events was similar among the 4 treatment groups
(76.9%, 77.5%, 82.1%, and 71.8% for AST-120
9.0-g, 6.3-g, and 2.7-g and placebo groups, re-
spectively). The most frequently occurring treat-
ment-emergent adverse events (reported by ⱖ4
patients in any treatment group) were constipa-
tion, nausea, abdominal distension, and dyspnea
not otherwise specified. Treatment-related ad-
verse events were experienced by 21.7% of pa-
tients (34 of 157 patients): 23.1% (9 of 39 patients)
in the 9.0-g AST-120 treatment group, 27.5% (11 of
40 patients) in the 6.3-g AST-120 treatment group,
12.8% (5 of 39 patients) in the 2.7-g AST-120
treatment group, and 23.1% (9 of 39 patients) in the
placebo treatment group (Table 6).
The most frequently occurring treatment-
related adverse events (reported by ⱖ2 patients
in any treatment group) among patients treated
with 9.0, 6.3, and 2.7 g of AST-120 and placebo
were largely gastrointestinal adverse events: con-
stipation (12.8%, 10.0%, 0%, and 12.8%, respec-
tively), abdominal distension (0%, 10.0%, 5.1%,
and 0%, respectively), nausea (2.6%, 5.0%, 2.6%,
and 2.6%, respectively), flatulence (5.1%, 0%,
0%, and 5.1%, respectively), and diarrhea not
otherwise specified (0%, 0%, 5.1%, and 0%,
respectively). No patient died during the study or
within 30 days after study completion.
Fifteen patients were discontinued from the
study because of adverse events. Of these 15
patients, 14 patients discontinued because of
treatment-emergent adverse events: 4 patients
(10.3%) in the 9.0-g AST-120 treatment group, 6
patients (15.0%) in the 6.3-g AST-120 treatment
group, 2 patients (5.1%) in the 2.7-g AST-120
treatment group, and 2 patients (5.1%) in the
placebo treatment group.
Adverse events of hypertension aggravated,
hypertension not otherwise specified, or hyperten-
sive crisis appeared in 10.3%, 5.0%, 7.7%, and
2.6% of patients administered AST-120 9.0, 6.3,
and 2.7 g, or placebo, respectively. The majority
of hypertension-related events were mild to mod-
erate in severity and did not result in untoward
outcomes. In no patient was the increase in blood
pressure attributed to study drug therapy by the
investigator. Most patients with an adverse event
related to blood pressure increases had preexist-
ing hypertension and were on concomitant anti-
hypertensive therapy. Notably, during the 12-
week study course, mean blood pressure values
changed little within treatment groups.
DISCUSSION
Results of this study show that serum indoxyl
sulfate levels decreased progressively by increas-
ing doses of AST-120. At week 12, patients
randomly assigned to the 9.0-g AST-120 treat-
ment group showed a 39.3% decrease in change
from baseline in serum indoxyl sulfate levels. A
significant decrease of 21.1% in change from
baseline to week 12 also was observed in patients
treated with 6.3 g of AST-120. The 2.7-g AST-
120 treatment group and placebo group showed
little change, with decreases of 2.6% and 2.8%,
respectively.
In the Japanese study performed by Niwa et
al,13 22 patients treated with 6.0 g/d of AST-120
showed a decrease of 38.5% in serum indoxyl
sulfate levels from baseline to 1 month (mean
value, 2.52 to 1.55 mg/dL). Furthermore, patients
AST-120 LOWERS INDOXYL SULFATE LEVELS IN CKD
treated with AST-120 (6.0 g/d) and following a
low-protein diet (0.6 g/kg/d) showed a 34.0% (from
mean of 1.62 to 1.07 mg/dL) decrease in serum
indoxyl sulfate levels in 13 patients with CKD in
Japan for a 6-month period.19 Because the 9.0-g
AST-120 treatment group showed almost the same
decrease in US patients as the Japanese experience,
this dosage may be adequate for US patients.
Indole is synthesized in the intestine as a
metabolite of tryptophan by intestinal bacteria
and absorbed from the intestine into blood. In-
doxyl sulfate then is synthesized from indole to
indoxyl in the liver. Orally administrated AST-
120 adsorbs indole in the intestine and is ex-
creted in feces, thereby inhibiting the synthesis
of indoxyl sulfate from indole in the liver.12 The
amount of tryptophan is in proportion to ingested
food, and the amount of food may be in propor-
tion to body weight. It should be noted that
dietary protein intake was neither quantified nor
controlled in this study. However, mean weight
of patients in this study was approximately 90
kg, and mean weight of patients in the Japanese
phase III study was approximately 55 kg. Be-
cause the amount of adsorption for indole is in
proportion to the amount of orally administered
AST-120, the daily dose of 9.0 g/d of AST-120
may be a reasonable amount for the US popula-
tion.
Malaise, a frequently observed uremic symp-
tom in patients with CKD, improved signifi-
cantly for patients treated with 6.3 and 9.0 g of
AST-120 in a dose-dependent fashion. It is note-
worthy that this finding was shown in a relatively
short time and in a small study population and
occurred despite a lack of change in blood urea
nitrogen values during the course of the study.
There were no significant differences in other ure-
mic symptoms (nausea, anorexia, pruritus, halito-
sis, and neuropathy), perhaps because of the small
sample size and lower rates of occurrence of these
symptoms at baseline compared with malaise. A
larger study is needed to evaluate the effect on
various uremic symptoms. In Japan, AST-120 im-
proved symptoms of anemia,14 nausea, anorexia,
pruritus, and halitosis.20
During the course of the study, there were no
significant changes in values for serum albu-
min, serum prealbumin, 24-hour urine urea
nitrogen, and body weight, suggesting that
dose-related changes in serum indoxyl sulfate
575
were not the result of changes in diet or nutri-
tional status.
Patients treated with AST-120 showed no
consistent or dose-related changes in values
for serum creatinine, reciprocal of serum creat-
inine, creatinine clearance, or urine protein.
The lack of change in these measures of renal
function likely is caused by the short study
period. AST-120 can adsorb creatinine in vitro.
A key finding is that urinary creatinine excre-
tion changed little, suggesting there was no
meaningful transluminal gastrointestinal ad-
sorption of creatinine in vivo. Transport or
diffusion of creatinine from the intestinal cap-
illary bed into the intestinal lumen did not
occur in any meaningful quantity. This impor-
tant finding indicates that serum creatinine
values observed in a longer term study14 will
be a direct reflection of renal function, rather
than an artifact of extrarenal adsorption.
Results of this study support the notion of using
a composite end point of doubling of serum creati-
nine level, transplantation, or initiation of hemodi-
alysis therapy as a hard end point for nephroprotec-
tive effects in a future therapeutic confirmatory
study. Similar end points were accepted in other
studies that examined therapeutic interventions in
slowing the progression of CKD.3,4
There were no significant changes in vitamins
D and K levels or such indices of nutritional
status as serum albumin and serum prealbumin
levels. Furthermore, there were no findings on
physical examination or electrocardiogram trac-
ings. These results suggest that AST-120 can be
administered for a prolonged period. Despite the
requirement to take 30 capsules/d, patients in this
12-week study showed a high degree of compli-
ance, which indicates that AST-120 was well
tolerated.
Safety results show that the most frequently
occurring treatment-emergent adverse events and
treatment-related adverse events were mainly
gastrointestinal disorders, on a par with Japanese
experiences.21 The incidence of these adverse
events was similar among the 3 AST-120 treat-
ment groups and placebo group, as well as the
overall incidence of all adverse events. From
these safety results, it is suggested that AST-120
showed no specific safety issues. Because AST-
120 is not absorbed, the compound should have
no potential for systemic side effects. Safety
576
results suggest that AST-120 had no potential for
pharmacodynamic attenuation of antihyperten-
sive drug efficacy.
Overall, these results indicate that AST-120
can safely decrease levels of serum indoxyl sul-
fate, a uremic toxin, in patients with CKD. A
therapeutic confirmatory study is planned to de-
termine whether this effect can attenuate the
progression of CKD.
ACKNOWLEDGMENT
The authors thank all participants of this study for their
substantial contribution.
APPENDIX
The following persons participated in this study:
Gerald Schulman (Vanderbilt University School
of Medicine, Nashville, TN), Muralidhar Acharya
(Outcomes Research International Inc, Hudson,
FL), Rajiv Agarwal (Richard Roudebush VA
Medical Center, Indianapolis, IN), Patricia Aris-
timuno (University of Texas Medical Branch,
Galveston, TX), Tomas Berl (University of Colo-
rado Health Science Center, Denver, CO), Rich-
ard Bilinsky (Lincolnland Dialysis Center,
Springfield, IL), Samuel Blumenthal (Zablocki
VA Medical Center, Milwaukee, WI), Chaim
Charytan (Nephrology Associates, Brooklyn,
NY), Glenn Chertow (University of California,
San Francisco, CA), Daniel Coyne (Washington
University School of Medicine, St Louis, MO),
Danny Fischer (Kidney and Hypertension Cen-
ter, Cincinnati, OH), Paul Kimmel (George Wash-
ington University Medical Center, Washington,
DC), Nelson Kopyt (Northeast Clinical Research
Centers Inc, Allentown, PA), Lawrence Lehrner
(NEA Research, Las Vegas, NV), Robert Lynn
(Bronx Westchester Medical Group, New York,
NY), Robert McCrary (Arkansas Nephrology
Services Inc, Hot Springs, AR), Ravindra Mehta
(University of California, San Diego, CA), Daniel
Ornt (Strong Memorial Hospital, Rochester, NY),
Mark Pohl (Cleveland Clinic Foundation, Cleve-
land, OH), Jeffrey Posner (Mid-Atlantic Nephrol-
ogy Associates, Baltimore, MD), Daeyoung Roh
(Nephrology Associates, Riverside, CA), Melvin
Seek (Discovery Medical Research Group Inc,
Ocala, FL), Marvin Sinsakul (Rush-Presbyte-
rian, St Luke’s Medical Center, Chicago, IL),
Douglas Somers (University of Iowa, Iowa City,
IA), Moses Spira (National Institute of Transplan-
SCHULMAN ET AL
tation, Los Angeles, CA), Suzanne Swan (DaVita
Clinical Research, Minneapolis, MN), Robert
Toto (University of Texas Southwestern Medical
Center, Dallas, TX), Michael Walczyk (NW Re-
nal Clinic, Portland, OR), Thomas Wiegmann
(Kansas City VA Medical Center, Kansas City,
MO), Mark Williams (Joslin Diabetes Center,
Boston, MA), Duane Wombolt (Clinical Re-
search Associates of Tidewater, Norfolk, VA),
and Steven Zeig (Pines Clinical Research Inc,
Pembroke Pines, FL).
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