We investigated the long-term effect of AST-120, which has been proposed as a therapeutic option against renal disease progression, in patients with advanced chronic kidney disease (CKD).
We performed
The two arms did not differ significantly in the occurrence of composite primary outcomes (log-rank
Long-term use of AST-120 has potential for renal protection, especially in diabetic patients, as well as cardiovascular benefits. Reduction of the serum indoxyl sulfate level may be used to identify patients who would benefit from AST-120 administration.
The chronic kidney disease (CKD) prevalence in Korean adults was 7.2% in 2007 according to the Korean National Health and Nutrition Examination Survey [
Dietary protein-derived tryptophan is metabolized into indole, which is then absorbed into the blood stream and oxidized into indoxyl sulfate (IS) in the liver [
AST-120 reduced glomerular sclerosis and the SCr levels [
Here, we re-analyzed the K-STAR study with a per-protocol group to clarify the long-term effect of AST-120 on renal disease progression and to characterize patients who benefit from AST-120.
K-STAR was a prospective, 11-center, randomized, open-label, controlled study. Participants recruited from March 2009 to August 2010 were followed up for 36 months (clinicaltrials.gov: NCT00860431). The primary outcome was a composite of SCr doubling, 50% reduction of eGFR, or initiation of renal replacement therapy. Secondary outcomes were (1) the rate of eGFR changes (Δ eGFR/month), (2) changes in the urinary protein excretion, (3) all-cause mortality, (4) all-cause hospitalization other than planned surgery or interventions, and (5) changes in the health-related quality of life. We prospectively collected data about severe adverse events including diagnosis and progress as well as event period. We compared the major adverse cardiovascular events (MACE) (myocardial infarction, unstable angina, cardiovascular death, revascularization, fatal/non-fatal accident, peripheral arteriopathy, and aortic events) between the two treatment arms.
The eligibility criteria, randomization, interventions, and measurements from the K-STAR study were introduced in a previously published article [
This study was an investigator-initiated one using data from the K-STAR study, and participants allowed us to perform further analyses using their data when they provided the informed consent. The protocol was approved by the institutional review board of Seoul National University Hospital (IRB approval number 1606-073-711). We conducted this study in compliance with the principles of the Declaration of Helsinki.
We performed the
We evaluated 465 patients in the per-protocol group (
The mean age of the analyzed patients was 57 years, and 67.5% were men. Diabetic nephropathy was reported in 229 (49.2%) patients. Systolic and diastolic blood pressure values were 129 ± 15.3/76 ± 9.9 mmHg. The mean SCr level was 247.5 ± 59.23 μmol/L and mean eGFR was 26.8 ± 7.26 mL/min/1.73m2. The mean urinary protein excretion rate was 2.0 ± 2.01 g/g Cr. ACE inhibitors or ARBs were taken by 416 (89.5%), beta-blockers by 245 (52.7%), calcium channel blockers by 316 (68.0%), diuretics by 284 (61.1%), and lipid modifiers by 321 (69.0%). The baseline characteristics did not differ significantly between two arms (
By the end of the study period, 194 patients (41.7% of analyzed participants) reached a primary outcome. A SCr doubling or a > 50% eGFR reduction was observed in 120 patients (57 control and 63 AST-120 cases), and renal replacement therapy was initiated in 74 patients (40 control, 34 AST-120). The two arms did not differ significantly in their cumulative rate of composite primary outcome events (log-rank
When we divided patients according to the AST-120 medication compliance, the highest tertile was more than 96.5% and lowest tertile was less than 90.9%. Baseline characteristics based on the AST-120 compliance were not statistically different (
Analyzed in conjunction with time (
The urinary protein excretion rate was also decreased during the study period (from 2.0 ± 1.98 g/g Cr to 1.8 ± 2.02 g/g Cr in the control arm, and from 2.0 ± 2.05 g/g Cr to 1.2 ± 1.20 g/g Cr in the AST-120 arm). The amount of daily proteinuria at the last visit was significantly lower in the AST-120 arm (
The serum and urine IS levels were significantly lower in the AST-120 arm than in the control arm throughout the study period. We calculated the ratio of the serum IS level one year after AST-120 treatment and compared it to the level at the time of randomization. The first tertile of the ratio was < 0.6825 and the third was > 2.0000. Daily proteinuria one year after randomization was lower in the first tertile (1.6 ± 1.94 vs. 2.3 ± 2.74 g/g Cr,
A total of 40 MACE cases occurred during the study period (13 in the AST-120 arm vs. 27 in the control arm;
While the AST-120 combination proved to be more protective of renal function (eGFR and slope of 1/SCr) than standard treatment alone, especially in patients with diabetic nephropathy, AST-120 did not delay the onset of composite primary outcomes. However, greater reduction in the serum IS, as well as high AST-120 compliance in the AST-120 arm, were related to the lower composite primary outcome occurrence. AST-120 also had a protective effect on the occurrence of MACEs.
IS is known to be associated with renal disease progression through increased expression of fibrogenic genes and oxidative stress [
In the present study, AST-120 did not specifically demonstrate that AST-120 has a beneficial effect on composite primary outcomes in CKD patients. In participants whose renal disease was too far advanced (mean eGFR, 26 mL/min/1.73m2) for AST-120 to reverse its progression and the intervention period was relatively short (≤ 36 months). In a previous study, the greatest preservation of renal function was observed in patients who had been receiving AST-120 the longest (> 30 months) [
AST-120 preserved eGFR in diabetic nephropathy patients. In CKD patients, AST-120 treatment decreases the serum and urinary levels of AGEs [
Our finding that a higher reduction ratio of the serum IS improves the clinical outcome (reduced daily protein-uria and fewer primary outcomes) was significant, even after adjusting for renal function and urinary protein excretion. Additionally, daily proteinuria one year after randomization was lower in the higher serum IS reduction group. Residual albuminuria during therapy was reported as a strong marker of poor renal outcome, and reducing proteinuria as much as possible is usually recommended [
This study also shows that AST-120 has favorable effects on the MACE in advanced CKD patients, although we could not determine the patients’ cardiovascular events prior to study participation. Previous reports declared that AST-120 ameliorated aortic calcification, left ventricular mass, and cardiac fibrosis [
This study has a limitation in the study design itself. We cannot extrapolate the results to entire advanced CKD patients because this study selected a per-protocol group of patients. Patients who did not complete the study may have their own reasons for not adhering to the protocol or may have developed complications related to the AST-120 treatment. As a strength, our study suggests a novel approach for selecting patient subgroups likely to benefit from AST-120 treatment. AST-120 slowed renal function deterioration, especially benefiting patients with diabetic nephropa-thy and higher AST-120 compliance was related with better renal outcome. Regular measurement of the serum IS during follow-up is valuable and should be implemented to evaluate treatment response and compliance.
In conclusion, long-term use of AST-120 delays renal function deterioration in advanced CKD patients. Furthermore the beneficial effect is more evident in patients with diabetic nephropathy. AST-120 also had a protective effect against the occurrence of cardiovascular events. The serum IS concentration may have clinical significance as a marker for predicting renal disease progression. A longer clinical trial with patients at an earlier stage of kidney disease should be instituted to clarify the clinical usefulness of AST-120.
All authors have no conflicts of interest to declare.
Diagram of participant enrollment and analysis, the Kremezin study against renal disease progression in Korea (K-STAR).
Log-rank
(A) From whole per-protocol participants (
Log-rank
Baseline characteristics of per-protocol participants
Variable | Control ( |
AST-120 ( |
|
---|---|---|---|
Age (yr) | 57 ± 12.9 | 56 ± 13.4 | 0.51 |
Gender (female:male) | 81/158 (33.9/66.1) | 70/156 (31.0/69.0) | 0.55 |
ESRD cause | 0.85 | ||
Diabetic | 119 (49.8) | 110 (48.7) | |
Non-diabetic | 120 (50.2) | 116 (51.3) | |
BMI (kg/m2) | 24.5 ± 3.38 | 24.8 ± 3.84 | 0.37 |
BSA (m2) | 1.7 ± 0.18 | 1.7 ± 0.17 | 0.59 |
SBP (mmHg) | 129.5 ± 15.97 | 129.5 ± 14.59 | 0.97 |
DBP (mmHg) | 75.6 ± 9.94 | 76.1 ± 9.78 | 0.57 |
Serum Cr (μmol/L) | 248.4 ± 60.91 | 247.5 ± 56.66 | 0.89 |
eGFR (mL/min/1.73m2) | 26.6 ± 7.07 | 27.1 ± 7.47 | 0.46 |
CKD stage 3/4 | 78/161 (32.6/67.4) | 72/154 (31.9/68.1) | 0.86 |
Urinary protein (g/g Cr) | 2.0 ± 1.98 | 1.97 ± 2.05 | 0.73 |
Hemoglobin (g/L) | 113.0 ± 17.20 | 115.0 ± 19.70 | 0.28 |
Albumin (g/L) | 39.9 ± 4.91 | 40.4 ± 4.00 | 0.30 |
Uric acid (μmol/L) | 480.0 ± 97.25 | 494.3 ± 123.30 | 0.17 |
LDL (mmol/L) | 2.4 ± 0.78 | 2.4 ± 0.72 | 0.51 |
CRP (mg/dL) | 0.9 ± 3.32 | 0.7 ± 2.51 | 0.49 |
Serum |
6.8 ± 2.50 | 6.5 ± 2.26 | 0.21 |
Serum IS (mg/dL) | 0.7 ± 0.84 | 0.6 ± 0.55 | 0.19 |
Urine IS (mg/dL) | 7.6 ± 7.66 | 6.7 ± 5.17 | 0.11 |
RAS inhibitor | 211 (88.3) | 205 (90.7) | 0.45 |
Beta-blocker | 121 (50.6) | 124 (54.9) | 0.40 |
Ca++ channel blocker | 163 (68.2) | 153 (67.7) | 0.92 |
Diuretics | 138 (57.7) | 146 (64.6) | 0.16 |
Lipid modifier | 160 (67.0) | 161 (71.2) | 0.37 |
Data are presented as mean ± standard deviation or number (%).
β2–MG, beta2–microglobulin; BMI, body mass index; BSA, body surface area; CKD, chronic kidney disease; Cr, creatinine; CRP, C–reactive protein; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; ESRD, end stage renal disease; IS, indoxyl sulfate; LDL, low-density lipoprotein; RAS, rennin-angiotensin-aldosterone system; SBP, systolic blood pressure.
Baseline characteristics based on the AST-120 medication compliance
Variable | Lowest tertile ( |
Intermediate ( |
Highest tertile ( |
|
---|---|---|---|---|
Age (yr) | 56 ± 12.9 | 55 ± 13.9 | 59 ± 12.6 | 0.06 |
Gender (female:male) | 23/52 (30.7/69.3) | 20/56 (26.3/73.7) | 27/47 (36.5/63.5) | 0.41 |
ESRD cause | 0.76 | |||
Diabetic | 34 (45.3) | 39 (51.3) | 37 (50.0) | |
Non-diabetic | 41 (54.7) | 37 (48.7) | 37 (50.0) | |
BMI (kg/m2) | 24.2 ± 3.73 | 25.3 ± 3.88 | 24.96 ± 3.91 | 0.22 |
BSA (m2) | 1.7 ± 0.17 | 1.8 ± 0.17 | 1.7 ± 0.18 | 0.24 |
SBP (mmHg) | 127.2 ± 14.53 | 130.2 ± 16.00 | 131.4 ± 13.00 | 0.20 |
DBP (mmHg) | 75.4 ± 8.96 | 76.5 ± 10.61 | 76.6 ± 9.84 | 0.74 |
Serum Cr (μmol/L) | 251.9 ± 58.79 | 255.5 ± 60.996 | 235.1 ± 47.82 | 0.08 |
eGFR (mL/min/1.73m2) | 26.6 ± 7.55 | 27.2 ± 6.68 | 27.2 ± 8.23 | 0.84 |
CKD stage 3/4 | 23/52 (30.7/69.3) | 26/50 (34.2/65.8) | 22/52 (29.7/70.3) | 0.83 |
Urinary protein (g/g Cr) | 1.9 ± 1.87 | 1.9 ± 1.97 | 2.2 ± 2.32 | 0.54 |
Hemoglobin (g/L) | 112.0 ± 20.50 | 115.0 ± 16.80 | 116.0 ± 21.50 | 0.38 |
Albumin (g/L) | 40.3 ± 3.95 | 40.5 ± 3.75 | 40.4 ± 4.39 | 0.97 |
Uric acid (μmol/L) | 507.96 ± 129.96 | 490.7 ± 114.68 | 481.2 ± 122.77 | 0.19 |
LDL (mmol/L) | 2.3 ± 0.72 | 2.3 ± 0.76 | 2.5 ± 0.69 | 0.19 |
CRP (mg/dL) | 0.8 ± 1.78 | 1.0 ± 3.82 | 0.4 ± 0.80 | 0.28 |
Serum |
6.6 ± 2.16 | 6.6 ± 2.28 | 6.4 ± 2.28 | 0.75 |
Serum IS (mg/dL) | 0.6 ± 0.53 | 0.7 ± 0.58 | 0.6 ± 0.51 | 0.79 |
Urine IS (mg/dL) | 6.4 ± 4.66 | 7.2 ± 5.79 | 6.54 ± 5.01 | 0.63 |
Data are presented as mean ± standard deviation or number (%).
β2–MG, beta2–microglobulin; BMI, body mass index; BSA, body surface area; CKD, chronic kidney disease; Cr, creatinine; CRP, C-reactive protein; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; ESRD, end stage renal disease; IS, indoxyl sulfate; LDL, low-density lipoprotein; SBP, systolic blood pressure.
Cox proportional-hazard analysis for composite primary outcome according to AST-120 compliance in the AST-120 arm
Variable | Composite primary outcome | ||
---|---|---|---|
| |||
HR | 95% CI | ||
Age (yr) | 0.95 | 0.93–0.97 | < 0.001 |
Gender (female) |
0.71 | 0.45–1.12 | 0.14 |
CKD cause (diabetic nephropathy) |
1.10 | 0.64–1.89 | 0.72 |
Urinary protein (g/g Cr) | 1.68 | 1.50–1.88 | < 0.001 |
eGFR | 0.89 | 0.86–0.93 | < 0.001 |
Intermediate tertile of AST-120 compliance | 0.62 | 0.38–1.01 | 0.05 |
Highest tertile of AST-120 compliance |
0.44 | 0.25–0.76 | 0.003 |
CI, confidence interval; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HR, hazard ratio.
Reference:
male,
non-diabetic nephropathy,
lowest tertile of AST-120 compliance.
Cox proportional-hazard analysis for composite primary outcome according to change in serum indoxyl sulfate level over 1 year in the AST-120 arm
Variable | Composite primary outcome | ||
---|---|---|---|
| |||
HR | 95% CI | ||
Age (yr) | 0.94 | 0.92–0.96 | < 0.001 |
Gender (female) |
0.66 | 0.38–1.14 | 0.14 |
CKD cause (diabetic nephropathy) |
0.94 | 0.48–1.85 | 0.86 |
Urinary protein (g/g Cr) (12 mo) | 1.32 | 1.20–1.45 | < 0.001 |
eGFR (12 mo) | 0.79 | 0.75–0.84 | < 0.001 |
Second tertile of serum IS ratio | 1.59 | 0.82–3.07 | 0.17 |
Third tertile of serum IS ratio |
2.11 | 1.07–4.17 | 0.031 |
CI, confidence interval; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HR, hazard ratio; IS, indoxyl sulfate.
Reference:
male;
non-diabetic nephropathy;
first tertile of serum IS ratio, 1 year/randomization.
Cox proportional-hazard analysis for major adverse cardiovascular events
Variable | Major adverse cardiovascular events | ||
---|---|---|---|
| |||
HR | 95% CI | ||
Age (yr) | 1.05 | 1.02–1.08 | 0.002 |
Gender (female) |
0.77 | 0.39–1.55 | 0.47 |
CKD cause (diabetic nephropathy) |
2.09 | 1.05–4.14 | 0.035 |
Urinary protein (g/g Cr) | 0.94 | 0.79–1.12 | 0.46 |
CKD stage 4 |
2.11 | 0.83–5.32 | 0.12 |
AST-120 |
0.51 | 0.26–0.99 | 0.046 |
CI, confidence interval; CKD, chronic kidney disease; HR, hazard ratio.
Reference:
male,
non-diabetic nephropathy,
CKD stage 3,
control arm.