Effect of oral sorbent, AST-120, on serum concentration of indoxyl sulfate in uremic rats

Indoxyl sulfate is a metabolite of tryptophan. Indole is synthesized in intestine from tryptophan by intestinal bacteria. The absorbed indole is converted to indoxyl sulfate through indoxyl in liver. Serum concentration of indoxyl sulfate is markedly increased as an inhibitor of drug-binding in uremic patients as compared with healthy subjects. Since indoxyl sulfate is bound to serum albumin, it cannot be removed efficiently by hemodialysis, and it tends to accumulate in uremic serum. To determine if oral sorbent, AST-120, could adsorb indole in intestine and then decrease serum concentration of indoxyl sulfate, it was administered to nephrectomized uremic rats. Serum concentration of indoxyl sulfate was markedly decreased in uremic rats fed with oral sorbent as compared with control uremic rats. However, serum concentrations of creatinine and urea nitrogen were not significantly decreased in the uremic rats fed with oral sorbent as compared with the control uremic rats. Serum concentration of tryptophan was not decreased but rather increased in the uremic rats fed with oral sorbent as compared with the control uremic rats. Concentration of indoxyl sulfate in bile of a uremic rat was much lower than that in the uremic serum, suggesting that the adsorption of indoxyl sulfate in intestine is not a major mechanism of decreasing the serum concentration of indoxyl sulfate. These results demonstrate that oral sorbent, AST-120, can decrease serum concentration of indoxyl sulfate in uremia due to adsorption of indole in intestine.     

An oral adsorbent, AST-120, suppresses oxidative stress in uremic rats

BACKGROUND: The production of reactive oxygen species (ROS) has been suggested to play an important role in the progression of chronic kidney disease (CKD). An oral adsorbent, AST-120, removes uremic toxins such as indoxyl sulfate (IS) and delays the progression of CKD, but the effect on ROS production is unknown. The present study aimed to determine whether AST-120 reduces oxidative stress in uremic rat kidneys using markers of ROS production such as acrolein and 8-hydroxy-2'-deoxyguanosine (8-OHdG). METHODS: Daily administration of AST-120 was started 6 weeks after 5/6 nephrectomy and continued for 18 weeks. The changes in metabolic data, serum and urine IS levels, urinary excretion of markers of oxidative stress, and renal histological findings were investigated in uremic rats with or without AST-120 treatment. RESULTS: In parallel with the increase in serum and urine IS, the serum creatinine, urinary protein and acrolein levels started to increase at 6 weeks, but urinary 8-OHdG remained unchanged and significantly increased at 18 weeks in uremic rats. AST-120 markedly and significantly attenuated increases in uremic toxins and oxidative stress levels as well as the histological changes in glomerular sclerosis, interstitial fibrosis, and the tubular staining of 8-OHdG. CONCLUSION: AST-120 suppressed the progression of CKD, at least in part, via attenuation of oxidative stress induced by uremic toxin.     

Oral adsorbent AST-120 ameliorates gut environment and protects against the progression of renal impairment in CKD rats

Background

Oral charcoal adsorbent AST-120 (AST) is reported to ameliorate renal dysfunction by the absorption of toxic substance in the gut. Recent study revealed that, in CKD, gut environment is disturbed including the decrease in tight junctions and Lactobacillus (Lact). In this study, we examined whether AST improves the renal dysfunction through gut environment.

Method

Six-week-old spontaneously hypertensive rats (SHR) were rendered CKD by 5/6th nephrectomy (Nx). SHRs were divided into SHR (Sham), SHR with Nx (Nx), and Nx given AST (Nx?+?AST) (n?=?10, each). After 12 weeks, rats were killed and biochemical parameters were explored. The gut flora was analyzed. Furthermore, gut molecular changes in tight junctions and toll-like receptors were examined. We also investigated the effects of the combination therapy with AST and Lact.

Results

The increase in serum urea nitrogen and urinary protein excretion in Nx was restored in Nx?+?AST. The increased renal glomerulosclerosis in Nx was ameliorated in Nx?+?AST. Increases in serum uremic toxins and IL-6 in Nx were ameliorated in Nx?+?AST. The gut flora analysis revealed that the decrease in Lact in Nx was restored in Nx?+?AST. The downregulation in the tight junction and TLR2 in Nx was mitigated by AST. However, combination therapy failed to exhibit additional effects.

Conclusion

AST ameliorated renal function with the restoration of Lact and tight junction through TLR pathway, which would mitigate systemic inflammation and contributed to their renoprotective effects. Our study provides a novel mechanism of the renoprotective effects by AST.

     

Oral ADSORBENT AST-120 decreases carotid intima-media thickness and arterial stiffness in patients with chronic renal failure

BACKGROUND/AIM: Intima media thickness (IMT) and stiffness of the carotid arteries is related to coronary artery disease, and chronic renal failure patients are at high risk for such diseases. An oral adsorbent, AST-120 (Kremezin; Kureha Chemical Industry, Tokyo, Japan), can delay the progression of chronic renal failure in undialyzed uremic patients. The aim of the present study was to determine whether AST-120 affects carotid artery IMT and pulse wave velocity (PWV) in patients with chronic renal failure not undergoing dialysis. METHODS: Fifty patients with non-diabetic chronic renal failure were randomly divided into two groups: 30 patients (18 men and 12 women; mean age 53.5 years; mean serum creatinine 3.2 mg/dl) who were given AST-120 (6.0 g/day) and 20 patients (12 men and 8 women; mean age 52.0 years; mean serum creatinine 3.5 mg/dl) who were not given AST-120. Thirty healthy age-matched subjects (18 men and 12 women; mean age 51.5 years; mean serum creatinine 0.9 mg/dl) were also included. The treatment period was 24 months. IMT and arterial stiffness were measured before and after treatment. RESULTS: The slope of the reciprocal serum creatinine concentration over time became significantly less steep in the AST-120 group than in the non-AST-120 group (p < 0.001). Before treatment, carotid artery IMT differed little between the AST-120 group (0.90 +/- 0.22 mm) and the non-AST-120 group (0.88 +/- 0.20 mm). IMT in these two groups was significantly greater than IMT in the control group (0.64 +/- 0.14 mm) (p < 0.01). Carotid IMT in the AST-120 group decreased slightly but not significantly to 0.84 +/- 0.20 mm after 12 months and then significantly after 24 months to 0.78 +/- 0.18 mm (p < 0.05). Carotid IMT in the non-AST group showed little change throughout the experimental period. PWV differed little between the AST-120 group (1,980 +/- 330 cm/s) and the non-AST group (1,940 +/- 360 cm/s) before treatment. PWV values in these two groups were significantly greater than PWV in the control group (1,280 +/- 240 cm/s) (p < 0.01). After 12 and 24 months, PWV in the AST-120 group decreased significantly to 1,840 +/- 280 cm/s (p < 0.05) and to 1,780 +/- 260 cm/s (p < 0.05), respectively; however, PWV in the non-AST group showed a slight increase during the experimental period. CONCLUSION: The data suggest that AST-120 may reduce arterial stiffness and IMT in non-diabetic chronic renal failure patients before dialysis.     

Effect of an oral adsorbent (AST-120) in rats with daunomycin-induced chronic renal failure

The effect of an oral adsorbent (AST-120) was examined in rats with daunomycin-induced chronic renal failure. Sixteen pairs of daunomycin rats which had similar levels of proteinuria at 4 weeks after being injected with daunomycin were selected. One rat of each pair served as a control and was fed on a standard diet, while the other rats were fed on a diet containing AST-120. The blood creatinine and blood urea nitrogen (BUN) were significantly lower in the rats fed with AST-120 than in the controls. Moreover, the life span of the rats fed with AST-120 was significantly prolonged as compared to that of the control rats. These findings suggest that oral administration of AST-120 may help to prevent rapid deterioration of renal function in experimental chronic renal failure induced by daunomycin in rats.     

Effect of oral-adsorbent (AST-120) in chronic renal failure (CRF) in rats

The progression of renal failure has been suggested to be altered by dietary manipulation of protein based on the presumption that the progressive nature of CRF may be caused by the vicious cycle driven by some toxic metabolite uncleared by failing kidney. We studied 29 female Sprague-Dawley rats aged 12 weeks weighing 226 to 290 gm subjected to a 5/6 nephrectomy. 2 days after, group C (16 rats) were given a commercially prepared diet (CE-2, Japan Kurea). While group A (13 rats) were given the same diet and 5% AST-120. Initial serum creatinine of both group was 2.2 mg/dl. After 9 weeks, all surviving rats were sacrificed for evaluation of renal histology. During the observation period, survival rate, Ccr, urinary creatinine and urea excretion were significantly better in group A rats. Result also showed a better weight increase with concomitant increase in protein catabolic rate in group A rats. These result showed the beneficial effect of AST-120 in uremic rats in terms of survival rate and delaying the progression of CRF despite the presence of increased protein catabolic rate. Based on this study, one way of preventing the progression of renal failure is through removal of some toxic metabolite in the gastrointestinal tract by the use of oral adsorbent as exemplified by AST-120.     

Pathological study on the effect of oral adsorbent AST-120 on chronic renal failure in rats]

In order to evaluate the direct or indirect effect of AST-120 on chronic renal failure (CRF) in rats, histological and electron microscopical examinations were performed. A total of 30 Sprague-Dawley rats (aged 11 weeks and weighing 226 to 229 gm) with CRF induced by 5/6 nephrectomy were prepared. Rats were fed by a commercial diet (CE-2, Japan Kurea) and were divided into two groups: A (16 rats) and B (14 rats). AST-120 (5% content) was only administered to group B. After two months, kidneys were removed and prepared for the histological and electron microscopical examinations. On histological examination, group A kidneys showed severe glomerular hyalinization (more than 80%) and frequent crescents, as well as tubulo-interstitial fibrosis and many protein casts. In contrast, segmental glomerular lesions were identified in group B kidneys. Tubulo-interstitium were also well preserved. Furthermore, the ultrastructural findings of group B were milder than that of group A. The preservation of renal tissue in group B revealed the beneficial effect of AST-120 on CRF rats' kidneys. In conclusion, this beneficial effect is provided by the removal of the serum toxic metabolite (uremic toxin) and the precursor substance of the toxin by orally administered AST-120.     

Effect of oral adsorbent AST-120 in rats with chronic renal failure--mechanism of progression of renal failure by dietary protein]

Progression of renal insufficiency was evaluated in partially nephrectomized Sprague-Dawley rats at the age of 10 weeks, fed on the low (6%), usual (20%), and high (36%) protein diet (group 6C, 20C, and 36C). Effects of oral adsorbent AST-120 on these experimental uremic models were also examined (group 6A, 20A, 36A). All the rats underwent paired feeding, and survived during the experimental period of 3 weeks. GFR (inulin clearance) and RPF (para-amino hippurate clearance), as well as Ccr was measured before the sacrifice. Initial serum creatinine and Ccr were 1.7 mg/dl and 0.27 ml/min. The rats of group 36C showed progressive elevation of serum creatinine level and decrease in Ccr. At the end of the study, GFR was significantly lower in group 36C than in group 6C and 20C (0.19, 0.68, 0.87 ml/min respectively). Significant elevation of filtration fraction in group 36C suggested that the decrease in GFR mainly resulted from low RPF. Even in group 36C, no glomerular sclerosis was histologically demonstrated in the remnant kidney, and the mean planar area of the remnant glomeruli was significantly small, which might reflect low RPF. Tubulo-interstitial changes like dilatation of the urinary space and tubular epithelial flattening were prominent in group 36C. Beneficial effect of AST-120 was obvious in high protein diet groups. GFR and RPF were rather well preserved in group 36A (0.36 and 0.78 ml/min) with normal filtration fraction. Tubulo-interstitial damage was evidently mild in group 36A. These data suggested the presence of some humoral factors, which can be adsorbed by AST-120 in gastrointestinal tract, and responsible for the deterioration of renal function and tubulo-interstitial damage induced by high protein diet in the uremic condition. Besides hyperfiltration and glomerular hypertrophy, such humoral factors as suggested in this study may contribute to the progression of chronic renal failure to some extent.     

Effect of oral adsorbent (AST-120) on renal function,acquired renal cysts and aortic calcification in rats with adriamycin nephropathy

AIMS: The effect of oral adsorbent, AST-120, on the experimental renal disease induced by adriamycin, uninephrectomy and high protein diet proposed as a model of acquired cystic disease of the kidney was investigated. METHODS: 3 mg of adriamycin was injected into the tail vein of rats and 4 weeks later right-side nephrectomy was performed, 2 weeks thereafter 26 rats with urinary protein excretion between 100 and 358 mg/day were selected from 60 rats. Two groups, 13 rats in each group, namely the AST-120-treated group and control group, both of which had equal renal damage before the administration of AST-120 or placebo. AST-120 (0.4 g/100 g BW/day) was administered for 19 weeks. RESULTS: Serum creatinine and BUN in the AST-120-treated group were significantly lower (serum creatinine: 3.3 +/- 2.1 vs. 7.1 +/- 2.7 mg/dl, p < 0.003) and creatinine clearance was higher (0.62 +/- 0.49 vs. 0.29 +/- 0.30 ml/min, p < 0.05) at the final examination than in the control group. Survival rate which was examined using another set of 9 rats was higher in AST-120-treated rats than in AST-120-untreated rats. Serum indoxyl sulfate was significantly lower at all times after using AST-120 in the AST-120-treated group than in contrast to the control group. Histological examination revealed less severe interstitial and cystic changes in the AST-120-treated group. This suggests that AST-120 can prevent or retard the development of acquired renal cystic disease in this model. Aortic calcification tended to be less severe in the AST-120-treated group because of less serum Ca x P products. CONCLUSION: The AST-120-treated group significantly decreased serum creatinine and increased creatinine clearance with less severe renal cystic changes in this model during the later weeks of administration of AST-120 or at death, accompanied with the tendency of less severe aortic calcification.     

Effects of oral adsorbent AST-120 (Kremezin) on renal function and glomerular injury in early-stage renal failure of subtotal nephrectomized rats

The aim of the present study was to determine if treatment with an oral adsorbent (AST-120, Kremezin) might decrease the urinary albumin excretion and serum indoxyl sulfate (s-IS), and prevent glomerular sclerosis in early-stage renal failure, i.e. 0.9-1.2 mg/dl of serum creatinine (s-Cr) and 60-95 mg/dl of blood urea nitrogen (BUN), in subtotal (3/4) nephrectomized rats. Levels of s-Cr and s-IS in the AST-120-treated rats were significantly lower than those in the untreated control rats. The AST-120-treated rats showed an increase of creatinine clearance. Urinary protein and indoxyl sulfate excretion in the AST-120-treated rats were also significantly lower than those in the untreated control rats. The ratio of glomerular tuft area to the area of Bowman's capsules (GT/BC) in the AST-120-treated rats was significantly lower than that in the untreated control rats. The degree of glomerular sclerosis and tubulointerstitial fibrosis in the AST-120-treated rats was significantly lower than that in the untreated control rats. Furthermore, there was a significant relationship among the degree of GT/BC, glomerular sclerosis, tubulointerstitial fibrosis and the levels of urinary protein excretion. It appears that AST-120 might decrease the accumulation of s-Cr and s-IS, and prevent glomerular sclerosis in early stage renal failure in the subtotal nephrectomized rats.     

Oral adsorbent AST-120 ameliorates interstitial fibrosis and transforming growth factor-beta(1) expression in spontaneously diabetic (OLETF) rats

Diabetic nephropathy is a common cause of end-stage renal disease. The administration of an oral adsorbent, AST-120, prevents the progression of chronic renal failure in uremic rats and undialyzed uremic patients. This study was designed to determine if AST-120 slows the progression of diabetic nephropathy using Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of non-insulin-dependent diabetic mellitus. At 21 weeks of age the OLETF rats were divided into 2 groups: AST-120-administered OLETF rats (n = 7), and control OLETF rats (n = 7). LETO rats, which are genetically similar to the OLETF rats but not diabetic, were also included. After the oral administration of AST-120 for 65 weeks, renal function and pathological changes were investigated in the 3 groups. The administration of AST-120 to the OLETF rats attenuated the progression of glomerular sclerosis, interstitial fibrosis, tubular injury as well as renal dysfunction, and reduced the serum and urinary levels of indoxyl sulfate. Furthermore, AST-120 administration reduced the interstitial expression of transforming growth factor (TGF)-beta(1) and tissue inhibitor of metalloproteinase (TIMP)-1, as well as interstitial infiltration of macrophages. The TGF-beta(1)-stained interstitial area showed positive correlations with the interstitial fibrosis area, the number of TIMP-1-positive cells, and the number of macrophages, and showed a negative correlation with creatinine clearance. In conclusion, AST-120 reduced the interstitial expression of TGF-beta(1) and TIMP-1, and the interstitial infiltration of macrophages, and ameliorates the progression of diabetic nephropathy in OLETF rats.     

Zinc nutritional status modifies renal osteodystrophy in uremic rats.

BACKGROUND: Previous studies from our laboratories suggested that zinc depletion reduces the circulating level of 1,25-dihydroxycholecalciferol (1,25(OH)2D, calcitriol) in calcium- and phosphorus-depleted rats with normal renal function, and rats with uremia. Since calcitriol synthesis is in part dependent on renal function, we studied levels of circulating vitamin D metabolites, PTH response, mineral balance and bone histomorphometry in animals with different zinc nutritional and renal functional status. METHODS: Fifty-eight male Sprague-Dawley rats were pair-fed zinc-replete (+) or -deplete (-) diets for two weeks. Thereafter, half of each paired group underwent nephrectomy (N), while half had sham (S) operations. Animals were observed for eight weeks after surgery. External mineral balances of zinc, calcium, phosphate and magnesium were determined before surgery, and 1, 2 and 7 weeks after surgery. Plasma creatinine, zinc, calcium, phosphorus, magnesium, 25-hydroxycholecalciferol, calcitriol and PTH were determined at sacrifice. Static and dynamic bone histomorphometry was determined by standard techniques. RESULTS: After an 8-week observation period, zinc-depleted animals had lower plasma zinc levels, and nephrectomized animals had lower creatinine clearances than respective controls at sacrifice. Plasma calcium and phosphorus concentrations were similar in all four groups at sacrifice. Plasma magnesium concentrations were similar in groups with renal insufficiency, regardless of zinc nutritional status. Plasma 25-hydroxycholecalciferol and calcitriol levels were similar in all groups. There was no difference between mean PTH concentration in sham-operated animals, regardless of zinc nutritional status. Although nephrectomized groups' PTH levels were increased compared to S controls, PTH levels were increased in +Zn/N animals compared to the -Zn/N group. Zinc-deplete groups had consistent negative net zinc balance, however, there was no consistent effect of nephrectomy on external calcium, phosphorus, or magnesium balance, when nephrectomized groups of different zinc nutritional status were compared. Nephrectomized animals had histomorphometric changes indicative of higher bone turnover and abnormal mineralization. Zinc deficiency was associated with less evidence of increased parathyroid hormone activity on bone in nephrectomized rats. CONCLUSIONS: Zinc depletion limits the increase in plasma PTH concentration and the expression of secondary hyperparathyroid bone disease during the development of renal insufficiency in the renal ablation model of uremia in rats. The mechanism underlying this effect is unknown, but may involve a direct effect of zinc on the synthesis, release, metabolic clearance, and/or action of PTH on the cellular level, on the interrelationship of calcitriol and PTH, or a direct effect of zinc on bone mineral metabolism. These data highlight the potential relevance of zinc nutritional status to mineral metabolism in patients with chronic renal insufficiency and end-stage renal disease.     

Molecular insights into preventive effects of AST-120 on the progression of renal failure

Circulating uremic toxins are considered to be involved in the progression of chronic renal failure (CRF). An oral adsorbent AST-120 (Kremezin) is effective in removing circulating uremic toxins from the digestive tract, and retards the progression of CRF. The administration of AST-120 combined with an angiotensin-converting enzyme inhibitor or a low-proein diet has an additive effect on the progression of CRF. In a variety of experimental models of CRF, AST-120 attenuates the progression of interstitial fibrosis and inflammation, as well as attenuating that of glomerular sclerosis. However, the precise mechanism by which AST-120 delays the progression of CRF had not been clear. Indoxyl sulfate, a dietary protein metabolite, is a circulating uremic toxin that stimulates the progression of CRF. AST-120 reduces the serum and urine levels of indoxyl sulfate and the accumulation of indoxyl sulfate in remnant tubular cells, by adsorbing its precursor, indole, in the intestine. The administration of indoxyl sulfate to uremic rats stimulated the expression of transforming growth factor (TGF)-β1, tissue inhibitor of metalloproteinase (TIMP)-1, and pro-α1(I)collagen in the kidneys. The administration of AST-120 to uremic rats reduced the extent of glomerular sclerosis and interstitial fibrosis, as well as reducing the renal expression of TGF-β1 and TIMP-1, by alleviating the overload of indoxyl sulfate in remnant tubular cells. We propose the protein metabolite theory, i.e., that endogenous protein metabolites such as indoxyl sulfate play an important role in the progression of CRF, and that AST-120 is effective in retarding the progression of CRF by adsorbing these protein metabolites in the intestine. Received: August 31, 2001 / Accepted: September 11, 2001     

Suppressed serum and urine levels of indoxyl sulfate by oral sorbent in experimental uremic rats.

In uremic patients, the serum concentration of indoxyl sulfate is markedly increased. To determine if oral sorbent (AST-120) suppresses the endogenous synthesis of indoxyl sulfate, it was administered to experimental uremic rats, and the serum concentration and urinary excretion of indoxyl sulfate were quantified by high-performance liquid chromatography. Oral sorbent decreased both the serum concentration and urinary excretion of indoxyl sulfate, suggesting that there was suppression of the endogenous synthesis of indoxyl sulfate by the oral sorbent. Oral sorbent did not decrease the serum concentration and urinary excretion of hippuric acid, but it did alleviate the deterioration of renal function in the experimental uremic rats.     

Randomized Placebo-Controlled EPPIC Trials of AST-120 in CKD

Reduced GFR in patients with CKD causes systemic accumulation of uremic toxins, which has been correlated with disease progression and increased morbidity. The orally administered spherical carbon adsorbent AST-120 reduces systemic toxin absorption through gastrointestinal sequestration, which may slow disease progression in these patients. The multinational, randomized, double-blind, placebo-controlled Evaluating Prevention of Progression in CKD (EPPIC)-1 and EPPIC-2 trials evaluated the effects of AST-120 on the progression of CKD when added to standard therapy. We randomly assigned 2035 adults with moderate to severe disease (serum creatinine at screening, 2.0–5.0 mg/dl for men and 1.5–5.0 mg/dl for women) to receive either placebo or AST-120 (9 g/d). The primary end point was a composite of dialysis initiation, kidney transplantation, and serum creatinine doubling. Each trial continued until accrual of 291 primary end points. The time to primary end point was similar between the AST-120 and the placebo groups in both trials (EPPIC-1: hazard ratio, 1.03; 95% confidence interval, 0.84 to 1.27; P=0.78) (EPPIC-2: hazard ratio, 0.91; 95% confidence interval, 0.74 to 1.12; P=0.37); a pooled analysis of both trials showed similar results. The estimated median time to primary end points for the placebo groups was 124 weeks for power calculations, but actual times were 189.0 and 170.3 weeks for EPPIC-1 and EPPIC-2, respectively. Thus, disease progression was more gradual than expected in the trial populations. In conclusion, the benefit of adding AST-120 to standard therapy in patients with moderate to severe CKD is not supported by these data.     

Uremic toxins adsorbed by AST-120 promote tubular hypertrophy and interstitial fibrosis in nephrectomized rats

BACKGROUND: Uremic toxins have been shown to promote glomerular hypertrophy. The present study was performed to elucidate the relation between uremic toxins and tubulointerstitial changes. METHODS: Sixty male Sprague-Dawley rats underwent 2/3 nephrectomy (Nx; n = 30) and 4/5 Nx (n = 30). Experiments were initiated 2 weeks after surgery, and were performed over an 8-week period. Half of each group (Nx-A) was administered 1 g/day of an oral carbonaceous adsorbent, AST-120, with pair-feeding, and the other half (Nx-C) served as controls. All rats were sacrificed at week 8 after a clearance study. RESULTS: The shortest diameter of proximal tubules (PTD) and interstitial fibrosis area (IFA) at week 8 in 2/3 Nx-A rats was significantly decreased compared to that in 2/3 Nx-C rats (similar body weights, systolic blood pressures, glomerular filtration rates, and urinary protein excretion levels). The values of PTD and IFA, glomerular filtration rate and urinary protein excretion level at week 8 in 4/5 Nx-A rats were significantly decreased compared to those in 4/5 Nx-C rats (similar body weights and systolic blood pressures). CONCLUSION: Administration of AST-120 minimized the appearance of proximal tubular hypertrophy and interstitial fibrosis, and subsequently prevented the occurrence of proteinuria and decreased renal function. The present study indicates that uremic toxins adsorbed by AST-120 promote tubular hypertrophy and interstitial fibrosis in nephrectomized rats.