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.     

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.     

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 the rat model of chronic renal failure induced by adriamycin]

The effect of AST-120 was examined in the rat model of CRF induced by adriamycin (ADM), which is known to induce focal glomerular sclerosis (GS). ADM (2mg/kg) was injected intravenously twice at a 3-wk interval. After 14 wks, rats were paired with control (C) and AST-120 (A) groups according to levels of BUN and proteinuria. Then, the rats were fed regular rat chow with (A, n = 10) or without (C, n = 10) AST-120. After 28 wks, there were more GS in C. Averaged sclerosis index (SI, 0-4 scale) in C was 1.97 (0.94-3.22), while 1.61 (0.60-2.97) in A. When GS was advanced in C (SI > 2.0), largely ameliorated SI was noted in A (2.61 vs. 1.97, C vs. A, p < 0.05 by paired W-test, n = 5 each). Also, in these rats, BUN, serum creatinine and Ht were all improved in A (p < 0.05). Thus, AST-120 was effective in CRF rats induced by ADM when uremia was advanced. The data also indicates that a reduction of uremic toxins could improve glomerular histology and renal function in CRF.     

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 carbonic adsorbent (AST-120) on kidney of early-stage chronic kidney disease rats

Abstract

Aim: to investigate the therapeutic effects of oral carbonic adsorbent on rats with early-stage renal failure. Methods: The early-stage renal failure model was established with three-fourth subtotal nephrectomy Wistar rats. Four weeks after the subtotal nephrectomy, the rats were randomly divided into four groups: (1) adsorbent diet (AD) rats; (2) low protein diet (LPD) group; (3) low protein and AD rats; and (4) normal diet rats as control (ctrl) group. Sham operation group is set as well. The therapeutic effects of adsorbent were examined after 15 weeks treatment. Results: The level of 24 hours urinary protein excretion, serum creatinine (Scr), index of glomerulosclerosis (GSI) and tubulointerstitial fibrosis score (TIFS) of rats with adsorbent or LPD treatment are significantly lower than ctrl group rats. The combination of adsorbent and LPD lowered level of 24 hours urinary protein excretion, Scr, index of GSI and TIFS compared with LPD or adsorbent treatment alone. Conclusion: Both AST-120 and LPD treatment lowered the Scr and blood urea nitrogen level as well as ameliorated the proteinuria and glomerular and tubulointerstitial damage of rats with early stage renal failure. The combined treatment of oral carbonic adsorbent and LPD showed greater therapeutic effects.     

Cost-effectiveness of the oral adsorbent AST-120 versus placebo for chronic kidney disease

Aim:   This study was designed to evaluate the cost-effectiveness of AST-120, an oral adsorbent that attenuates the progression of chronic kidney disease.
Methods:   We developed a Markov model with six health states, including four levels of serum creatinine, haemodialysis and death, using data from a randomized clinical trial conducted in Japan. Direct costs relevant to chronic kidney disease were calculated from a Japanese reimbursement perspective. Projected quality-adjusted life years (QALY) and costs were compared between the AST-120 and placebo groups. The target population was nondiabetic patients with serum creatinine levels from 5.0 to 8.0 mg/dL (442–707 µmol/L) at baseline. Probabilistic sensitivity analysis was performed to evaluate the stability of the results.
Results:   At 3 years, mean total costs per patient were estimated at ¥6.67 million (US$56 982) in the AST-120 group and ¥9.38 million (US$80 196) in the placebo group. Mean total costs were ¥2.72 million (US$23 205) lower among patients receiving AST-120. QALY per patient were 0.295 (approximately 3.5 months) greater for patients receiving AST-120 than for those receiving placebo over 3 years. The finding that treatment with AST-120 dominated placebo (i.e. was less costly and resulted in more QALY) was upheld in sensitivity analyses.
Conclusion:   The use of AST-120 in patients with advanced chronic kidney disease may help to slow the rate of growth in expenditures for kidney disease.     

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 repeated oral administrations of the oral adsorbent AST-120 on serum creatinine and other markers of renal function. A randomized controlled study in patients with chronic kidney disease

BACKGROUND: AST-120 is an orally administered adsorbent used in Japan for prolonging time to initiation of hemodialysis and improving uremic symptoms in patients with chronic kidney disease (CKD). As AST-120 is suspected to reduce the progression of CKD by adsorbing renal toxins in the gastrointestinal tract, the objective of the current study was to determine whether binding of AST-120 to creatinine in the intestines could acutely alter creatinine balance, thereby limiting the utility of serum creatinine (sCr) as a measure of progression of renal function. Such information may be critical for the design of future studies to assess the efficacy of AST-120 in CKD patients. METHODS: Patients with CKD (n = 20) received oral doses of AST-120(3 g t.i.d.) and placebo in a two-way crossover study. Blood and urine were collected for determination of sCr, 24-hour urinary creatinine (UcrV), creatinine clearance (Ccr), and urea nitrogen clearance (URCL). Differences between treatments were assessed using an ANCOVA model. RESULTS: Following AST-120 and placebo treatments, mean sCr (1.73 and 1.79 mg/dl, respectively) and UcrV (1,264.73 and 1,286.05 mg) values were not significantly different. No significant differences were observed for Ccr and URCL. CONCLUSION: These results indicate that AST-120 has no acute impact on creatinine balance in patients with CKD. Consequently, sCr and other markers of renal function are acceptable measures for assessing changes in renal function following AST-120 treatment.     

The oral adsorbent AST-120 attenuates the progression of hyperlipidemia and glomerulosclerosis in spontaneous hypercholesterolemic rats (SHCRs)

Background. The oral adsorbent, AST-120 Kureha Chemical, has been shown to attenuate the progression of chronic renal failure in rats and humans. Spontaneous hypercholesterolemic male rats, (SHC rats; SHCRs) have been introduced for experimentation because they develop progressive hyperlipidemia and glomerulosclerosis on a cholesterol-free standard diet by their 30th week of life. Methods. The effects of AST-120 were studied in SHCRs. Twenty 10-week-old SHCRs were divided into two groups: a control group (n = 10), and an AST-120 group (n = 10). The experiment was begun at the 12th week and completed at the 34th week of life. Results. At the end of the experiment, we found that the serum levels of total cholesterol were 40% lower in the AST-120 rats than in the control rats (P < 0.01). The creatinine clearance in the AST group was 40% higher than that in the controls (P < 0.05). At the age of 20 weeks, postheparin lipoprotein lipase in the AST-120 SHCRs and in Sprague-Dawley rats with normal serum lipid levels was comparable, but was clearly lower in the control SHCRs. Finally, in a pathological investigation that determined a sclerosis index for all kidneys, this was significantly lower in the AST group than in the control animals (P < 0.01). Conclusions. The reduction of serum lipid levels following the administration of the AST-120 oral adsorbent is associated with amelioration of renal functional and structural changes in SHCRs. Received: January 8, 1999 / Accepted: June 15, 1999     

An oral adsorbent, AST-120, combined with a low-protein diet and RAS blocker, for chronic kidney disease

BACKGROUND: A low-protein diet and treatment with renin-angiotensin system (RAS) blockers can delay the progression of chronic kidney disease (CKD). The oral adsorbent AST-120 (Kremezin) has a renoprotective effect by reducing serum levels of uremic toxins. We investigated the influence of AST-120 on the preservation of renal function in patients with CKD. METHODS: Twenty-eight patients were randomized to 2 groups: 15 patients receiving 6.0 g of AST-120 daily for 12 months plus a low-protein diet and RAS blocker therapy (group A) and 13 patients who were not given AST-120 (group B). All of them had shown progressive deterioration of renal function with basal treatment. Mean baseline serum creatinine level (+/- standard deviation) was 2.4 +/- 0.8 mg/dL in group A and 2.7 +/- 0.8 mg/dL in group B. There were no significant differences in background parameters before AST-120 therapy. RESULTS: The change in the estimated glomerular filtration rate (eGFR) was significantly smaller in group A than in group B. The change was also significantly smaller in patients with a baseline serum creatinine <2.4 mg/dL and in patients with rapid progression. After 12 months, the slope of the eGFR curve was significantly less steep compared with baseline in group A (-1.77 vs. -0.52 ml/min per month), but there was no significant change in group B. The slope was also significantly less steep in patients with rapid progression. CONCLUSIONS: Adding AST-120 to a low-protein diet and RAS blocker therapy may delay the deterioration of chronic renal failure, especially in patients with early or rapid progression.     

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.     

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.

     

Effects of oral adsorbent in the rat model of chronic renal failure.

The effects of oral adsorbent, AST-120 (Kureha Chemical Ind. Co., Tokyo), were studied in the rat model of subtotal nephrectomy. In 34 female Sprague-Dawley rats, three quarters of the renal mass were removed from the left kidney by ligation of 3 branches of the left renal artery. One week later, the right kidney was removed. Two days after right nephrectomy, control rats were fed standard rat chow ad libitum, while AST-120-treated rats were fed standard rat chow containing AST-120 ad libitum. The animals were observed for 9 weeks. Of the control rats, some became severely ill and appeared to be almost dying before 9 weeks, while paired AST-120-treated rats appeared well. Body weight was maintained better in AST-120-treated rats than in control rats. At completion of the study, levels of BUN and serum creatinine were lower and glomerular filtration rate and renal plasma flow rate were higher in AST-120-treated than in control rats (p < 0.05), although there was no statistically significant difference in proteinuria. Serum uremic peak 2a measured by high-performance liquid chromatography, which is considered to correspond to uremic toxins, was statistically lower in AST-120-treated rats (p < 0.05). Finally, a marked reduction in the degree of glomerular sclerosis was noted in AST-120-treated versus control rats (p < 0.05). The results indicate that AST-120 is effective in the treatment of chronic renal failure in terms of reducing uremic symptoms as well as preserving renal function and glomerular architecture. The data also indicate that a reduction in uremic toxins could delay the progressive damage of renal function and glomerular architecture in chronic renal failure.     

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