A orally administered Beaded Activated Carbon which strongly adsorbs Dietary Advanced Glycation Endproducts and Uremic Toxins
Below we present a summary of the major research results for Kremezin (also called AST-120 and Merckmezin), taken from published studies in the scientific peer-reviewed literature. Kremezin is made by the Japanese Kureha Corporation and is currently available for therapeutic use in Japan and Korea for chronic renal failure. It is also available for the same purpose for cats under the name Covalzin. (The Internet archived page for Covalzin as it was sold by Sankyo Lifetech Animal Products is being provided because although that company was sold to Novartis Animal Health in early 2007, Novartis is not yet showing Covalzin among its own products.)
Safety and Interactions
"Since AST-120 is not absorbed, it is unlikely that the mechanism of AST-120 antioxidant activity directly participates in radical scavenging in blood; rather, we hypothesize an indirect manifestation of activity, in which substances causing oxidative stress or their precursors are adsorbed in the gastrointestinal tract, thus suppressing their levels in blood."R
"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. ... All doses of AST-120 were well tolerated and did not adversely affect the general health status of patients."R
"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. ... 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). ... Following AST-120 and placebo treatments, ... 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."R
Proven and Potential Benefits
"The effect of AST-120, an oral adsorbent, on oxidative stress in the systemic circulation in chronic renal failure (CRF) was examined and the potential role of indoxyl sulfate (IS), an uremic toxin adsorbed by AST-120, in inducing the formation of reactive oxygen species (ROS) in the vascular system was studied, in vitro and in vivo [in CRF rats]. ... An increase in the ratio of oxidized to unoxidized albumin was determined ... compared to a control group. The ratio was significantly reduced in the group that received AST-120 of 4 weeks, suggesting that AST-120 inhibits oxidative stress in CRF. ... We propose that AST-120 reduces IS concentrations in the blood that induces ROS production in endothelial cells, thereby inhibiting the subsequent occurrence of oxidative stress in the systemic circulation in renal failure.R
"The pathological role of the non-enzymatic modification of proteins by reducing sugars has become increasingly evident in various disorders. It is now well established that early glycation products undergo progressive modification over time in vivo to the formation of irreversible cross-links, after which these molecules are termed "AGEs (advanced glycation end products)". AGEs have been implicated in the development of many of the pathological sequelae of diabetes and aging, such as diabetic microangiopathy, ischemic heart disease and neurodegenerative diseases. Recently, digested food-derived AGEs are also found to play an important role in the pathogenesis of AGE-related disorders. Diet is a major environmental source of pro-inflammatory AGEs. Indeed, restriction of dietary glycotoxins decreases excessive AGE levels and subsequently reduces the inflammatory responses in patients with diabetes. These observations suggest that inhibition of absorption of dietary AGEs may be a novel target for therapeutic intervention in the above-mentioned AGE-related disorders. AST-120 (Kremezin(R)) is an oral adsorbent that attenuates the progression of chronic renal failure (CRF) by removing uremic toxins. We have recently found that AST-120 binds to carboxymethyllysine (CML), one of the well-characterized, digested food-derived AGEs in vitro and that administration of AST-120 decreases serum levels of AGEs in non-diabetic CRF patients. These findings suggest that digested food-derived AGEs such as CML may be a novel molecular target for oral adsorbent AST-120 and that AST-120 could exert beneficial effects on CRF patients by adsorbing diet-derived AGEs and subsequently decreasing serum AGE levels. If our speculation is correct, AST-120 may have therapeutic potentials for the treatment of patients with various AGE-related disorders as well. In this paper, we would like to propose the possible ways of testing our hypotheses. Does the long-term treatment of AST-120 decrease serum and tissue levels of AGEs in diabetic patients? Does this treatment also reduce the risk for the development and progression of diabetic vascular complications such as diabetic retinopathy or ischemic heart disease? If the answers are yes, do the serum and/or tissue levels of AGEs after AST-120 treatment predict its beneficial effects on diabetic vascular complications? How about the effects of AST-120 on Alzheimer's disease, another AGE-related neurodegenerative disorder? Does the treatment of AST-120 reduce the risk for Alzheimer's disease and/or improve the cognitive impairment of patients with this disorder? These prospective studies will provide further valuable information whether the inhibition of absorption of dietary AGEs by AST-120 could be clinically relevant."R
"Indoxyl sulfate shows nephrotoxicity and is a stimulating factor for progression of chronic kidney disease (CKD). ... [In rats] Administration of Kremezin significantly decreased serum and urine levels of indoxyl sulfate and serum creatinine and significantly increased creatinine clearance as compared with control values. The change in serum indoxyl sulfate noted from the initial to the final week showed a positive correlation with the change in serum creatinine and a negative correlation with the change in creatinine clearance. Kremezin significantly reduced urine levels of acrolein, a marker of oxidative stress, as compared with control levels. CONCLUSIONS: The indoxyl sulfate-lowering capacity of oral adsorbents affects the prognosis of kidney function in CKD. The more serum indoxyl sulfate is reduced, the better kidney function is preserved. Kremezin alleviates oxidative stress in the kidneys by reducing serum levels of indoxyl sulfate."R
"We previously reported a significant increase in plasma TGF-beta1 in patients with chronic renal failure (CRF). Progression of CRF may be caused by persistent renal production of TGF-beta1. In CRF rat models, an oral carbonic absorbent (AST-120) reduces the expression of the TGF-beta1 gene in the kidney, and delays the progression of CRF, in part by alleviating the overload of indoxyl sulfate. The aim of this study was to evaluate the effect of AST-120 on plasma levels of indoxyl sulfate and TGF-beta1 in CRF patients. METHODS: Ten CRF patients (aged 59.3 +/- 9.5 years, 5 men, serum creatinine 4.37 +/- 1.72 mg/dl) were enrolled in this study. All patients maintained a regular dietary therapy and the same medication throughout the study. AST-120 was added at a dose of 6 g/day. ... Administration of AST-120 significantly reduced the plasma levels of indoxyl sulfate (1.42 +/- 1.50 vs. 1.26 +/- 1.40 mg/dl, P < 0.05) and TGF-beta1 (17.9 +/- 7.2 vs. 10.6 +/- 4.7 ng/ml, P < 0.05) and improved the slope of the reciprocal of serum creatinine (-0.061 +/- 0.041 vs. -0.032 +/- 0.055 dl/mg/year, P < 0.05). CONCLUSIONS: These results support the notion that indoxyl sulfate and TGF-beta1 may be involved in the progression of CRF, and that the oral adsorbent AST-120 may suppress the progression, at least in part, by reducing overproduction of TGF-beta1."R
"We studied whether adding the spherical adsorptive carbon AST-120 to conventional treatments is effective in inhibiting progression of chronic kidney disease (CKD) at the stage of moderate decrease in renal function. METHODS: 43 CKD patients with moderately impaired renal function indicated by glomerular filtration rate (GFR) of 20-70 ml/min ... were enrolled in the study. 26 patients showing a decrease of GFR by 5 ml/min during a 1-year observation period were randomized to receive ongoing treatments only (control group, 12 cases) or with AST-120 co-administered with ongoing treatment (AST-120 group, 14 cases). The intervention period was 1 year and the change in GFR was the primary evaluation variable. RESULTS: ... the rate of decline in GFR was significantly retarded (p < 0.001) in the AST-120 group while no significant difference was observed in the control group. CONCLUSION: These results suggest that co-administration of AST-120 with conventional treatments retards decline in renal function in CKD patients with moderate decrease in renal function."R
"Advanced glycation end products (AGEs) are senescent macroprotein derivatives that are formed at an accelerated rate in patients with chronic renal failure (CRF). AGE formation and accumulation in plasma and vascular tissues contribute to accelerated atherosclerosis in this devastating disorder. AST-120 is an oral adsorbent that attenuates the progression of CRF by removing uremic toxins. Recently, AST-120 has been reported to reduce the progression of atherosclerosis as well. However, whether AST-120 decreases serum levels of AGEs and subsequently exerts atheroprotective properties remains to be elucidated. Ten nondiabetic CRF patients were enrolled in this study. All patients were kept on regular therapeutic diet and medications throughout the study. Serum AGE levels before and after AST-120 treatments were measured using enzyme-linked immunosorbent assay. ... Administration of AST-120 (6 g/day) for 3 months significantly decreased serum levels of AGEs in nondiabetic CRF patients, whereas AGE levels remained unchanged in age- and renal function-matched CRF patients without AST-120 treatment (n = 6). Patient serum after AST-120 treatment significantly reduced mRNA levels of receptor for AGEs, monocyte chemoattractant protein-1, and vascular adhesion molecule-1 in HUVECs [cultured human umbilical vein endothelial cells] compared with serum before treatment. Moreover, in vitro, AST-120 was found to adsorb carboxymethyllysine (CML), one of the well-characterized, digested food-derived AGEs. This study suggests that atheroprotective properties of AST-120 can be ascribed, at least in part, to its AGE-lowering ability via absorption of CML."R
"Using a rat model ... focusing on indoxyl sulphate (IS) as a representative UTx [uraemic toxin], we analysed the effect of an oral charcoal adsorbent AST-120, which removes uraemic toxins and their precursors from the gastrointestinal tract, on bone turnover. ... In rats treated with vehicle, serum IS level increased with time after renal dysfunction, while bone formation decreased accompanied by down-regulation of the parathyroid/parathyroid-related peptide hormone receptor, alkaline phosphatase and osteocalcin genes. Administration of AST-120 inhibited the accumulation of IS in blood and ameliorated bone formation. Bone formation rate was 2.4 +/- 1.7 microm(3)/m(2)/year in controls given vehicle and was 11.7 +/- 2.4 microm(3)/m(2)/year in rats administered with AST-120 (P < 0.05). AST-120 treatment also reversed the down-regulation of osteoblast-related genes. ... Administration of the oral charcoal adsorbent AST-120 decreases the osteoblast cytotoxicity of UTx including IS, and suppresses progression of low bone turnover in uraemic rats."R
"A novel charcoal compound, AST-120, has been used for over a decade in Japan to prevent progression of CKD. It is thought that the oral administration of AST-120 blocks the intestinal absorption of tryptophan-derived indole. This prevents the hepatic conversion of indole to indoxyl sulfate (IS). IS has been shown to stimulate the production of profibrotic cytokines such as transforming growth factor-beta. AST-120 lowers IS in a dose dependent fashion and does not change the creatinine appearance rate in the urine."R
"Kremezin was given to 48 enrolled undialyzed patients with a median Scr [serum creatinine} level of 4.3 mg/dL. Rates of decline of 1/Scr, as well as the time for Scr level to reach 10 mg/dL, the critical value requiring dialysis, were compared before and after administration of Kremezin. RESULTS: During the 2-year therapeutic period, 1/Scr gradients were significantly attenuated (P = 0.0083), and the estimated time to dialysis was prolonged from 16.3 +/- 16.3 months to 29.8 +/- 24.1 months (P = 0.002). When the patients were divided into two groups, based on of systolic blood pressure (SBP), defined by the World Health Organization (WHO) classification, a significantly smaller number of patients in the low blood pressure group (SBP < 160 mmHg) were introduced to dialysis (P = 0.0005), and the estimated time to dialysis was significantly extended in the low blood pressure group (P = 0.0125). CONCLUSION: In addition to the control of blood pressure in undialyzed patients, Kremezin has additive salutary effects to halt the progressive loss of renal function, resulting in the delay of dialysis."R
"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. ... 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."R
"Tryptophan (TRP), an essential amino acid, is bound mostly to albumin in plasma. However, it is reported that binding is inhibited by indoles that accumulate in uremic plasma. This may be responsible for the malnutrition observed in uremic patients. AST-120, an oral adsorbent of uremic toxins, can reduce concentrations of indoxyl sulfate (IS), the most abundant indolic metabolite in uremic plasma. We therefore investigated whether AST-120 recovers TRP binding to plasma proteins and improves the nutritional state of uremic patients. METHODS: The in vitro binding ratio of TRP to bovine serum albumin (BSA) was measured in the presence of IS by the equilibrium dialysis technique. In addition, five predialysis patients with chronic renal failure (CRF) were administered AST-120 for 2 months. Plasma concentrations of total TRP, IS, and free TRP were measured in five healthy volunteers (normal [N] group) and five patients with CRF before and after 2 weeks of AST-120 therapy (6 g/d). Their nutritional statuses also were compared before and after 2 months of AST-120 administration. RESULTS: IS inhibited in vitro binding of TRP to BSA in a dose-dependent manner. Total TRP concentrations and protein-binding ratios in patients with CRF (0.90 +/- 0.08 mg/dL and 68.7% +/- 6.8%, respectively) were significantly lower than those in the N group (2.45 +/- 0.45 mg/dL and 92.0% +/- 1.4%, respectively). However, a 2-week administration of AST-120 significantly reduced IS levels from 1.79 +/- 1.01 to 1.15 +/- 0.85 mg/dL (N group, 0.06 +/- 0.01 mg/dL), increased total TRP levels (1.16 +/- 0.18 mg/dL), and improved the TRP plasma protein-binding ratio to 83.1% +/- 3.8%, whereas total protein and albumin levels remained unchanged. After 2 months of AST-120 administration, serum albumin and transferrin levels increased significantly. CONCLUSION: AST-120 improves nutritional state, at least partly through correcting impaired TRP metabolism, in patients with CRF."R
"AST-120 significantly reduced renal expression of intercellular adhesion molecule (ICAM)-1, osteopontin, monocyte chemotactic protein (MCP)-1, and transforming growth factor (TGF)-beta1, as well as clusterin. ... AST-120 also decreased serum and urinary levels of indoxyl sulfate and the overload of indoxyl sulfate in tubular cells. CONCLUSIONS: AST-120 ameliorates tubulointerstitial injury by reducing renal expression of ICAM-1, osteopontin, MCP-1, TGF-beta1 and clusterin in 1/2NxOLETF rats."R
The relationship between insulin resistance and local uremic toxins was examined using an oral adsorbent. Fourteen rats demonstrating a diabetic state underwent two-thirds, nephrectomy and were divided into two groups. The control group was fed standard rat chow, and the test group was fed standard rat chow containing 5% AST-120. The target level of blood glucose was achieved by controlling the dosage of exogenous insulin. All rats were sacrificed at week 6. Body weight, blood glucose level, and renal function at week 6 were not significantly different between both groups. However, the mean blood glucose level and the mean dose of exogenous insulin in the AST-120-fed group were significantly reduced as compared with the control group. The results of the present study indicate that administration of an oral adsorbent in diabetic nephropathy decreases the doses of exogenous insulin and improves insulin resistance, and that uremic toxins which exist in the gastrointestinal tract play important roles."R
"We have reported that oral sorbent AST-120 (AST) is effective in delaying the induction of dialysis in patients with chronic renal failure (CRF) because of its effect on lipid metabolism. To clarify the precise mechanism of AST in lipid abnormalities in CRF, we examined the effect of AST on plasma lipid profile, total bile acids (TBA), and lipoprotein lipase (LPL) activity in experimental uremic rats. METHODS: Uremic rats were prepared using male Wistar rats by ligating 5/6 of the renal artery. Uremic rats were randomly divided into two groups as follows: a control group in which rats were maintained on the standard diet and an AST group in which rats were maintained on a diet containing 5 g of AST per 100 g of standard diet for 10 weeks. Plasma LPL activity was measured as free fatty acid (FFA) generation after intravenous administration of heparin. RESULTS: Plasma creatinine at 1.5 +/- 0.1 mg/dl was lower in the AST group than the 1.9 +/- 0.5 mg/ml level in the control group. AST significantly decreased plasma total cholesterol from 192 +/- 29 to 142 +/- 25 mg/dl, triglycerides from 198 +/- 71 to 99 +/- 38 mg/dl, and TBA from 19.6 +/- 2.6 mumol/liter to 8.8 +/- 3.5 mumol/ml. Plasma LPL activity at 0.22 +/- 0.01 mumol FFA/min/hr was significantly higher in the AST group than 0.15 +/- 0.03 mumol FFA/min/hr in the control group. CONCLUSIONS: These results suggest that AST may improve plasma lipid abnormalities by binding to bile acids in the intestinal lumen and preventing their reabsorption and inhibiting the reduction of LPL activity in experimental uremic rats."R
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