Carbonic-adsorbent AST-120 reduces overload of indoxyl sulfate and the plasma level of TGF-β1 in patients with chronic renal failure

Iida, Shuji; Kohno, Keisuke; Yoshimura, Junko; Ueda, Seinosuke; Usui, Michiaki; Miyazaki, Hiroshi; Nishida, Hidemi; Tamaki, Kiyoshi; Okuda, Seiya

doi:10.1007/s10157-006-0441-8

Cited by 38 publications

(20 citation statements)

References 21 publications

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“…Most studies reported the effect in lowering indoxyl sulfate and the decrease by AST-120 is dose-dependent [18]. Similar to the dose we used in the present study, a reduction rate of indoxyl sulfate was 11-34% in previous studies [17,18,19]. Only one study investigated the effect of AST-120 in HD patients [13].…”

Section: Discussionsupporting

confidence: 61%

“…It is therefore necessary to develop a strategy to prevent the production or reduce the burden of uremic retention compounds. AST-120 is an oral adsorbent that is able to inhibit intestinal absorption of protein-bound uremic toxins and thus can reduce their blood levels [17,18,19,20]. One recent study found that AST-120 can even attenuate the disruption of the tight junction of colon epithelia cells [21].…”

Section: Discussionmentioning

confidence: 99%

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Effects of AST-120 on Blood Concentrations of Protein-Bound Uremic Toxins and Biomarkers of Cardiovascular Risk in Chronic Dialysis Patients

Lee¹,

Hsu

Tain

et al. 2014

Blood Purif

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Background: Removal of protein-bound uremic toxins by dialysis therapy is limited. The effect of oral adsorbent AST-120 in chronic dialysis patients has rarely been investigated. Methods: AST-120 was administered 6.0 g/day for 3 months in 69 chronic dialysis patients. The blood concentrations of indoxyl sulfate, p-cresol sulfate and biomarkers of cardiovascular risk were determined before and after AST-120 treatment. Results: AST-120 significantly decreased both the total and free forms of indoxyl sulfate and p-cresol sulfate ranging from 21.9 to 58.3%. There were significant simultaneous changes of the soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK, 24% increase), malondialdehyde (14% decrease) and interleukin-6 (19% decrease). A significant association between the decrease of indoxyl sulfate and changes of sTWEAK and interleukin-6 was noted. Conclusions: AST-120 effectively decreased indoxyl sulfate and p-cresol sulfate levels in both total and free forms. AST-120 also improved the profile of cardiovascular biomarkers.

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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Effects of AST-120 on Blood Concentrations of Protein-Bound Uremic Toxins and Biomarkers of Cardiovascular Risk in Chronic Dialysis Patients

Lee¹,

Hsu

Tain

et al. 2014

Blood Purif

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“…18,19 Administration of IS also accelerated the aggravation of renal fibrosis, whereas treatment to decrease IS level resulted in a stabilization of renal function. 3,6,20 One of the most important findings of this study was an induction of EMT by IS, which was confirmed by morphological transition and cell migration of cultured murine EMT. 11,12 The presence of EMT in renal fibrosis was first demonstrated by Strutz et al, 21 and confirmed by others in in vivo and in vitro experiments.…”

Section: Discussionmentioning

confidence: 66%

Indoxyl sulfate-induced epithelial-to-mesenchymal transition and apoptosis of renal tubular cells as novel mechanisms of progression of renal disease

Kim

Ryu

et al. 2012

Laboratory Investigation

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Indoxyl sulfate (IS), one of the uremic toxins, is regarded to have a substantial role in the progression of chronic kidney disease (CKD). Epithelial-to-mesenchymal transition (EMT) and apoptosis of renal tubular cells are known to be the critical mechanisms of the development and aggravation of CKD. We investigated the effect of IS on EMT and apoptosis in renal proximal tubular cells, NRK-52E cells. IS significantly inhibited cell proliferation and induced cell migration with a morphological transition from cuboidal epithelial cells to spindle-shaped scattered fibroblast-like cells. IS downregulated the expressions of zonula occluden-1 and E-cadherin, whereas upregulated a-SMA expression at 48 h, which was blocked by a pretreatment of the organic anion transporter, probenecid. IS also induced apoptosis of NRK cells from a concentration of 25 mg/ml with an activation of ERK1/2 and p38 MAP kinase (MAPK). Pretreatment of ERK1/2 or p38 MAPK inhibitors, PD98059 or SB203580, resulted in no significant effect on IS-induced EMT, whereas it ameliorated IS-induced apoptosis of NRK cells. These findings suggested phenotypic transition and apoptosis as potential mechanisms of IS-induced renal damage and the differential role of MAPK activation in IS-induced EMT and apoptosis of renal tubular cells. KEYWORDS: apoptosis; chronic kidney disease; epithelial-to-mesenchymal transition; indoxyl sulfate; MAPKinase Indoxyl sulfate (IS) is one of the protein-bound uremic solutes derived from tryptophan, which is converted to indole and subsequently undergoes sulfate conjugation in hepatocytes to form IS.1 It is taken by organic anion transporters (OATs) at the basolateral membrane of proximal tubular cells, and excreted mostly into urine through tubular secretion.2 Therefore, IS accumulates in patients with chronic kidney disease (CKD), 3 demonstrated as an increase in serum level and positive immunostaining area of IS in the kidneys. 4 Although IS is regarded as a marker of renal dysfunction, recent data have revealed that IS also has a substantial role in the progression of CKD.5 Indole, the precursor of IS, caused glomerular sclerosis in uremic rats, 6 and oral administration of IS increased serum creatinine and decreased inulin clearance in uremic rats.3 In a clinical study, patients with urinary IS levels 490 mg/day showed faster progression rate of CKD than did those with urinary IS o30 mg/day.7 Furthermore, the administration of oral adsorbent of IS resulted in a decrease in glomerular sclerosis and interstitial fibrosis in uremic rats associated with a decrease in plasma and urinary IS levels.3 Lowering IS also resulted in an improvement of renal function and a delay in the initiation of dialysis in CKD patients. 8 In a multicenter, randomized clinical study, Schulman et al 9 showed that an administration of AST-120, oral adsorbent of IS, ameliorated uremic symptoms in a dose-dependent manner with a decrease in serum IS and a stable maintenance of serum creatinine. The mechanism of IS-induced renal progression has been expla...

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“…probiotics, prebiotics and dietary modification) and adsorbent therapies that bind precursors of the various uremic retention solutes in the intestines to reduce their absorption. Several studies have indicated retardation of CKD progression by AST-120, an orally ingested activated charcoal adsorbent [32,33,34,35,36]. …”

Section: Discussionmentioning

confidence: 99%

Very Low Protein Diet Reduces Indoxyl Sulfate Levels in Chronic Kidney Disease

Marzocco¹,

Piaz²,

Micco³

et al. 2013

Blood Purif

138

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Background and Objectives: High levels of indoxyl sulfate (IS) are associated with chronic kidney disease (CKD) progression and increased mortality in CKD patients. The aim of this pilot study was to assess whether a very low protein diet (VLPD; 0.3 g/kg bw/day), with a consequent low phosphorus intake, would reduce IS serum levels compared to a low protein diet (LPD; 0.6 g/kg bw/day) in CKD patients not yet on dialysis. Material and Methods: This is a post hoc analysis of a preceding cross-over study aimed to analyze FGF23 during VLPD. Here we performed a prospective randomized controlled crossover study in which 32 patients were randomized to receive either a VLPD (0.3 g/kg bw/day) supplemented with ketoanalogues during the first week and an LPD during the second week (group A, n = 16), or an LPD during the first week and a VLPD during the second week (group B, n = 16 patients). IS serum levels were measured at baseline and at the end of each study period. We compared them to 24 hemodialysis patients (HD) and 14 healthy subjects (control). Results: IS serum concentration was significantly higher in the HD (43.4 ± 12.3 µM) and CKD (11.1 ± 6.6 µM) groups compared to the control group (2.9 ± 1.1 µM; p < 0.001). IS levels also correlated with creatinine values in CKD patients (R² = 0.42; p < 0.0001). After only 1 week of a VLPD, even preceded by an LPD, CKD patients showed a significant reduction of IS serum levels (37%). Conclusions: VLPD supplemented with ketoanalogues reduced IS serum levels in CKD patients not yet on dialysis.

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Carbonic-adsorbent AST-120 reduces overload of indoxyl sulfate and the plasma level of TGF-β1 in patients with chronic renal failure

Abstract: 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.

Cited by 38 publications

References 21 publications

Effects of AST-120 on Blood Concentrations of Protein-Bound Uremic Toxins and Biomarkers of Cardiovascular Risk in Chronic Dialysis Patients

Effects of AST-120 on Blood Concentrations of Protein-Bound Uremic Toxins and Biomarkers of Cardiovascular Risk in Chronic Dialysis Patients

Indoxyl sulfate-induced epithelial-to-mesenchymal transition and apoptosis of renal tubular cells as novel mechanisms of progression of renal disease

Very Low Protein Diet Reduces Indoxyl Sulfate Levels in Chronic Kidney Disease

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