Indoxyl Sulfate Reduces Superoxide Scavenging Activity in the Kidneys of Normal and Uremic Rats

Owada, Shigeru; Goto, Sumie; Bannai, Kenji; Hayashi, Hideo; Nishijima, Fuyuhiko; Niwa, Toshimitsu

doi:10.1159/000112823

Cited by 93 publications

(62 citation statements)

References 41 publications

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“…Also, other groups reported that indoxyl sulfate promoted oxidative stress in endothelial cells and the kidney. [16][17][18][19] These results strongly suggest the involvement of uremic toxins in the development of atherosclerosis. AST-120 has been known to decrease serum levels of indoxyl sulfate significantly in CKD rat models and also in CKD patients.…”

Section: Discussionmentioning

confidence: 71%

AST-120 Treatment in Pre-Dialysis Period Affects the Prognosis in Patients on Hemodialysis

Ueda¹,

Shibahara²,

Takagi

et al. 2008

Renal Failure

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Background/Aims. An oral adsorbent, AST-120, has been shown to retard the deterioration of renal function in patients with chronic kidney disease (CKD) by decreasing serum nephrotoxic substances such as indoxyl sulfate. Recent studies have suggested that a high level of serum indoxyl sulfate may be one of the mechanisms underlying the progression of atherosclerotic lesion, which is the leading cause of cardiovascular event or death in dialysis patients. In this study, we examined retrospectively whether AST-120 given to patients in the pre-dialysis period influences the prognosis after the initiation of dialysis. Methods. One hundred and ninety-two CKD patients on dialysis were studied. The survival and causes of death after the initiation of dialysis were compared between patients who were administrated AST-120 (AST-120 group, n = 101) and those not administrated AST-120 (non-AST-120 group, n = 91) prior to the initiation of dialysis. Results. The five-year survival rate was 72.6% in the AST-120 group and 52.6% in the non-AST-120 group, and was significantly higher in the AST-120 group (p = 0.018). The risk of death was increased 1.91-fold in the non-AST-120 group. However, no difference in the causes of death was observed between two groups. Conclusion. This study suggests that AST-120 given prior to the initiation of dialysis improves the prognosis of CKD patients under dialysis, although there is no association between AST-120 treatment and death caused by cardiovascular diseases such as heart failure, myocardial infarction, and cerebral hemorrhage. Further studies are needed to elucidate the effect of AST-120 on cardiovascular events and the prognosis in dialysis patients.

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Section: Discussionmentioning

confidence: 71%

AST-120 Treatment in Pre-Dialysis Period Affects the Prognosis in Patients on Hemodialysis

Ueda¹,

Shibahara²,

Takagi

et al. 2008

Renal Failure

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“…All rats underwent five-sixths renal ablation using the method described earlier. 17,19 Eight weeks later, the subtotally nephrectomized rats (age 17 weeks) were divided randomly into two groups (n¼12 in each group): the first group was fed a normal diet (MF; Oriental Yeast, Osaka, Japan) (Nx) and the second group was fed a normal diet containing 0.4 g of AST-120 per 100 g body weight per day (Kureha, Tokyo, Japan) (Nx+AST). Age-matched sham-operated rats fed a normal diet (Sham) were used for comparison.…”

Section: Animal Preparationmentioning

confidence: 99%

“…17 In addition, IS induced free radical production in renal proximal tubular cells 18 and reduced superoxide scavenging activity in the kidneys of normal and uremic rats. 19 We previously showed that endothelial dysfunction was associated with enhanced vascular oxidative and nitrative stress in rats with obesity and renal injury. 20,21 The aim of this study was to determine whether AST-120 improves endothelial dysfunction and reduces vascular oxidative/nitrative stress in subtotally nephrectomized rats.…”

Section: Introductionmentioning

confidence: 97%

Oral adsorbent AST-120 ameliorates endothelial dysfunction independent of renal function in rats with subtotal nephrectomy

et al. 2009

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It is important to consider a strategy to halt the development of cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). Oral adsorbent AST-120 retards deterioration in renal function, reducing indoxyl sulfate (IS) accumulation. The aim of this study was to determine whether AST-120 improves endothelial dysfunction by reducing oxidative/nitrative stress in a rat-CKD model. Subtotally nephrectomized (Nx) rats aged 17 weeks were divided into two groups: control rats and rats orally treated with AST-120. Two weeks after initiation of AST-120, serum and urinary IS levels, renal histological scores and endothelium-dependent vascular responses (EDVRs) in the aorta were investigated. EDVR in 5-h incubation with 250 lg ml À1 IS was also examined in normal rat aortas. Nitrotyrosine content, mRNA expression of p47phox, a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase component, and expression and phosphorylation (serine-1177) of endothelial nitric oxide synthase (eNOS) in the aorta were examined in untreated and treated Nx rats. At the end of treatment, renal function and histological scores were not different in the two groups. AST-120 prevented the elevation of serum IS level in Nx rats, reducing urinary IS excretion, and ameliorated decreased EDVR in Nx rats. Incubation with IS tended to reduce EDVR in normal aortas, albeit insignificantly. AST-120 also suppressed nitrotyrosine accumulation and inhibited p47phox expression in Nx rats. The eNOS expression and phosphorylation were similar in the two groups. In conclusion, AST-120 ameliorated endothelial dysfunction and alleviated oxidative/nitrative stress in the aorta through reduced accumulation of IS, independent of renal function, in a rat CKD model.

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“…A 5/6-subtotal nephrectomy (STNx) rat model showed a significant 6.6-fold (65.7 μmol/L) increase in serum IS levels at 2 weeks after 5/6-STNx compared with sham animals, whereas a nonsignificant 3.7-fold (37.1 μmol/L) increase is observed in a 3/4-STNx model. 126 Importantly, an increase in circulating IS levels can occur in the early stages (2 and 3) of CKD, 127 and the combined prevalence of stages 2 and 3 is 67% of all CKD stages; 128 the harmful biological activity of elevated IS, therefore, should receive therapeutic attention before consideration of renal replacement therapy.…”

Section: Is Indoxyl Sulfate a Culprit Inmentioning

confidence: 99%

“…141 IS administration also impaired renal superoxide scavenging activity that is associated with renal dysfunction in uremic (3/4-and 5/6-STNx) rats. 126 There also is evidence that the profibrotic and oxidative stress-inducing effects of IS may be interrelated. One study demonstrated that an antioxidant can suppress IS-induced NF-κB activation in proximal tubular cells, and inhibition of NF-κB in turn suppressed TGF-β1 protein expression in uremic rats.…”

Section: Kidneymentioning

confidence: 99%

Cardiorenal Syndrome

Lekawanvijit

Kompa

Wang

et al. 2012

Circulation Research

152

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Cardiorenal syndrome is a condition in which a complex interrelationship between cardiac dysfunction and renal dysfunction exists. Despite advances in treatment of both cardiovascular and kidney disease, cardiorenal syndrome remains a major global health problem. Characteristic of the pathophysiology of cardiorenal syndrome is bidirectional cross-talk; mediators/substances activated by the disease state of 1 organ can play a role in worsening dysfunction of the other by exerting their biologically harmful effects, leading to the progression of the syndrome. Accumulation of uremic toxins is a hallmark of renal excretory dysfunction. Removal of some toxins by conventional dialysis is particularly problematic because of their high protein binding. In this review, we demonstrate that protein-bound uremic toxins may play an important role in progression of cardiovascular disease in the setting of chronic kidney disease. The highly protein-bound uremic toxin indoxyl sulfate has emerged as a potent toxin adversely affecting both the kidney and heart. Direct cardiac effects of this toxin have been recently demonstrated both in vitro and in vivo. Specifically, potent fibrogenic and prohypertrophic effects, as well as oxidative stress-inducing effects, appear to play a central role in both renal and cardiac pathology. Many of these adverse effects can be suppressed by use of a gut adsorbent, AST-120. Potential mechanisms underlying indoxyl sulfate−induced cardiorenal fibrosis are discussed. Future research and clinical implications conclude this review.

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Indoxyl Sulfate Reduces Superoxide Scavenging Activity in the Kidneys of Normal and Uremic Rats

Cited by 93 publications

References 41 publications

AST-120 Treatment in Pre-Dialysis Period Affects the Prognosis in Patients on Hemodialysis

AST-120 Treatment in Pre-Dialysis Period Affects the Prognosis in Patients on Hemodialysis

Oral adsorbent AST-120 ameliorates endothelial dysfunction independent of renal function in rats with subtotal nephrectomy

Cardiorenal Syndrome

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