Oral charcoal adsorbent (AST-120) prevents progression of cardiac damage in chronic kidney disease through suppression of oxidative stress

Fujii, Hideki; Nishijima, Fuyuhiko; Goto, Shunsuke; Sugano, Mikio; Yamato, Hideyuki; Kitazawa, Riko; Kitazawa, Sohei; Fukagawa, Masafumi

doi:10.1093/ndt/gfp007

Cited by 126 publications

(103 citation statements)

References 24 publications

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“…99 For cardiac endpoints, 5/6 nephrectomy rats treated with AST-120 showed a significant reduction in serum IS levels, cardiac fibrosis, cardiac TGF-β protein expression, cardiac NF-κB phosphorylation and cardiac oxidative stress. 47, 48 These findings support the proposed ROS/NF-κB/TGF-β1 mechanistic signaling pathway of IS-induced cardiac fibrosis. 100 Clinical Outcomes in Clinical Studies In predialysis CKD patients, an improvement in renal function was observed after 1 year of AST-120 treatment, 101 and a risk reduction for initiation of dialysis or reaching ESRD was achieved after 2 years of treatment.…”

Section: Renal Endpoints In Preclinical Studiessupporting

confidence: 56%

Role of Gut-Derived Protein-Bound Uremic Toxins in Cardiorenal Syndrome and Potential Treatment Modalities

Lekawanvijit

2015

Circ J

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Section: Renal Endpoints In Preclinical Studiessupporting

confidence: 56%

Role of Gut-Derived Protein-Bound Uremic Toxins in Cardiorenal Syndrome and Potential Treatment Modalities

Lekawanvijit

2015

Circ J

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“…148 In that study, adverse cardiac effects of IS were demonstrated to be strongly associated with increased cardiac expression of oxidative stress markers, 8-hydroxydeoxyguanosine and acrolein. 148 Collectively, it is suggested that: IS is likely to be at least partly responsible for the development of cardiac fibrosis in the CKD setting; the reduction of cardiac fibrosis by AST-120 treatment is partially directly because of its IS-lowering effect and not secondary to improved renal function; and IS-induced cardiac fibrosis may be mediated via the proposed ROS/NF-κB/TGF-β1 pathway of IS-induced renal fibrosis. 130 However, further investigation is needed to confirm this mechanistic pathway.…”

Section: Heartmentioning

confidence: 91%

“…When renal function is impaired, waste Cardiac fibrosis in vivo 147,148 Increased cardiac oxidative stress 148 Functional impairment 116,133,134 Renal inflammation with increased proinflammatory cytokine gene expression 135,137 Glomerulosclerosis and renal interstitial fibrosis with activation of profibrotic gene and protein expression 116,133,134,136,170 Enhancing renal oxidative stress, both in vitro and in vivo 64 including 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid, 2-methoxyresorcinol, p-OHhippuric acid, other indoles (kinurenine, kynurenic acid, quinolinic acid, and melatonin), advanced glycation end products (3-deoxyglucosone, fructoselysine, glyoxal, methylglyoxal, N ε -(carboxymethyl)lysine, and pentosidine), polyamines (putrescine, spermidine, and spermine), and peptides (leptin and retinol-binding protein).…”

Section: Uremic Toxinsmentioning

confidence: 99%

Cardiorenal Syndrome

Lekawanvijit

Kompa

Wang

et al. 2012

Circulation Research

145

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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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“…NADPH oxidases are major sources of reactive oxygen species, and activation of NADPH oxidases was associated with the incidence of AF 29, 30, 31, 32, 33, 34, 35, 36. Furthermore, several studies demonstrated that oxidative stress plays an important role in renal dysfunction–induced cardiac fibrosis, and AST‐120 prevented cardiac damage by alleviating oxidative stress 13, 15. In the present study, expression of NOX2, a membrane‐spanning subunit of NADPH oxidases, and NOX4, which is predominantly localized in the mitochondria, was significantly upregulated in LA tissue isolated from 5/6Nx rats, and the expression of MDA was concomitantly upregulated.…”

Section: Discussionmentioning

confidence: 99%

“…Indoxyl sulfate (IS) is a poorly dialysable uremic toxin due to its high protein binding, and it has been proposed as a critical factor for the progression of inflammation and fibrosis in various tissues 9, 10, 11, 12. IS has been reported to exaggerate cardiac fibrosis via oxidative stress and inflammation in renal dysfunction, and AST‐120 (commonly used in clinical settings as an absorbent of uremic toxins) has been reported to ameliorate fibrosis by reducing circulating levels of IS 13, 14, 15. Given that atrial interstitial fibrosis is a substrate for the pathogenesis of AF,16, 17, 18 we hypothesized that IS may be a predisposing factor for AF in renal dysfunction mediated by aggravation of oxidative stress, inflammation, and atrial fibrosis.…”

mentioning

confidence: 99%

Role of Indoxyl Sulfate as a Predisposing Factor for Atrial Fibrillation in Renal Dysfunction

Aoki

Teshima

Kondo

et al. 2015

JAHA

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BackgroundRenal dysfunction is a major risk factor for atrial fibrillation (AF). The uremic toxin indoxyl sulfate may contribute to the progression of cardiac fibrosis and AF substrate in renal dysfunction.Methods and ResultsMale Sprague–Dawley rats were assigned randomly to the following groups: 5/6 nephrectomy (5/6Nx) with vehicle, 5/6Nx with AST‐120, sham procedure with vehicle, and sham procedure with AST‐120. Vehicle and AST‐120 were administered for 4 weeks. Serum levels of IS were significantly increased in 5/6Nx groups. Expression of malondialdehyde, an indicator of oxidative stress, was upregulated in the left atrium of 5/6Nx groups and was accompanied by an increase in expression of NADPH oxidase 2 and 4. Monocyte‐mediated inflammatory signals such as CD68, monocyte chemoattractant protein 1, and vascular cell adhesion molecule 1 were also upregulated in 5/6Nx groups. Interstitial fibrosis was promoted heterogeneously, and expression of profibrotic indicators such as transforming growth factor β1, α‐smooth muscle actin, and collagen type 1 was upregulated in left atrium tissue of 5/6Nx groups. In cultured atrial fibroblasts, incubation with IS upregulated expression of the markers of oxidative stress, inflammation, and profibrotic factors. These results suggest the direct effects of IS on the progression of AF substrate. AF was consistently and invariably induced by atrial extrastimuli in 5/6Nx groups in electrophysiological experiments. AST‐120 treatment significantly alleviated renal dysfunction–induced oxidative stress, inflammation, and atrial fibrosis and, consequently, attenuated AF inducibility.ConclusionsIndoxyl sulfate facilitates atrial fibrosis and AF and thus is a novel therapeutic target for prevention of renal dysfunction–induced AF.

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Oral charcoal adsorbent (AST-120) prevents progression of cardiac damage in chronic kidney disease through suppression of oxidative stress

Abstract: Oxidative stress is suggested to play a key role in the development of cardiac hypertrophy and fibrosis in CKD. AST-120 may suppress oxidative stress and reduce cardiac damage in CKD.

Cited by 126 publications

References 24 publications

Role of Gut-Derived Protein-Bound Uremic Toxins in Cardiorenal Syndrome and Potential Treatment Modalities

Role of Gut-Derived Protein-Bound Uremic Toxins in Cardiorenal Syndrome and Potential Treatment Modalities

Cardiorenal Syndrome

Role of Indoxyl Sulfate as a Predisposing Factor for Atrial Fibrillation in Renal Dysfunction

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