Impact of the Oral Adsorbent AST-120 on Organ-Specific Accumulation of Uremic Toxins: LC-MS/MS and MS Imaging Techniques

Sato, Emiko; Saigusa, Daisuke; Mishima, Eikan; Uchida, Taeko; Miura, Daisuke; Morikawa-Ichinose, Tomomi; Kisu, Kazuaki; Sekimoto, Akiyo; Saito, Ryosuke; Oe, Yuji; Matsumoto, Yotaro; Tomioka, Y.; Mori, Takefumi; Takahashi, Nobuyuki; Satô, Hiroshi; Abe, Takaaki; Niwa, Toshimitsu; Ito, Sadayoshi

doi:10.3390/toxins10010019

Cited by 63 publications

(64 citation statements)

References 52 publications

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“…However, the beneficial of AST-120 is still controversial. In a renal failure mouse model induced by adenine, AST-120 did not show an improvement in renal function and fibrosis despite a significant reduction in IS and pCS accumulation in the renal tissue [ 207 ]. Large scale randomized controlled trials in moderate to severe CKD (pre-dialysis) patients failed to show renal benefits of AST-120 on the delay in CKD progression despite a significantly better preservation of renal function in AST-120 treated than placebo groups [ 208 , 209 ].…”

Section: Cardiac Effects Of Protein-bound Moleculesmentioning

confidence: 99%

Cardiotoxicity of Uremic Toxins: A Driver of Cardiorenal Syndrome

Lekawanvijit

2018

Toxins

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Cardiovascular disease (CVD) is highly prevalent in the setting of chronic kidney disease (CKD). Such coexistence of CVD and CKD—the so-called “cardiorenal or renocardiac syndrome”—contributes to exponentially increased risk of cardiovascular (CV) mortality. Uremic cardiomyopathy is a characteristic cardiac pathology commonly found in CKD. CKD patients are also predisposed to heart rhythm disorders especially atrial fibrillation. Traditional CV risk factors as well as known CKD-associated CV risk factors such as anemia are insufficient to explain CV complications in the CKD population. Accumulation of uremic retention solutes is a hallmark of impaired renal excretory function. Many of them have been considered inert solutes until their biological toxicity is unraveled and they become accepted as “uremic toxins”. Direct cardiotoxicity of uremic toxins has been increasingly demonstrated in recent years. This review offers a mechanistic insight into the pathological cardiac remodeling and dysfunction contributed by uremic toxins with a main focus on fibroblastic growth factor-23, an emerging toxin playing a central role in the chronic kidney disease–mineral bone disorder, and the two most investigated non-dialyzable protein-bound uremic toxins, indoxyl sulfate and p-cresyl sulfate. Potential therapeutic strategies that could address these toxins and their relevant mediated pathways since pre-dialysis stages are also discussed.

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Section: Cardiac Effects Of Protein-bound Moleculesmentioning

confidence: 99%

Cardiotoxicity of Uremic Toxins: A Driver of Cardiorenal Syndrome

Lekawanvijit

2018

Toxins

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“…AST-120 is an oral carbonic adsorbent which is used to decrease the absorption of uremic toxins, such as indols and retard CKD in Japan [ 121 ]. In experimental CKD, it reduces tissue accumulation of IS and pCS in diverse tissues, including the kidney and protected the kidneys in several animal models of AKI and CKD [ 122 ], However, two large multinational trials (EPPIC-1 and EPPIC-2), failed to show benefit on CKD progression [ 123 ]. However, a post-hoc, hypothesis-generating analysis observed that in the subgroup of high risk patients (urinary creatinine ratio ≥1.0 and haematuria) who were additionally treated with renin-angiotensin system blockade, AST-120 may have provided additional benefit in retarding CKD progression [ 124 ].…”

Section: Nephroprotection Interventional Studies Targeting the Intmentioning

confidence: 99%

Impact of Altered Intestinal Microbiota on Chronic Kidney Disease Progression

Castillo-Rodríguez

Fernández-Prado

Esteras

et al. 2018

Toxins

116

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In chronic kidney disease (CKD), accumulation of uremic toxins is associated with an increased risk of CKD progression. Some uremic toxins result from nutrient processing by gut microbiota, yielding precursors of uremic toxins or uremic toxins themselves, such as trimethylamine N-Oxide (TMAO), p-cresyl sulphate, indoxyl sulphate and indole-3 acetic acid. Increased intake of some nutrients may modify the gut microbiota, increasing the number of bacteria that process them to yield uremic toxins. Circulating levels of nutrient-derived uremic toxins are associated to increased risk of CKD progression. This offers the opportunity for therapeutic intervention by either modifying the diet, modifying the microbiota, decreasing uremic toxin production by microbiota, increasing toxin excretion or targeting specific uremic toxins. We now review the link between nutrients, microbiota and uremic toxin with CKD progression. Specific focus will be placed on the generation specific uremic toxins with nephrotoxic potential, the decreased availability of bacteria-derived metabolites with nephroprotective potential, such as vitamin K and butyrate and the cellular and molecular mechanisms linking these toxins and protective factors to kidney diseases. This information provides a conceptual framework that allows the development of novel therapeutic approaches.

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“…AST-120, a kind of absorbent, has been reported to absorb indole in the gut, thus, decreasing the amount of absorbed indole leading to decreased IS concentrations and delayed CKD progression. 27 , 28 These reports have proven that decreasing gut indole production may be an attractive and promising strategy for delaying CKD progression. However, modulation of the gut microbial metabolic pathway and indole production by small molecules has not yet been reported.…”

Section: Introductionmentioning

confidence: 99%

Targeting the gut microbial metabolic pathway with small molecules decreases uremic toxin production

Wang

Chen

et al. 2020

Gut Microbes

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Uremic toxins are a class of toxins that accumulate in patients with chronic kidney disease (CKD). Indoxyl sulfate (IS), a typical uremic toxin, is not efficiently removed by hemodialysis. Modulation of IS production in the gut microbiota may be a promising strategy for decreasing IS concentration, thus, delaying CKD progression. In the present study, we identified isoquercitrin (ISO) as a natural product that can perturb microbiota-mediated indole production without directly inhibiting the growth of microbes or the indole-synthesizing enzyme TnaA. ISO inhibits the establishment of H proton potential by regulating the gut bacteria electron transport chain, thereby inhibiting the transport of tryptophan and further reducing indole biosynthesis. This non-microbiocidal mechanism may enable ISO to be used as a therapeutic tool, specifically against pathologies triggered by the accumulation of the microbial-produced toxin IS, as in CKD. Herein, we have shown that it is possible to inhibit gut microbial indole production using natural components. Therefore, targeting the uremic toxin metabolic pathway in gut bacteria may be a promising strategy to control host uremic toxin production.

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Impact of the Oral Adsorbent AST-120 on Organ-Specific Accumulation of Uremic Toxins: LC-MS/MS and MS Imaging Techniques

Cited by 63 publications

References 52 publications

Cardiotoxicity of Uremic Toxins: A Driver of Cardiorenal Syndrome

Cardiotoxicity of Uremic Toxins: A Driver of Cardiorenal Syndrome

Impact of Altered Intestinal Microbiota on Chronic Kidney Disease Progression

Targeting the gut microbial metabolic pathway with small molecules decreases uremic toxin production

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