The effects of AST-120 on chronic kidney disease progression in the United States of America: a post hoc subgroup analysis of randomized controlled trials

Schulman, Gerald; Berl, Tomás; Beck, Gerald J.; Remuzzi, Giuseppe; Ritz, Eberhard; Shimizu, Miho; Shobu, Yuko; Kikuchi, Mami

doi:10.1186/s12882-016-0357-9

Cited by 48 publications

(41 citation statements)

References 23 publications

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“…Uremic toxin adsorbents such as AST-120 can adsorb uremic toxin precursors in the intestines and decrease uremic toxins in vivo . 27 However, adverse reactions such as constipation, nausea, and vomiting limited the use of AST-120. In addition, probiotics can reduce the production of uremic toxins by regulating the intestinal microenvironment, 46 but the effects of probiotics are not specific.…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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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Section: Discussionmentioning

confidence: 99%

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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“…Adding this pharmaceutical to the standard therapy of CKD patients showed reduced serum levels of indoxyl sulfate [32, 66], improvement in some of the uraemia symptoms [66] and a decrease in markers for cardiovascular disease [67]. Although clinical trials showed that treatment with AST-120 resulted in more gradual disease progression [66, 68], its overall benefit is yet to be proven [68, 69]. Other approaches to reducing gut-microflora-produced uraemic molecules are consumption of a low-protein diet and restoring the balance of gut microflora by probiotics and prebiotics [30, 34, 70].…”

Section: Discussionmentioning

confidence: 99%

Tryptophan metabolism, its relation to inflammation and stress markers and association with psychological and cognitive functioning: Tasmanian Chronic Kidney Disease pilot study

et al. 2016

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BackgroundAdults with chronic kidney disease (CKD) exhibit alterations in tryptophan metabolism, mainly via the kynurenine pathway, due to higher enzymatic activity induced mainly by inflammation. Indoles produced by gut-microflora are another group of tryptophan metabolites related to inflammation and conditions accompanying CKD. Disruptions in tryptophan metabolism have been associated with various neurological and psychological disorders. A high proportion of CKD patients self-report symptoms of depression and/or anxiety and decline in cognitive functioning. This pilot study examines tryptophan metabolism in CKD and explores associations with psychological and cognitive functioning.MethodsTwenty-seven adults with CKD were part of 49 patients recruited to participate in a prospective pilot study, initially with an eGFR of 15–29 mL/min/1.73 m2. Only participants with viable blood samples and complete psychological/cognitive data at a 2-year follow-up were included in the reported cross-sectional study. Serum samples were analysed by Liquid Chromatography coupled to Mass Spectrometry, for tryptophan, ten of its metabolites, the inflammation marker neopterin and the hypothalamic–pituitary–adrenal (HPA) axis marker cortisol.ResultsThe tryptophan breakdown index (kynurenine / tryptophan) correlated with neopterin (Pearson R = 0.51 P = 0.006) but not with cortisol. Neopterin levels also correlated with indoxyl sulfate (R = 0.68, P < 0.0001) and 5 metabolites of tryptophan (R range 0.5–0.7, all P ≤ 0.01), which were all negatively related to eGFR (P < 0.05). Higher levels of kynurenic acid were associated with lower cognitive functioning (Spearman R = −0.39, P < 0.05), while indole-3 acetic acid (IAA) was correlated with anxiety and depression (R = 0.52 and P = 0.005, R = 0.39 and P < 0.05, respectively).ConclusionsThe results of this preliminary study suggest the involvement of inflammation in tryptophan breakdown via the kynurenine pathway, yet without sparing tryptophan metabolism through the 5-HT (serotonin) pathway in CKD patients. The multiple moderate associations between indole-3 acetic acid and psychological measures were a novel finding. The presented pilot data necessitate further exploration of these associations within a large prospective cohort to assess the broader significance of these findings.Electronic supplementary materialThe online version of this article (doi:10.1186/s12882-016-0387-3) contains supplementary material, which is available to authorized users.

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“…In conclusion, there was no effect of adding AST-120 to standard therapy in patients with moderate to severe CKD on a primary composite renal end point in the EPPIC trials [57]. It should be noted, however, that on the basis of the results of a subgroup analysis in the EPPIC trials, AST-120 delayed the time of reaching the primary renal end point in patients from the United States [58].…”

Section: Uremic Toxins and Premature Ageing In Ckdmentioning

confidence: 83%

Inflammation and Premature Ageing in Chronic Kidney Disease

Ebert

Pawelzik

Witasp

et al. 2020

Toxins

134

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Persistent low-grade inflammation and premature ageing are hallmarks of the uremic phenotype and contribute to impaired health status, reduced quality of life, and premature mortality in chronic kidney disease (CKD). Because there is a huge global burden of disease due to CKD, treatment strategies targeting inflammation and premature ageing in CKD are of particular interest. Several distinct features of the uremic phenotype may represent potential treatment options to attenuate the risk of progression and poor outcome in CKD. The nuclear factor erythroid 2-related factor 2 (NRF2)–kelch-like erythroid cell-derived protein with CNC homology [ECH]-associated protein 1 (KEAP1) signaling pathway, the endocrine phosphate-fibroblast growth factor-23–klotho axis, increased cellular senescence, and impaired mitochondrial biogenesis are currently the most promising candidates, and different pharmaceutical compounds are already under evaluation. If studies in humans show beneficial effects, carefully phenotyped patients with CKD can benefit from them.

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The effects of AST-120 on chronic kidney disease progression in the United States of America: a post hoc subgroup analysis of randomized controlled trials

Cited by 48 publications

References 23 publications

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

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

Tryptophan metabolism, its relation to inflammation and stress markers and association with psychological and cognitive functioning: Tasmanian Chronic Kidney Disease pilot study

Inflammation and Premature Ageing in Chronic Kidney Disease

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