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

Emiko Sato,Yuji Oe,Sadayoshi Ito,Takaaki Abe,Yoshihisa Tomioka,Kiyomi Kisu,Takefumi Mori,Nobuyuki Takahashi,Daisuke Miura,Eikan Mishima,Tomomi Morikawa-Ichinose,Ritsumi Saito,Yotaro Matsumoto,Hiroshi Sato,Akiyo Sekimoto,Daisuke Saigusa,Taeko Uchida,Toshimitsu Niwa

doi:10.3390/toxins10010019

Abstract

Elevated circulating uremic toxins are associated with a variety of symptoms and organ dysfunction observed in patients with chronic kidney disease (CKD). Indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are representative uremic toxins that exert various harmful effects. We recently showed that IS induces metabolic alteration in skeletal muscle and causes sarcopenia in mice. However, whether organ-specific accumulation of IS and PCS is associated with tissue dysfunction is still unclear. We investigated the accumulation of IS and PCS using liquid chromatography/tandem mass spectrometry in various tissues from mice with adenine-induced CKD. IS and PCS accumulated in all 15 organs analyzed, including kidney, skeletal muscle, and brain. We also visualized the tissue accumulation of IS and PCS with immunohistochemistry and mass spectrometry imaging techniques. The oral adsorbent AST-120 prevented some tissue accumulation of IS and PCS. In skeletal muscle, reduced accumulation following AST-120 treatment resulted in the amelioration of renal failure-associated muscle atrophy. We conclude that uremic toxins can accumulate in various organs and that AST-120 may be useful in treating or preventing organ dysfunction in CKD, possibly by reducing tissue accumulation of uremic toxins.

Highlights

We demonstrated that the uremic toxins Indoxyl sulfate (IS) and p-cresyl sulfate (PCS) accumulate in systemic organs and the circulation
We recently reported that accumulated IS in skeletal muscle induces metabolic alterations We recently reported that accumulated IS in skeletal muscle induces metabolic alterations by by oxidative stress, leading to uremic sarcopenia in chronic kidney disease (CKD) [17]
The present findings suggest that tissue that tissue accumulation of uremic toxins results in increased Pai1 expression and aryl hydrocarbon receptor (AhR) signaling, accumulation of uremic toxins results in increased Pai1 expression and AhR signaling, implying the implying the induction of inflammatory processes

Summary

Introduction

Uremic toxins accumulate in the circulation with the progression of chronic kidney disease (CKD).Because the accumulated uremic toxins exert deleterious effects, they increase morbidity in CKD.Beyond affecting the kidney, retention of uremic toxins is involved in the various complications that occur in CKD, including hypertension, cardiovascular diseases, neurological impairment, bone disorders, and muscle wasting syndrome [1,2,3,4,5].Indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are well-studied representative uremic toxins with cytotoxic, pro-inflammatory, and pro-fibrotic effects [5,6,7,8,9]. Uremic toxins accumulate in the circulation with the progression of chronic kidney disease (CKD). Because the accumulated uremic toxins exert deleterious effects, they increase morbidity in CKD. Retention of uremic toxins is involved in the various complications that occur in CKD, including hypertension, cardiovascular diseases, neurological impairment, bone disorders, and muscle wasting syndrome [1,2,3,4,5]. Indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are well-studied representative uremic toxins with cytotoxic, pro-inflammatory, and pro-fibrotic effects [5,6,7,8,9]. IS and PCS induce oxidative stress and pro-inflammatory effects in the kidney. The pro-inflammatory effect of IS occurs at least partly through activation of the aryl hydrocarbon receptor (AhR)/NF-κB pathway.

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