Untargeted plasma and tissue metabolomics in rats with chronic kidney disease given AST-120.

Thomas J Velenosi,Polydoros Kyriacou,Stephanie E Nevison,Michael A Kerr,David A Feere,Bradley L Urquhart,Laura E Mccuaig,Alvin Tieu,Andrew S Kucey,Anzel Hennop

doi:10.1038/srep22526

Thomas J Velenosi, Polydoros Kyriacou + Show 8 more

Open Access

https://doi.org/10.1038/srep22526

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Abstract

Chronic kidney disease (CKD) results in the accumulation of metabolic waste products that are normally cleared by the kidney, known as uremia. Many of these waste products are from bacteria metabolites in the gut. Accumulation of uremic toxins in plasma and tissue, as well as the gut-plasma-tissue metabolic axis are important for understanding pathophysiological mechanisms of comorbidities in CKD. In this study, an untargeted metabolomics approach was used to determine uremic toxin accumulation in plasma, liver, heart and kidney tissue in rats with adenine-induced CKD. Rats with CKD were also given AST-120, a spherical carbon adsorbent, to assess metabolic changes in plasma and tissues with the removal of gut-derived uremic toxins. AST-120 decreased >55% of metabolites that were increased in plasma, liver and heart tissue of rats with CKD. CKD was primarily defined by 8 gut-derived uremic toxins, which were significantly increased in plasma and all tissues. These metabolites were derived from aromatic amino acids and soy protein including: indoxyl sulfate, p-cresyl sulfate, hippuric acid, phenyl sulfate, pyrocatechol sulfate, 4-ethylphenyl sulfate, p-cresol glucuronide and equol 7-glucuronide. Our results highlight the importance of diet and gut-derived metabolites in the accumulation of uremic toxins and define the gut-plasma-tissue metabolic axis in CKD.

Highlights

A number of studies have quantified individual uremic toxin levels in patients with chronic kidney disease (CKD)
Rat plasma metabolic changes in CKD have been assessed in previous studies with the use of AST-12032,33
Renal metabolic profiles in negative electrospray ionization (ESI) mode have been evaluated in rats with CKD34; this study is the first to assess tissue metabolic signatures in heart, liver and kidney including the metabolic axis between plasma and tissues

Summary

Introduction

A number of studies have quantified individual uremic toxin levels in patients with CKD. Subsequent updates were published in 2007 and 2012, adding 14 and 56 uremic toxins, respectively[10,20] This is an effective method for determining mean patient uremic toxin levels; the uremic toxins reported are a result of targeted analysis, which can limit the identification of novel toxins. In the setting of CKD, metabolomics can provide uremic signatures directly associated with decreased renal function[22] This information can be used to determine mechanisms of kidney disease initiation and progression. Clinical and animal studies have begun to identify plasma uremic toxins using untargeted metabolomics[24,25,26] These metabolites have been identified using both NMR and LC-MS techniques. We assessed the plasma and tissue metabolic effects of removing gut-derived uremic toxins using AST-120 to further understand the gut contribution to the uremic condition in both plasma and tissues in CKD

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