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

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.

Microbiota-derived uremic retention solutes: perpetrators of altered nonrenal drug clearance in kidney disease

“…Only considering plasma concentrations of microbial toxins may not accurately reflect tissue distribution. For instance, some microbial toxins accumulate to higher concentrations in liver and kidney tissues than in plasma [49]. …”

The Impact of Uremia and Intestinal Dysbiosis on Hepatic Drug Metabolism in a Rat Model of Progressive Chronic Kidney Disease

“…Columns were maintained at 45°C and mobile phase flow set to 0.45 ml/min consisting of UPLCgrade water (A) and acetonitrile (B), both containing 0.1% formic acid. The RPLC anlysis was run as previously described (18). The HILIC column followed a gradient of 0-0.5 mins 99% B; 0.5-6 mins 99-50% B; 6-8 mins 50-30% B; 8-8.5 mins 30-99% B.…”

“…Samples were run separately in succession for both positive and negative electrospray ionization (ESI) modes on the UPLC-QTof/MS instrument. Mass spectrometer source, method, calibration and other parameters were identical to those in (18) and data was collected by MassLynx v4.1 software (Waters).…”

“…Gut derived uremic toxins that are potentially involved in CYP downregulation from this study include indoxyl sulfate, phenyl sulfate, 4-ethylphenyl sulfate, equol-4/7-O-glucournide and products of L-carnitine metabolism. Indoxyl sulfate and phenyl sulfate are two highly retained gut-derived uremic toxins(50,51) both found in CKD patients and animal models(18,52).…”

Effect of AST-120 in Chronic Kidney Disease Treatment: Still a Controversy?

“…sCr under AST-120 treatment is thus expected to authentically reflect the renal function. A recent animal study of a rat CKD model even demonstrated reductions in indoxyl sulfate accumulation in organs such as the kidney, heart, and liver [9] . In multiple animal CKD studies, AST-120 prevented proteinuria, glomerular hypertrophy, interstitial fibrosis, and CKD progression by interfering with the above-described mechanisms.…”