Phenylacetylglutamine and trimethylamine N‐oxide: Two uremic players, different actions

Abstract

BackgroundChronic kidney disease (CKD) patients exhibit a heightened cardiovascular (CV) risk which may be partially explained by increased medial vascular calcification. Although gut‐derived uremic toxin trimethylamine N‐oxide (TMAO) is associated with calcium‐phosphate deposition, studies investigating phenylacetylglutamine's (PAG) pro‐calcifying potential are missing.MethodsThe effect of TMAO and PAG in vascular calcification was investigated using 120 kidney failure patients undergoing living‐donor kidney transplantation (LD‐KTx), in an observational, cross‐sectional manner. Uremic toxin concentrations were related to coronary artery calcification (CAC) score, epigastric artery calcification score, and markers of established non‐traditional risk factors that constitute to the ‘perfect storm’ that drives early vascular aging in this patient population. Vascular smooth muscle cells were incubated with TMAO or PAG to determine their calcifying effects in vitro and analyse associated pathways by which these toxins may promote vascular calcification.ResultsTMAO, but not PAG, was independently associated with CAC score after adjustment for CKD‐related risk factors in kidney failure patients. Neither toxin was associated with epigastric artery calcification score; however, PAG was independently, positively associated with 8‐hydroxydeoxyguanosine. Similarly, TMAO, but not PAG, promoted calcium‐phosphate deposition in vitro, while both uremic solutes induced oxidative stress.ConclusionsIn conclusion, our translational data confirm TMAO's pro‐calcifying effects, but both toxins induced free radical production detrimental to vascular maintenance. Our findings suggest these gut‐derived uremic toxins have different actions on the vessel wall and therapeutically targeting TMAO may help reduce CV‐related mortality in CKD.

Generally-healthy individuals with aberrant bowel movement frequencies show enrichment for microbially-derived blood metabolites associated with reduced kidney function

“…3-IS has been associated with vascular disease and mortality in CKD patients 66 . PAG has been associated with CKD progression and mortality 29,30,61,62 . Ultimately, we see an enrichment in microbially- derived uremic toxins in the blood of generally-healthy individuals with lower BMFs.…”

Aberrant bowel movement frequencies coincide with increased microbe-derived blood metabolites associated with reduced organ function

“… 55 PAG has been associated with CKD progression and mortality. 26 , 27 , 50 , 51 Ultimately, we see an enrichment in microbially derived uremic toxins in the blood of generally healthy individuals with lower BMFs.…”

“…Consistent with our microbiome results, we found gut microbiome-derived protein fermentation byproducts, like PCS, PAG, and 3-IS, were enriched in the blood of individuals with lower BMFs ( Figure 5 ). 50 , 51 , 52 PCS has been associated with deteriorating kidney function and damage to nephrons, as well as cognitive decline and neuroinflammation. 53 , 54 3-IS has been associated with vascular disease and mortality in patients with CKD.…”