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Although gut\u2010derived uremic toxin trimethylamine N\u2010oxide (TMAO) is associated with calcium\u2010phosphate deposition, studies investigating phenylacetylglutamine's (PAG) pro\u2010calcifying potential are missing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The effect of TMAO and PAG in vascular calcification was investigated using 120 kidney failure patients undergoing living\u2010donor kidney transplantation (LD\u2010KTx), in an observational, cross\u2010sectional manner. Uremic toxin concentrations were related to coronary artery calcification (CAC) score, epigastric artery calcification score, and markers of established non\u2010traditional risk factors that constitute to the \u2018perfect storm\u2019 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>TMAO, but not PAG, was independently associated with CAC score after adjustment for CKD\u2010related risk factors in kidney failure patients. Neither toxin was associated with epigastric artery calcification score; however, PAG was independently, positively associated with 8\u2010hydroxydeoxyguanosine. Similarly, TMAO, but not PAG, promoted calcium\u2010phosphate deposition in vitro, while both uremic solutes induced oxidative stress.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In conclusion, our translational data confirm TMAO's pro\u2010calcifying effects, but both toxins induced free radical production detrimental to vascular maintenance. Our findings suggest these gut\u2010derived uremic toxins have different actions on the vessel wall and therapeutically targeting TMAO may help reduce CV\u2010related mortality in CKD.<\/jats:p><\/jats:sec>","DOI":"10.1111\/eci.14074","type":"journal-article","created":{"date-parts":[[2023,8,7]],"date-time":"2023-08-07T09:14:38Z","timestamp":1691399678000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Phenylacetylglutamine and trimethylamine N\u2010oxide: Two uremic players, different actions"],"prefix":"10.1111","volume":"53","author":[{"given":"Sam","family":"Hobson","sequence":"first","affiliation":[{"name":"Division of Renal Medicine, Department of Clinical Science, Intervention and Technology Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdul Rashid","family":"Qureshi","sequence":"additional","affiliation":[{"name":"Division of Renal Medicine, 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