Phenylacetylglutamine as a Novel Biomarker for Death and Cardiovascular Events in Patients with CKD

Background: Phenylacetylglutamine (PAG), a gut microbiota-derived metabolite, has been linked to cardiovascular disease, but its role in chronic kidney disease (CKD) outcomes remains unclear. This study investigated the association of serum PAG with all-cause mortality and major adverse cardiovascular events (MACE) in CKD, and explored related cardiovascular protein biomarkers. Methods: We conducted a prospective cohort study of 476 CKD patients. Primary outcomes included all-cause mortality and MACE, defined as a composite of acute coronary syndrome, cerebrovascular disease, or acute heart failure hospitalization. Cox proportional hazards models were used to assess the association between natural logarithmic transformation of PAG levels and outcomes, adjusting for demographics, comorbidities, and relevant laboratory parameters including estimated glomerular filtration rate (eGFR) and albuminuria. We also assessed the association between PAG and 184 cardiovascular proteins measured by Olink proteomics CVDII and CVDIII panels. Results: Patients in the highest PAG tertile were older, had lower hemoglobin, albumin, low-density lipoprotein cholesterol, and eGFR, and higher albuminuria compared to those in the lower tertiles. In Kaplan–Meier survival curve of overall survival and competing death risk method (Fine-Gray approach) of major cardiovascular events shows the highest PAG tertile showed significantly increased rates of mortality and MACE compared to the lowest tertile. In multivariable Cox regression models, natural log-transformed PAG remained independently associated with both mortality (HR 1.88, 95% CI 1.29-2.75) and MACE (subdistribution HR 1.73, 95% CI 1.17-2.56). Moreover, PAG levels were significantly associated with Insulin-like growth factor-binding protein 2 (IGFBP2), N-terminal prohormone brain natriuretic peptide (NT-proBNP), and Trefoil factor 3 (TFF3). Conclusion: Higher serum PAG levels were independently associated with mortality and MACE in CKD patients, even after adjustment for established risk factors. The associations with specific cardiovascular protein biomarkers suggest potential mechanistic links to cardiovascular pathology. PAG measurement may provide prognostic value and therapeutic insights into managing cardiovascular risk in CKD.