Carbamylation as a Novel Marker of Coronary Artery Calcification in People With CKD: Findings from a Phenome-Wide Association Study in CRIC.

RATIONALE & OBJECTIVE: Protein carbamylation, a urea-driven post-translational protein modification that increases in chronic kidney disease (CKD), affects diverse mechanisms relevant to the excess morbidity and mortality observed in this population. Given urea's ubiquitous presence in the body, we hypothesized that carbamylation would associate with a broad range of clinical phenotypes, specifically cardiovascular diseases. STUDY DESIGN: Observational cohort study. SETTINGS & PARTICIPANTS: 3,111 participants from the Chronic Renal Insufficiency Cohort (CRIC). EXPOSURE: Carbamylation burden assessed by carbamylated albumin (C-Alb). OUTCOME: Clinical phenotypes, and coronary artery calcification (CAC) prevalence, severity, and progression. ANALYTICAL APPROACH: A phenome-wide association study (PheWAS) evaluated associations between C-Alb and clinical phenotypes. Post-PheWAS analyses examined the association of carbamylation with CAC measured by Agatston and total volume scores. RESULTS: Across 212 phenotypes, multivariable adjusted comparisons identified 47 significant associations between C-Alb and clinical phenotypes after accounting for multiple testing. Blood urea nitrogen showed one of the greatest associations. Among the most significant continuous phenotypes correlated with C-Alb, those within the coronary calcification category exhibited the greatest magnitude of association prompting additional analysis. 1,046 participants had CAC assessments (median age 60 years, 46% female, median eGFR 43) with CAC present in 65% and the highest C-Alb quartile showing the greatest prevalence. Cross-sectional analysis revealed that each SD increase in log-transformed C-Alb associated with 41% greater CAC severity. Longitudinally, among 269 participants with baseline CAC zero, 55 developed incident CAC, while among 389 with baseline CAC > 0, 147 showed ≥50-unit annual CAC progression. C-Alb associated with progressive CAC in multivariable models adjusting for traditional risk factors. LIMITATIONS: Observational design, residual confounding, and limited power for incident CAC analyses. CONCLUSIONS: Among patients with CKD, our findings showcase a wide range of phenotypic associations with carbamylation, particularly cardiovascular phenotypes. Carbamylation may be an independent risk factor for CAC, suggesting its potential as a therapeutic target to mitigate cardiovascular risk in CKD populations.