title: Protein carbamylation predicts mortality in ESRD.
abstract: Traditional risk factors fail to explain the increased risk for cardiovascular morbidity and mortality in ESRD. Cyanate, a reactive electrophilic species in equilibrium with urea, posttranslationally modifies proteins through a process called carbamylation, which promotes atherosclerosis. The plasma level of protein-bound homocitrulline (PBHCit), which results from carbamylation, predicts major adverse cardiac events in patients with normal renal function, but whether this relationship is similar in ESRD is unknown. We quantified serum PBHCit in a cohort of 347 patients undergoing maintenance hemodialysis with 5 years of follow-up. Kaplan-Meier analyses revealed a significant association between elevated PBHCit and death (log-rank P<0.01). After adjustment for patient characteristics, laboratory values, and comorbid conditions, the risk for death among patients with PBHCit values in the highest tertile was more than double the risk among patients with values in the middle tertile (adjusted hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.5-3.9) or the lowest tertile (adjusted HR, 2.3; 95% CI, 1.5-3.7). Including PBHCit significantly improved the multivariable model, with a net reclassification index of 14% (P<0.01). In summary, serum PBHCit, a footprint of protein carbamylation, predicts increased cardiovascular risk in patients with ESRD, supporting a mechanistic link among uremia, inflammation, and atherosclerosis.
authors: Department of Cellular & Molecular Medicine, Cleveland Clinic, 4500 Euclid Avenue, NC-10, Cleveland, OH 44195, USA.
authors: Robert A
authors: RA
authors: Koeth
authors: Kamyar
authors: K
authors: Kalantar-Zadeh
authors: Zeneng
authors: Z
authors: Wang
authors: Xiaoming
authors: X
authors: Fu
authors: W H Wilson
authors: WH
authors: Tang
authors: Stanley L
authors: SL
authors: Hazen
mesh_terms: D000328:Adult; D000368:Aged; D050197:Atherosclerosis / Q000209:etiology; D002956:Citrulline / Q000031:analogs & derivatives* / Q000097:blood; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic / Q000150:complications / Q000378:metabolism / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000378:metabolism*; D006435:Renal Dialysis
chemical_list: D011506:Proteins; C001352:homocitrulline; D002956:Citrulline