Longitudinal Changes in Protein Carbamylation and Mortality Risk after Initiation of Hemodialysis

Background and objectives Carbamylation describes a post-translational protein modification associated with adverse outcomes in ESRD, but the risk implications of changes in carbamylation over time are not well understood. Design, setting, participants, & measurements We investigated the 1-year natural history of protein carbamylation in patients initiating maintenance hemodialysis and determined the prognostic value of longitudinal carbamylation changes in relation to mortality. In a nested patient-control study, we measured serial carbamylated albumin concentrations in select participants from a large incident dialysis cohort followed from 2004 to 2005 (n=10,044); 122 individuals who survived at least 90 days but died within 1 year of initiating hemodialysis (patients) were randomly selected along with 244 individuals who survived for at least 1 year (controls; matched for demographics). Carbamylated albumin concentration was measured using plasma collected at dialysis initiation and every subsequent 90-day period until 1 year or death. Results Baseline carbamylated albumin concentration was similar between controls and patients (mean +/- SD; 18.9 +/- 0.7 and 19.8 +/- 1.1 mmol/mol, respectively; P=0.94). From dialysis initiation to day 90, carbamylated albumin concentration markedly fell in all patients, with controls 29.9 +/- 0.8 mmol/mol (P<0.001) and patients -10.0 +/- 1.2 mmol/mol (P<0.001). Adjusted repeated measures analysis of carbamylated albumin concentration from dialysis initiation to 1 year or death showed that the mean change (95% confidence interval) in carbamylated albumin concentration from baseline to final measure differed significantly between groups (-9.3; 95% confidence interval, -10.8 to -7.7 for controls and -6.3; 95% confidence interval, -7.7 to -2.8 for patients; P<0.01). There were no such between-group differences in blood urea levels, Kt/V, or normalized protein catabolic rate. Mortality prediction assessed using c statistics showed that carbamylated albumin concentration, when modeled continuously as the difference from baseline to final, improved a fully adjusted model from 0.76 to 0.87 (P=0.03). Conclusions Protein carbamylation decreased with dialysis initiation, and a greater reduction over time was associated with a lower risk for mortality. Carbamylation changes were able to predict individuals'mortality risk beyond traditional variables, including markers of dialysis adequacy and nutrition.