Protein Carbamylation and the Risk of End-Stage Kidney Disease in Patients with Chronic Kidney Disease

Abstract

Background 

Protein carbamylation, a posttranslational protein modification partially driven by elevated blood urea levels, associates with adverse outcomes in end-stage kidney disease (ESKD). However, little is known about protein carbamylation’s relationship to clinical outcomes in the much larger population of patients with earlier stages of chronic kidney disease (CKD).

Methods 

To test associations between protein carbamylation and the primary outcome of progression to ESKD, we measured baseline serum carbamylated albumin (C-Alb) in 3111 patients with CKD stages 2–4 enrolled in the prospective observational Chronic Renal Insufficiency Cohort study.

Results 

The mean age of study participants was 59 (SD 10.8) years; 1358 (43.7%) were female and 1334 (42.9%) were White. The mean eGFR at the time of C-Alb assessment was 41.8 (16.4) ml/min per 1.73m² and the median C-Alb value was 7.8 mmol/mol (IQR, 5.8–10.7). During an average of 7.9 (4.1) years of follow up, 981 (31.5%) individuals developed ESKD. In multivariable adjusted Cox models, higher C-Alb (continuous or quartiles) independently associated with an increased risk of ESKD. For example, compared with quartile 1 (C-Alb ≤5.80 mmol/mol), those in quartile 4 (C-Alb >10.71 mmol/ mol) had a greater risk for ESKD (adjusted hazard ratio, 2.29; 95% confidence interval, 1.75 to 2.99), and the ESKD incidence rate per 1,000 patient-years increased from 15.7 to 88.5 from quartile 1 to quartile 4. Results remained significant across numerous subgroup analyses, when treating death as a competing event, and using different assessments of eGFR.

Conclusions 

Having a higher level of protein carbamylation as measured by circulating C-Alb is an independent risk factor for ESKD in individuals with CKD stages 2–4.