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Abstract: FR-OR23

Protein Carbamylation and the Risk of CKD Progression

Session Information

Category: CKD (Non-Dialysis)

  • 2201 CKD (Non-Dialysis): Epidemiology‚ Risk Factors‚ and Prevention

Authors

  • Kalim, Sahir, Massachusetts General Hospital, Boston, Massachusetts, United States
  • Zhao, Sophia, Analytica Now, Brookline, Massachusetts, United States
  • Tang, Mengyao, Massachusetts General Hospital, Boston, Massachusetts, United States
  • Rhee, Eugene P., Massachusetts General Hospital, Boston, Massachusetts, United States
  • Allegretti, Andrew S., Massachusetts General Hospital, Boston, Massachusetts, United States
  • Nigwekar, Sagar U., Massachusetts General Hospital, Boston, Massachusetts, United States
  • Lash, James P., University of Illinois Chicago, Chicago, Illinois, United States
Background

Protein carbamylation, a post-translational protein modification driven by urea, associates with mortality and adverse outcomes in ESKD, but less is known about its relationship to clinical outcomes in earlier stages of CKD.

Methods

In 3,111 patients with CKD stages 2 through 4 enrolled in the Chronic Renal Insufficiency Cohort study, we evaluated an established protein carbamylation marker (carbamylated albumin, C-Alb) as a risk factor for ESKD (primary); the composite ESKD or 50% decline in eGFR; and death.

Results

Participant demographics included mean [SD] age 59 [10.8] years; 1358 (43.7%) female; 1334 (42.9%) white. The mean [SD] eGFR at the time of C-Alb assessment was 41.8 [16.4] ml/min/1.73m2 and the median [IQR] C-Alb value was 7.8 mmol/mol [5.8 - 10.7]. During an average of 7.9 [4.1] years of follow up, 981 (31.5%) individuals reached the outcome of ESKD, and 1175 (37.8%) individuals reached the composite end point of ESKD or a 50% decline in eGFR. In multivariable adjusted Cox models, on a continuous scale or in quartiles, higher C-Alb levels independently associated with a monotonically increasing risk of both ESKD and the composite endpoint. 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 [HR], 2.29; 95% confidence interval [CI] 1.75-2.99), as well as a greater risk for the composite endpoint (HR 2.01; CI 1.59-2.53). Moreover, the top C-Alb quartile had a 1.58 (95% CI, 1.25 - 2.01) times increased risk of death compared to the bottom quartile. The results remained significant across numerous sub-group analyses, when treating death as a competing event in CKD progression analyses, using different assessments of eGFR, and after adjustment for blood urea nitrogen levels. Measures of risk discrimination showed significant improvement when C-Alb was added to fully adjusted models.

Conclusion

These results reflect the largest study of carbamylation in humans to date. Higher levels of protein carbamylation as measured by circulating C-Alb levels were an independent risk factor for CKD progression, ESKD, and death in individuals with CKD stages 2 to 4. Future studies should evaluate whether therapeutic interventions to prevent or lower carbamylation can improve CKD outcomes.

Funding

  • NIDDK Support