Clin J Am Soc Nephrol. 2026 Mar 17. doi: 10.2215/CJN.0000001061. Online ahead of print.
ABSTRACT
Protein carbamylation is a non-enzymatic post-translational protein modification driven by urea-derived cyanate and its reactive form isocyanic acid. Because chronic kidney disease (CKD) is characterized in part by sustained urea retention and thus prolonged protein exposure to cyanate, it represents the prototypical human model of the systemic consequences of excess carbamylation. Advances in analytical chemistry and translational nephrology research have reshaped our understanding of carbamylation, transforming it from a biochemical curiosity into a central mechanism linking azotemia to clinical pathology across multiple systems, including cardiovascular, renal, hematologic, and immune pathways. Mechanistic studies demonstrate effects on vascular biology, lipid handling, extracellular matrix remodeling, and immune function while clinically, carbamylation levels in people with CKD are associated with mortality, cardiovascular events, CKD progression, and interaction with biomarkers like glycated hemoglobin A1c. Promising applications include using carbamylation markers to target dietary or dialysis-based interventions that can lower carbamylation burden and using carbamylation to refine glycemic phenotyping. Despite these advances, major questions remain: the extent to which carbamylation is causal rather than associative; the relative importance of urea-derived versus other carbamylation pathways; and whether carbamylation is best positioned as a prognostic biomarker, a therapeutic target, or both. This review integrates biochemical, epidemiologic, and translational insights to clarify carbamylation's clinical relevance in CKD and outlines emerging opportunities for biomarker development, targeted interventions, and precision-medicine approaches that may soon bring carbamylation biology into clinical practice.
PMID:41842960 | DOI:10.2215/CJN.0000001061