title: Protein carbamylation in kidney disease: pathogenesis and clinical implications.
abstract: Carbamylation describes a nonenzymatic posttranslational protein modification mediated by cyanate, a dissociation product of urea. When kidney function declines and urea accumulates, the burden of carbamylation naturally increases. Free amino acids may protect proteins from carbamylation, and protein carbamylation has been shown to increase in uremic patients with amino acid deficiencies. Carbamylation reactions are capable of altering the structure and functional properties of certain proteins and have been implicated directly in the underlying mechanisms of various disease conditions. A broad range of studies has demonstrated how the irreversible binding of urea-derived cyanate to proteins in the human body causes inappropriate cellular responses leading to adverse outcomes such as accelerated atherosclerosis and inflammation. Given carbamylation's relationship to urea and the evidence that it contributes to disease pathogenesis, measurements of carbamylated proteins may serve as useful quantitative biomarkers of time-averaged urea concentrations while also offering risk assessment in patients with kidney disease. Moreover, the link between carbamylated proteins and disease pathophysiology creates an enticing therapeutic target for reducing the rate of carbamylation. This article reviews the biochemistry of the carbamylation reaction, its role in specific diseases, and the potential diagnostic and therapeutic implications of these findings based on recent advances.
authors.affiliation: Department of Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, MA; Harvard Medical School, Boston, MA.
authors.forename: Sahir
authors.initials: S
authors.lastname: Kalim
authors.affiliation: Harvard Medical School, Boston, MA; Division of Nephrology, Beth Israel Deaconess Medical Center, Boston, MA; Howard Hughes Medical Institute, Boston, MA.
authors.forename: S Ananth
authors.initials: SA
authors.lastname: Karumanchi
authors.affiliation: Department of Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, MA; Harvard Medical School, Boston, MA.
authors.forename: Ravi I
authors.initials: RI
authors.lastname: Thadhani
authors.affiliation: Harvard Medical School, Boston, MA; Department of Pathology, Division of Clinical Chemistry, Beth Israel Deaconess Medical Center, Boston, MA. Electronic address: ahberg@bidmc.harvard.edu.
authors.forename: Anders H
authors.initials: AH
authors.lastname: Berg
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002219:Carbamates / Q000378:metabolism*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000175:diagnosis* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D014511:Uremia / Q000175:diagnosis / Q000378:metabolism
chemical_list: D015415:Biomarkers; D002219:Carbamates; C070766:carbamic acid
keywords: Carbamylation; carbamoylation; chronic kidney disease (CKD); cyanate; end-stage renal disease (ESRD); inflammation; pathophysiology; posttranslational protein modification (PTM); urea; uremia