title: Carbamylation of serum albumin as a risk factor for mortality in patients with kidney failure.
abstract: Urea, the toxic end product of protein catabolism, is elevated in end-stage renal disease (ESRD), although it is unclear whether or how it contributes to disease. Urea can promote the carbamylation of proteins on multiple lysine side chains, including human albumin, which has a predominant carbamylation site on Lys(549). The proportion of serum albumin carbamylated on Lys(549) (%C-Alb) correlated with time-averaged blood urea concentrations and was twice as high in ESRD patients than in non-uremic subjects (0.90% versus 0.42%). Baseline %C-Alb was higher in ESRD subjects who died within 1 year than in those who survived longer than 1 year (1.01% versus 0.77%) and was associated with an increased risk of death within 1 year (hazard ratio, 3.76). These findings were validated in an independent cohort of diabetic ESRD subjects (hazard ratio, 3.73). Decreased concentrations of serum amino acids correlated with higher %C-Alb in ESRD patients, and mice with diet-induced amino acid deficiencies exhibited greater susceptibility to albumin carbamylation than did chow-fed mice. In vitro studies showed that amino acids such as cysteine, histidine, arginine, and lysine, as well as other nucleophiles such as taurine, inhibited cyanate-induced C-Alb formation at physiologic pH and temperature. Together, these results suggest that chronically elevated urea promotes carbamylation of proteins in ESRD and that serum amino acid concentrations may modulate this protein modification. In summary, we have identified serum %C-Alb as a risk factor for mortality in patients with ESRD and propose that this risk factor may be modifiable with supplemental amino acid therapy.
authors: Division of Clinical Chemistry, Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. ahberg@bidmc.harvard.edu
authors: Anders H
authors: AH
authors: Berg
authors: Christiane
authors: C
authors: Drechsler
authors: Julia
authors: J
authors: Wenger
authors: Roberto
authors: R
authors: Buccafusca
authors: Tammy
authors: T
authors: Hod
authors: Sahir
authors: S
authors: Kalim
authors: Wenda
authors: W
authors: Ramma
authors: Samir M
authors: SM
authors: Parikh
authors: Hanno
authors: H
authors: Steen
authors: David J
authors: DJ
authors: Friedman
authors: John
authors: J
authors: Danziger
authors: Christoph
authors: C
authors: Wanner
authors: Ravi
authors: R
authors: Thadhani
authors: S Ananth
authors: SA
authors: Karumanchi
mesh_terms: D000596:Amino Acids / Q000097:blood; D006801:Humans; D007676:Kidney Failure, Chronic / Q000378:metabolism* / Q000401:mortality; D012307:Risk Factors; D012709:Serum Albumin / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D012709:Serum Albumin