Urea the harmful end-product of protein catabolism is usually elevated in end-stage renal disease (ESRD) although it is usually unclear whether or how it contributes to disease. 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. studies showed that amino acids such as cysteine histidine arginine lysine as well as other nucleophiles such as taurine inhibited cyanate-induced C-Alb formation at physiologic pH and heat. 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 recognized serum %C-Alb as a risk factor for mortality in patients with ESRD and propose that this risk factor may be modifiable with supplemental p54bSAPK amino acid therapy. INTRODUCTION Chronic kidney disease (CKD) affects 5-10% of adults in industrialized countries Ostarine (1). For reasons that remain unclear individuals with CKD are 10-20 occasions more likely to pass away from cardiovascular causes than to survive until renal function is completely lost (2). Those who reach end stage kidney disease (ESRD) suffer an Ostarine annual mortality of 15-20% that is largely attributable to cardiovascular disease (CVD) (3). Yet efforts to treat the most modifiable cardiovascular risk factor hypercholesterolemia with statins have not improved outcomes in ESRD (4 5 This obtaining suggests that other mechanisms link ESRD to CVD (6). One possible mechanism for how ESRD increases the risk of CVD is the accumulation of urea in the blood of ESRD patients. Urea is usually generated in Ostarine the liver during catabolism of amino acids and other nitrogenous metabolites and is normally excreted into the urine by the kidneys as rapidly as it is usually produced. Patients with ESRD cannot make urine however and thus increasing concentrations of blood urea will continuously accumulate a condition that can only be treated with intermittent hemodialysis (HD) or kidney transplantation. Although HD ameliorates ESRD patients’ uremia it replaces only ~10% of normal renal function however so these patients still have chronic urea overload (uremia). Despite the strong association between ESRD and CVD the role of chronically elevated urea in this disease is usually controversial. For example common urea concentration does not predict mortality in CKD and the HEMO study Ostarine found no benefit for survival when frequency of HD was increased beyond the current requirements (7-10). This lack of effect could have been because the ~40% relative increase in waste removal only replaces ~14% of normal kidney filtration and still leave patients overloaded with waste products. Recent evidence suggests that chronically elevated blood urea contributes directly to cardiovascular risk via a pro-atherogenic protein modification called carbamylation. In one study of patients undergoing diagnostic cardiac catheterization subjects in the highest quartile of serum protein-bound carbamylated lysine experienced a 7-8 occasions higher risk of CVD; these authors also exhibited that low density lipoprotein (LDL) was a target for protein carbamylation and that carbamylated LDL binds scavenger receptors and produces lipid accumulation in macrophages. (11) In addition feeding urea to ApoE-deficient mice accelerated their rate of atherosclerosis nearly two-fold and increased accumulation of carbamylated LDL within atherosclerotic plaques (12). Together these findings suggest a potential mechanism for urea’s direct contribution Ostarine to atherogenesis. Protein carbamylation is an unavoidable consequence of extra urea (13 14 Urea is in equilibrium with cyanate (HNCO) a product of urea deamination whose central carbon is usually susceptible to nucleophilic attack from amines and thiols at the N-termini or side chains of proteins Ostarine in vivo (15). The degree to which proteins with long half-lives are carbamylated should therefore provide a time-averaged indication of urea concentration analogous to the relationship between serum glucose and glycated hemoglobin (16). Thus measurements of carbamylated proteins in blood circulation might provide a.