Carbamylation in Renal Disease-modulation With Amino Acid Therapy

As human kidney function declines so does the ability to excrete urea, the chief end product of nitrogen metabolism. Though elevated blood urea levels denote a loss of kidney function, they may also serve as a source for the pathophysiological consequences of kidney failure. Urea spontaneously dissociates to form cyanate, which in its unprotonated form can react with protein amino groups in a process known as carbamylation. Carbamylation-induced protein alterations may be involved in the progression of various diseases by changing the structure, charge, and function of enzymes, hormones, receptors, and amino acids. For example, proteins as diverse as collagen and low density lipoproteins (LDLs), are shown to induce the characteristic biochemical events of atherosclerosis progression when carbamylated. Our research seeks to examine how protein carbamylation contributes to the pathological sequelae of end stage renal disease (ESRD) and determine if novel therapeutics can attenuate this process. Percent carbamylated albumin level can be used as a measure of overall carbamylation burden. Our preliminary work shows a negative correlation between subjects' percent carbamylated albumin level and circulating amino acids, suggesting that free amino acids may be active scavengers for reactive isocyanate. Furthermore, ex vivo studies show that amino acid supplementation attenuates the carbamylation reaction from occurring. To better assess the biologic pathways affecting carbamylation in dialysis patients and to bring discoveries closer to clinical and therapeutic application, we aim to conduct a pilot study evaluating the effect of amino acid supplementation on carbamylation in participants with ESRD undergoing maintenance hemodialysis. We believe elevated urea and amino acid deficiencies may play dominant roles in the carbamylation of proteins in ESRD and protein carbamylation may be modifiable by amino acid therapy. The proposed pilot study will directly assess this concept. The specific aims of the study are to evaluate the effect of amino acid supplementation on carbamylation in ESRD patients undergoing maintenance hemodialysis: (1) by evaluating safe and optimal amino acid supplement dosing and (2) by investigating the effect of amino acid supplementation on plasma carbamylated albumin levels.