Work to date has established that alpha-keto analogues of five essential amino acids (valine, leucine, isoleucine, methionine and phenylalananine) are aminated in normal liver using nitrogen derived from glutamine and in normal muscle using nitrogen derived in part from alanine. In patients with chronic renal failure, administration of these ketoacids reduces blood urea. In portal-systemic encephalopathy, glutamine falls initially and ammonia falls in most cases by the following morning. In starving obese subjects, urea production decreases and remains low after ketoacids are discontinued. We propose to design specific mixtures of these keto-analogues, as well as the corresponding alpha-hydroxy analogues, for use in the management of chronic renal failure, portal-systemic encephalopathy, and nitrogen- wasting disorders, particularly as exemplified by total starvation. Mechanism of action will be assessed by determining changes in insulin and glucagon levels as well as activities of urea cycle enzymes and transminases. Role of intestinal bacteria in these metabolic transformations will be examined. Intestinal absorption and contribution of the intestine to these metabolic transformations of these compounds will be assessed. The role of intestinal ureolysis providing nitrogen for protein synthesis will be determined. In renal failure, long-term therapy with these analogues will be compared to therapy with essential amino acids.