Malnutrition at the cellular level in uremia: a new frontier for research

Previously reported studies showed that protein-calorie malnutrition (PCM) in children is associated with significant alterations in muscle cell composition, characterized by increased cell water and Na, with decreased concentrations of K, Mg, and some glycolytic and citric acid cycle metabolites. In PCM, the i.c. H2O and levels of Na and K were significantly related, by multiple regression analysis, to the combined set of simultaneously measured levels of cell metabolites, phosphoenolpyruvate, pyruvate, alpha-ketoglutarate, and oxaloacetate. Cell bioactivities also were affected by PCM. Activities of the enzymes pyruvate kinase and malic and isocitric dehydrogenases were significantly reduced in muscle homogenates of PCM children. Kinetic analysis of pyruvate kinase indicated an 8-10-fold reduction in maximal velocity of the enzyme, consistent with a reduction in enzyme protein. Additionally, reduced levels of ATP and the equilibrium constant of the adenylate kinase system were observed in leukocytes of PCM children. Alterations in the activity of the energy-dependent Na pump have been noted by others in association with the accumulation of i.c. Na in severe malnutrition. Neither protein synthesis nor amino acid pools was measured in these previously reported studies. Recent data from several laboratories show that the "profiles" of i.c. and plasma amino acids are very different, both in uremics and in control subjects. In control subjects, with leukocytes as the cell model, the level of protein synthesis can be predicted by multiple regression analyses from simultaneously measured levels of plasma or i.c. amino acids. Intracellular amino acids are better predictors. Of 19 intracellular amino acids, a combination of five accounted for 54% of the variance in protein synthesis in normal, healthy adults. Levels of these predictor cell amino acids can, in turn, be predicted by different combinations of apparently unrelated plasma amino acids. In adult uremic patients stabilized by hemodialysis, with leukocytes as the cell model, levels of ATP, energy charge, adenylate kinase and pyruvic kinase activities were reduced. Others have reported increased i.c. water and Na contents, and impaired Na pump activity. Cell levels of methionine and the branched-chain amino acids, valine, leucine, and isoleucine, and protein synthesis also were significantly reduced. By multiple regression analysis, the observed levels of protein synthesis and energy charge in the hemodialyzed uremic patients were largely accounted for by different combinations of intracellular amino acid than in healthy subjects.(ABSTRACT TRUNCATED AT 400 WORDS)