Determinants of ureagenesis, with particular reference to renal failure

Abstract

The absolute rate at which urea is degraded by bacterial urease in the gastrointestinal tract in chronic uremia is not different from normal, although the fraction of synthesized urea degraded is high. Urea production is therefore comprised of two portions, urea derived from enterohepatic circulation of urea nitrogen and the ureas that serves to eliminate excess labile nitrogen. This latter quantity, termed urea appearance, is defined as excretion plus accumulation of urea in body fluids, and can be estimated by measurements of body weight and serum urea nitrogen concentration. The importance of urea appearance is that nitrogen balance in chronic uremia can be estimated as the difference between nitrogen intake and urea appearance, plus an average rate of 2.5 g of nitrogen per day for excretion of nitrogen in forms other than urea. Regulation of ureagenesis in normal subjects and in uremic subjects is chiefly a function of the systemic concentration of urea precursors (amino acids). Rapid activation of ureagenesis occurs after amino acid loads of 0.5 to 2 g/kg, mediated by N-acetyl glutamate, an activator of mitochondrial carbamyl phosphate synthetase. The rapid rise in N-acetyl glutamate is apparently secondary to a rapid increase in liver glutamate, thereby promoting N-acetyl glutamate synthesis by a substrate effect. No clear evidence for significant enzymatic anormalities in uremic liver has been found. Nevertheless, the acutely uremic liver converts amino acids to urea at an abnormally high rate. Furthermore, acute uremia augments the peripheral release of amino acids, especially from muscle. This suggests that loss of renal function increases urea production by an unknown mechanism. Demonstration that the virtual absence of urea production need not impair growth and that urea appearance can be lowered by nutritional means suggests that nitrogen balance could be safely maintained at extremely low rates of urea appearance. The development of new methods to achieve this goal may prove useful in uremia and other disorders characterized by protein intolerance.