Toxicity of urea and its role in the pathogenesis of uremia

It is generally assumed that urea is nontoxic and that even the high concentrations present in uremia are innocuous and do not contribute to the symptoms encountered in this condition. In sup-port of this assumption is the fact that the blood in the elasmobranch fishes contains 330 to 440 mM (about 2 per cent) of urea per L. The origi-nal purpose of the present study was to utilize this assumed inertness of urea in order to determine the effect of the presence of one molecular species in high concentration on the electrolyte and water composition of the body. However, it soon became apparent that urea in high concentrations, con-trary to the generally accepted notion, was lethal and that many of the abnormalities noted in ure-mia could be elicited by this substance. METHODS General procedure. Intermittent peritoneal lavage, as described elsewhere (1), was utilized to maintain the de-sired level of urea in the extracellular fluid of the nephrec-tomized dog. The kidneys were removed under ether anesthesia through the dorsolumbar approach with an in-terval of 7 to 14 days between the two operations. Sterile solutions available commercially (Peridial®)1 or prepared as described previously (1) were utilized for the peritoneal exchanges. One L. of the solution, the electrolyte and water composition of which approximated normal extracellular fluid, was injected intraperitoneally and exchanged, twice daily (2). Varying amounts of urea (5 to 30 Gm. per L.) were added to these solutions in order to maintain the concentration at the desired level. The animals were killed by exsanguination after 4 to 10 days, at a time when they manifested severe symptoms of uremia. Analytical procedures. The tissues were placed in dry, glass-stoppered weighing bottles and dried in vacuo at 40° C. to constant weight. They were then defatted with petroleum ether, dried again, reweighed and extracted *This work was supported in part by the Dixie an