Does Elevated Blood Urea Participate in the Pathogenesis of the Uremic Syndrome

Abstract

REA is quantitatively the most abundant of the various products of protein catabolism in mammals, accounting for 85% of the excreted urinary nitrogen. It is not surprising, therefore, that it was one of the earliest chemical substances to be identified and measured specifically in the blood and urine. By 1823, Prevost and Dumasi reported that bilateral nephrectomy in dogs caused a rise in blood urea. Shortly afterward, Christison2.3 recognized that in patients with renal failure, the urea concentration increased in the blood and decreased in the urine. The term “uremia,” meaning literally “urine in the blood,” was introduced by Piorry and L’heritier4 in 1840 to describe the clinical syndrome resulting from renal failure severe enough to result in retention in the blood of nitrogen products of protein metabolism. In 1836, Richard Bright5 raised the question of the possible role of urea as a uremic toxin, but evidence implicating urea specifically was not forthcoming until the early 1900s when attempts were made to produce uremic symptoms in nephrectomized dogs and cats and normal human subjects by rapid administration of large quantities of urea. The designs of many of these experiments are open to criticism, as pointed out in the monograph by Schreiner and Maher. In normal human subjects and animals with normal renal function, the blood concentrations of urea found in uremic patients are difficult to attain because of the rapid excretion of urea. Large doses, therefore, must be given in a short time to overcome the osmotic diuretic effects of urea. Although urea diffuses rapidly across most cell membranes, it is possible by rapid parenteral administration to create osmotic gradients between, for example, blood and brain or blood and intraocular fluids. These osmotic gradients in themselves could lead to symptoms, such as headache and nausea. Oral administration is unpleasant because of the large bulk of urea needed to raise the blood urea in subjects with normal renal function. In longer-term experiments, other products may be formed from urea, such as cyanate and ammonia, which may lead to