The Comparison of Urea with Urea + Ammonia Clearances in Acidotic Dogs.

In 1921 Nash and Benedict (11) advanced the hypothesis that urinary ammonia is formed in the kidney from some precursor in the blood. This conclusion was based upon the observation that the concentration of ammonia was higher in the renal vein than in the renal artery, that the quantity of ammonia in arterial blood was too small to supply the ammonia found in the urine, and that the arterial ammonia concentration was unaffected by acidosis, alkalosis, and nephrectomy, which procedures modify the excretion of ammonia. This hypothesis has been supported by Loeb, Atchley and Benedict (8) and Rabinowitch (13). The nature of the precursor is, however, not established; Bliss (2) has suggested amide nitrogen of protein, Krebs (7) has suggested amino nitrogen, and Nash and Benedict (11), Keeton (6), Mann and Bollman (9) have suggested urea nitrogen. Steenbock, Nelson and Hart (18) and Keeton (6) have claimed that in acidosis a reciprocal relation exists between the excretion of urea and ammonia nitrogen, such that the increased excretion of the latter is compensated by a decreased excretion of the former, but McCollum and Hoagland (10) and Adolph (1) have asserted that the total nitrogen excretion increases to an extent equivalent to the increased ammonia excretion. Van Slyke, Page, Hiller and Kirk (21), accepting the hypothesis that ammonia is formed in the kidney from urea, have recommended that the sum of urea + ammonia nitrogen in the urine be used in calculating the equivalent of the urea clearance in acidosis. This urea + ammonia clearance, they believe, has the same functional significance in acidotic individuals as has the urea clearance under normal conditions. In support of their hypothesis they present comparisons of the urea clearance in normal men on a normal diet with urea + ammonia clearances on a low protein diet with induced acidosis. It is known that in both dog and man (17) the urea clearance is considerably less than the rate of glomerular filtration, the deficit in the urea clearance being commonly attributed to the reabsorption of urea. It would be unjustified to link this deficit in the urea clearance with the process of ammonia formation, since it exists at all times, whether ammonia is being excreted or not. Nevertheless, any decomposition of filtered urea would reduce the urea clearance to a further extent, and thus supplement the normal deficit. (Such decomposition might occur either in the lumen of the renal tubules, or in the tubule cells after the reabsorption of a fraction of the filtered urea from the tubular urine). In fact, if the conclusions of Van Slyke et al. (21) are correct -i.e., if the urea + ammonia clearance in acidosis is of the same magnitude and has the same functional significance as has the urea clearance in the normal-it follows that ammonia excretion does in fact create a further deficit in the urea clearance, and that urinary ammonia is derived directly or indirectly from urea that has been initially present in the glomerular filtrate. And by the same reasoning, if the implied reciprocal relation between the clearances were an exact one, the formation of ammonia from any other nitrogenous precursor would be ruled out of consideration. Van Slyke, Page, Hiller and Kirk do not comment on these and other physiological implications necessarily issuing from their conclusions. The problem seemed, therefore, of sufficient interest to justify further examination. There are certain features, moreover, in the observations of these investigators that render their interpretation uncertain. It is known that all renal clearances in both man and dogs are affected by the protein content of the diet (3, 5, 12, 14, 15). It seemed not beyond possibility that on a protein-poor diet such as was used by Van Slyke and his coworkers in acidotics, all