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According to the usually accepted concept, the urea removed from the blood by the kidneys is excreted in two forms, chiefly as urea itself, but partly as ammonia. That the ammonia of the urine is formed in the kidneys was demonstrated by Nash and Benedict (1921), in work which has been confirmed by other authors (cf. Peters and Van Slyke, I, p. 373). Evidence from animal experiments in v4vo has indicated urea as the probable chief source of the ammonia formed by the kidney (cf. Peters and Van Slyke (1931) p. 373). Krebs' recent work (1933) with kidney tissue in vitro has indicated the possibility that blood amino acids may, also be a direct source of the ammonia formed by the kidney, but whether an important part of the ammonia actually excreted comes from them has not been demonstrated. If urinary ammonia is entirely or chiefly formed from the blood urea, the urea cleared from the blood per minute by the kidneys is represented more accurately by the excretion of urea + ammonia rather than of urea alone. It appears possible, therefore, that urea clearances calculated from the excretion of urea + ammonia may measure the work of the kidneys in excreting urea from the blood more accurately than clearances calculated in the usual manner from the output of urea alone. It therefore appears to be a problem of physiological interest to ascertain whether, when the ammonia: urea ratio in urine varies markedly, more consistent values for the urea clearance are calculated from the excretion rate of urea alone, or of urea + ammonia. For clinical interpretation, as already pointed out by Bell, Gilmour and Cameron '(1934), it would seldom make a serious difference if, in the formula for calculating the urea clearance (Moller, McIntosh and Van Slyke (1928, a)), urine urea nitrogen were replaced by urea + ammonia nitrogen. Since the ammonia nitrogen ordinarily equals 1 to 10 per cent of the urea nitrogen, the clearance calculated from urea + ammonia would be from 1 to 10 per cent higher than that calculated from the urea excretion alone. In nephritis the proportion of nitrogen excreted as ammonia is likely to be less than in normal subjects, because the damaged kidney turns a smaller proportion than normal of the urinary nitrogen into ammonia (see literature quoted by Peters and Van Slyke (1931), p. 378; also data in Table III, present paper). Conditions do occur, however, in which the ammonia: urea ratio may be unusually high. Such are the acidoses of diabetes and starvation, and the depression of urea output caused by very low protein, high calory, diets. If the urea clearance is measured in such a condition, it is of interest to know whether more consistent values may be expected when the calculation is based on the output of urea, or of urea + ammonia. Aside from this, and the physiological interest of the problem, the question has some practical bearing on the convenience of procedures for determining the urea clearance. If a method for determining urinary urea is used which depends upon estimation of the ammonia formed when the urea is hydrolyzed by heat or urease, it is simpler to determine urea + ammonia than urea alone, since thereby one avoids an extra operation to remove or determine the preformed ammonia. Likewise, if the hypobromite gasometric method is used, it is simpler to determine urea + ammonia, since the reagent gives practically the same yields of N2 from both. Furthermore, if, by bladder infection or delay in analyzing urine, part of the urea is decomposed into ammonia before analysis, no error is introduced into the figure representing the sum of urea + ammonia.

the journal of clinical investigation/the journal of clinical investigation

STUDIES OF UREA EXCRETION. IX. COMPARISON OF UREA CLEARANCES CALCULATED FROM THE EXCRETION OF UREA, OF UREA PLUS AMMONIA, AND OF NITROGEN DETERMINABLE BY HYPOBROMITE