College, London. NITROGEN IN THE URINE. BY OTTO VERAGUTH, steadily hour by hour to the fifth hour, when it reached its maximum

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1 THE EFFECT OF A MEAL ON THE EXCRETION OF NITROGEN IN THE URINE. BY OTTO VERAGUTH, M.D., Zurich. (Twelve Figures in Text.) From the Department of Pathological Chemistry, University College, London. DR TSCHLENOFF1 published in 1896 an interesting paper from the Laboratory of Professor Drechsel, in which he showed that the quantity of nitrogen eliminated per hour after a meal did not steadily rise in the human subject to a maximum and then as steadily fall, but showed two maximum points, so that an interrupted curve was obtained as against the final rise and fall which older observers believed to occur. This new fact is contrary to the teaching of even the most recent text-books which still state the results of Becher2 and Voit, so that it appeared of interest to investigate the point. Becher as long ago as 1855 showed that the hourly output of nitrogen after a midday meal rich in proteids was followed even as soon as the second hour by an increase in the urea output, which rose steadily hour by hour to the fifth hour, when it reached its maximum and then more gradually fell. Voit" in experiments he also did on man after a meal consisting of meat and eggs, found that even during the first hour there was a distinct increase in the urea excretion, which steadily rose up to the seventh hour, when it reached its highest point, and then, slowly, during the next seventeen hours, declined. Ludwig put these results together in a curve in his text-book, and these have been copied from text-book to text-book and accepted as a settled fact. Panum4 who experimented with a dog, collecting the urine by 1 B. Tschlenoff. Correspondenz-Blattf. Schweizer Aerzte 1896, No Becher. Studien fiber Respiration 2. Absch. Zurich, Voit. Physiol.-chem. Untersuchungen. Augsburg, Panum. Nordiskt. med. Arkiv., No., 1874.

2 NITROGEN IN THE URINE. 113 means of a catheter, found that with a meat diet some increase in the urea output occurred, the rise reaching its maximum between the third and sixth hour, and that by the seventh to the 74 hours after the meal a half of the total nitrogen given had been eliminated. Falckl also showed with what rapidity a given quantity of nitrogen taken at one meal is eliminated in the urine, and practically confirmed the results of Panum.. Feder2 and Graffenberger8 came to practically the same results, so that Tschlenoff's experiments became of greater interest, and it was necessary before accepting them-as they were performed on a single individual-to repeat them. At the suggestion of Prof. Vaughan Harley, I decided to investigate the subject, and beg here to express my gratitude to him for his kind assistance and advice throughout the experiments, which were carried out in his laboratory. Tschlenoff, in his experiments, took a proteid diet consisting of 200 grams of meat, 300 c.c. of tea and 100 grams of bread, in the morning after having emptied his bladder, collected the urine hourly, and found in the first experiment quoted, the first rise in the nitrogen output reached its maximum by the third hour, falling somewhat during the fourth and fifth hour to rise steadily during the sixth hour to a higher point than the maximum at the third hour, and then fell as suddenly during the seventh, eighth and ninth hour, when it was even lower than the hour preceding the meal. In the second experiment the first maximum lasted during the third and fourth hour, there only being a small fall during the fifth hour, and then the principal maximum was reached at the sixth hour and as progressively fell during the seventh, eighth and ninth hour. The same occurred in the third experiment. Tschlenoff considered the first rise during the second and third hour to be due to an absorption from the stomach, the fall between the fourth and fifth hour occurring while the acid chyme was passing into the intestines there to be neutralised and digested, and the second rise to occur when the principal absorption was taking place in the intestines. He had hoped by means of this urea analysis after a proteid diet, to be able to differentiate the activity of gastric absorption, so that it might be of service in the diagnosis of diseases of the stomach. I F alek. Beitrige zur Physiol., Pharmakol. u. Tozikol. Stuttgart, Feder. Zeit.f. Biologie, Graffenberger. Zeit.f. Biol

3 114 1O. VERAGUTH. In connection with the theory of circulatory and organic proteids these results of Tschlenoff's are of the greatest theoretical interest. The experiments I performed can be divided into two groups. First, a repetition of Tschlenoff's experiments on a diet rich in proteids, as in his case, and further on a diet containing only a small quantity of proteids, and upon an ordinary mixed diet. The second group of experiments, the further investigation into the quarter or half-hourly elimination of nitrogen after a meal, to see if any further rise and fall would be demonstrated. In an investigation like the present, before carrying out the experiments on myself, it was necessary to be sure that as far as chemistry could reveal, my stomach was not only apparently normal, but that it was functionally active. For this purpose I not only made a chemical analysis of the stomach contents after a test breakfast, but also investigated the digestive powers after its removal from the stomach, and found them in every. way normal, so that any danger due to pathological conditions would in this research be obviated. The method employed throughout the experiments was on waking in the morning to empty the bladder, and then during each hour, halfhour, or quarter-of-an-hour, collecting the urine separately. In the second group of experiments, when it was necessary to collect the urine every quarter or half-hour, a cup of weak tea was drunk in the morning on waking in order to act as a diuretic. Throughout the experiments very little exercise was taken except on one occasion when, on the evening beforehand, three hours' skating had no effect on the curve during the following day. The urea estimation was done by means of the Knop-Hufner method, as in experiments like this it is important to have a rapid method of estimating the quantity, rather than a more complicated and more accurate one which would require greater time, and owing to the complications possibly contaminate the results. In all cases the quantity of nitrogen obtained was corrected to temperature and barometer, and with control analysis was found to be sufficiently accurate for the purpose required. The first group of experiments, in which the urea output was estimated each successive hour after a meal containing proteids, is practically a repetition of Tschlenoff's experiments.

4 NITROGEN IN THE URINE. 115 The Nitrogen Elimination on a diet rich in Proteids. After a night's fast a meal consisting of 180 grims. of dried meat, 2 eggs, and 50 grms. of Nestle's condensed milk with 500 grms. of water was taken. In this case the quantity of nitrogen in the various articles of diet was estimated by Kjeldahl's method, and the total was found to be 17-5 grnis c.c Exp. 1. Diet rich in Proteids 'at 8.30 a.m grs P J c.c grs At a.m. two cups of weak tea were taken and at 7 p.m. two eggs and tea , c r 6 1.4' ~ ~ ~ ~ ~~~~I FIG. 1. In the above experiment the quantity and the urea before the food was taken was not estimated, but at 8.30 at which time the diet was taken, it contained 0-62 grms.. It fell somewhat at 9.30 to rise at to to the first maximum, when it reached to 1-36 grms.. There was then a fall at 1, a slight rise at 2. The principal rise of the second curve was at 6, when 1-93 grms. of

5 VERAGUTH. nitrogen were eliminated; after which the eggs were taken, so that the fall, although apparent, is not so marked as it otherwise would have been İn this experiment we have the two rises as described by Tschlenoff; the first three hours after the meal, and the second eight hours after. Exp. 2. Diet rich in Proteide 1at 8.80 a.m c.c.? 3 94 c.a grs grs Two cups of tea taken at 7.30 and a.m., nothing else until after 9p.m a ~ ~- 09P 8<, _-_ X 1 - FIG. 2. It is seen here that after the diet there is a rise during the first three hours, and then a very marked rise during the fourth hour, after which there is a fall, followed by two successive rises and then the last fall. Here the curves are not so well marked; and the first rise, that at 1 p.m., is more marked than the second. At the same time, it is seen that there is not a steady increase in the quantity during the first five hours as the teaching of Voit would show.

6 NIT'ROGEN IN THE URINE c.c EnP. 3. Diet rich in Proteids taken at 8 a.m. 1P25 grs c.c P27 grs FIG. 3. In this case the first rise occurred at 10 and, there then being a fall and the second marked rise at 4 p.m. which was not traced descending. In the above experiments, it is seen that they agree with the results obtained by Tschlenoff, there being a rise in the quantity during the first two or three hours, when a fall occurs during the next one or two hours, and then a second steady rise to about the sixth or eighth hour, when the maxinmum as a rule is reached. In the experiments 1 and 2 the hourly collections continue until 9 p.m. in order to follow the descending curve. The tea taken was merely as a slight diuretic and did not influence the curves to any marked extent. The nitrogen elimination on a diet containing amount of proteids. a minimum The diet consisted of coffee and some bread food being taken during the rest of the time. and butter; no solid PH. XXI. 9

7 Exp VE,RA G UTH. Diet poor in Proteids Iat 8 a.m. 45 c.c grs. 135 c.c A cup of tea at 7.30 a.m gre : FIG. 4. It is seen in Experiment 4 that there was a rapid rise in the quantity of nitrogen eliminated after the meal was taken at nine, followed by a fall at ten and then a rise at eleven and one, after which there was a marked fall. Exp. 5. On the same diet as Exp c.c grs c.c grs X X72 After this meal there was a slight rise during the first hour and then a fall, followed by the second rise during the next two hours when the steady fall occurred.

8 NITROGEN IN THE URINE I T I 1 1 IT A -- ;; ; \" AAI br -- FIG. 5. In the above two experiments (4 and 5) in which only coffee and bread and butter were taken, there is seen to be the same two rises, although not so distinctly separated, as in a diet rich in proteids, and they both occur rather sooner. The Nitrogen elimination on a diet containing a moderate amount of proteids. Exp. 6. Diet mediumly rich in Proteids. Nestle's milk and about 200 grammes of biscuit were taken at c.c grs c.c. 0'70 grs n I- pi -.v I 1.-1 I I.8 la _1 1.7 t -E ~ 1.2- c ~ FIG

9 0 0. VERA G UTH. In this case there is a slight rise two hours after the meal followed by a fall, and then a more marked rise four hours after the meal which is followed by the last falf, so that one has two curves, the second being the maximum one Exp. 7. The same diet was taken as in Exp. 6 at 8 a.m. 52 c.c grs c.c grs FIG. 7. In this experiment the first rise followed immediately after the meal, reaching a maximum in the first hour, and was followed by a fall during the next hour, and then an alternate rise and fall in the two successive hours, when the steady fall occurred. In these two experiments the nitrogen taken was moderate in amount although the quantity was not estimated, and the curves produced were also less pronounced and of shorter duration than on a diet rich in proteids. Having obtained the above results, Professor Harley drew my attention to the fact that he had found while working with Mosso's Ergograph that the mere taking of food caused an immediate increase in the muscular power, so that it was possible the increase of power might be due to a reflex stimulation causing the increased metabolism and output of nitrogen. The first rise during the third hour after a

10 NITROGEN IN THE URINE. 1 meal might be due to the increased muscular action of the stomach and intestines, due to the stimulation of the food. In order to see if there was any increase in urea caused by the mere taking of food, in the following experiments the urine was collected every quarter or half-hour, to see what took place during the first three hours. Exp grammes of meat, 50 grammes of Nestle's milk, 2 eggs and 500 grammes water were taken between 8.30 and 9.15, the urine being collected every quarter an hour c.c grs '50 0' c.c grs ,15 Of of iz,i FIG. 8. Between 7.45 and 8.30, when the meal was commenced, there was a fall in the quantity, this continued to 9.15, after which there was a slight rise at 9.30, followed by a second fall up to 10, when the first big rise described by Tschlenoff occurred up to

11 2 0. VERA GUTH. Exp. 9. Diet the same as in Exp. 8 between 8.15 and 8.45 a.m C.C grs C grs eli I I I _ 'Al- -Ii FIG. 9. The meal was taken at 8.15 to 8.45; during this time there was a fall in the quantity from 1-25 grammnes to 025 grammes; at nine it rose to 0 43 grammes, to remain practically the same height at 9.15, when the fall occurred at 9.30 and then a gradual rise up to twelve o'clock. It is seen then that on a diet rich in proteids in the above two experiments the quantity of nitrogen eliminated falls during the meal, to be followed immediately after by a slight rise before the first rise described by Tschlenoff. The experiments were now repeated on a diet poor in nitrogen. ExP. 10. Diet poor in Proteids at 8.15 a.m C.C grs , c.c grs

12 NITROGEN IN THE URINE. 3 FIG. 10. At 8.15 coffee and bread and butter were taken, this was followed by a rise from 8.15 to 8.30, and fall from 8.30 to A rise occurred at nine, after which there was a gradual rise up to c.c Exp. 11. Diet poor in Proteids at 8.15 a.m grs c.c grs _ FIG. 11. The same as in Experiment 11. Coffee and bread and butter were taken at Immediately following this at 8.30 was the first rise, followed by a more marked fall at 9.0, 9.15 and 9.30, when there was a gradual rise to and then a slight fall at 11.0 followed by a rise to.0. In these experiments it is seen that the rise following the food was marked, but the fall was still more brought out during the next hour.

13 4 0. VFRAGUTIR. Exp.. In this experiment Nestle's milk and 0 grammes of biscuits were taken at 8 a.m c.c grs c.c grs ' ' A '-. -~~I zz I i.0.1 FiG.. The above experiment brings out in a most typical manner the curve following the diet. The food being taken at 8a,m. when 0-70 grammes were excreted which was followed by a rise at 8.30, immediately after which a fall to 0 47 at 8.45 and 0 33 at 9.0. At 9.30 was a very slight rise to 0 37, more marked at 10.0 to 0 70, and continuing on to 11.0 when it reached So that we have in this experiment most typically brought out a rise immediately after the food has been taken, followed by a fall before the first rise described by Tschlenoff occurs. The results brought out by this second group of experiments show that after food containing proteids, there are three rises in the quantity eliminated, and not merely the two rises described by Tschlenoff. In the first group of experiments, in which the analysis was only carried out every hour as was done by Tschlenoff, the same results were found, but when the analyses were reduced to every quarter or half hour, there is seen the first rise which occurs immediately after the food has entered the stomach. In fact, it begins so quickly after the food has been taken that it is impossible to explain it by any absorption from the stomach. It would seem to be more probable that it was due to an increased metabolism following the muscular action of

14 NITROGEN IN THE URINE. swvallowing, and the general motility of the stomach and intestines which are known to occur in the taking of food, as it would be hardly possible for an absorption of proteids to have taken place from the stomach and their elimination by the kidneys in so short a time. It interested me to investigate still further whether these characteristic curves with three distinct rises would be altered by living on a moulntain, considering the totally changed appetite and diuresis which occurs, so these experiments were repeated on exactly the same diet as employed in London at Seewis in Switzerland 1000 metres above the sea level, both during the time of the acclinmatisation and after. The results obtained were exactly conformatory to those above described, so that the altered appetite, and other conditions produced by living in the mountains, had no influence on these curves. RESUM The output of nitrogen in the urine after a meal rich in proteids does not in the human being occur in a steady line, but in a curve which shows three rises; one irnmediately after taking food, the second two to four hours after food, and the third from six to seven hours. 2. If the food contains a small quantity of nitrogen the three rises are still visible. The first immediately after the meal is the most constant; the second and third vary, sometimes one and sometimes the other being most marked, and are not so defined as on a diet rich in proteids. 3. This curve giving the three rises is the same whether the subject is living on the sea level or a 1000 metres high on the mountains, in spite of the change in appetite and diuresis, as well during, as after, the acclimatisation.