THE EXCRETION OF CHLORIDES AND BICARBON- ATES BY THE HUMAN KIDNEY. BY H. W. DAVIES, M.B., B.S., J. B. S. HALDANE, M.A. AND G. L. PESKETT, B.A. (From the Laboratory, Cherwell, Oxford.) AM BARD and PAPI N (1) showed that in any individual, man or dog, there is a definite maximum to the possible concentration of urea in the urine; that this concentration can easily be reached; and that it is, to a considerable extent at least, independent of the concentration of chlorides simultaneously excreted. They also brought forward some evidence to show that the limiting concentration for chloride in man is between *3 N and *4 N, while in the dog, according to Bailey and Bremer(2) it is about *17 N. Davies, Haldane and Kennaway(3) have shown that the maximum attainable concentration of bicarbonate is of the same magnitude. The experiments here recorded were made to determine the relations between the various concentrations which are possible in the urine at the same time. All experiments but one were made on J. B. S. H. (weight 95 kilos.). Chlorides were estimated by Volhard's method, bicarbonates with J. S. Haldane's(4) blood-gas apparatus, phosphates with uranium acetate and cochineal, and urea by Krogh's5) or Marshall's(6) method. Concentrations are expressed in terms of normality, or for phosphates molarity. Volumes are given in c.c., weights in grams. When strong solutions of NaCl were drunk the urinary chloride concentration rose rapidly to a value varying between *29 N and *33 N, the value being independent of the volume excreted per hour, and only rising slightly when more salt was taken. Table I gives the results of a typical experiment. Here 18 grams of NaCl in 200 c.c. of water were drunk at 13 hours, and again at 16.15. TABLE I. Time....... 10-12 12-13 13-14 14-15 15-16 16-17 17-18 18-19 Volume per hour 41 43 78 154 162 115 181 211 Chloride concentration *201 *259.300.304 *312 *331 *328 *324 The limit of 330 N was only passed during extreme thirst, the highest value recorded being *338 N. The maximum did not vary in J. B. S. H. PH. LVI. 18
270 H. W. DAVIES, J. B. S. HALDANE AND G. L. PESKETT. during 18 months, but higher values were found in two other healthy men, lower in one. Out of 70 bicarbonate concentrations determined on J. B. S. H. only one exceeded *330 N. In this case the value recorded, *358 N, is probably erroneous. Values higher than *320 N were, however, reached on several occasions. The maximum molecular concentrations of chloride and bicarbonate are therefore practically identical. When chloride and bicarbonate were taken together or successively both appeared in the urine in large amounts. Neither reached its maximum concentration, but the sum of the two reached a value which (expressed in normality) was equal to the maximum of either. Thus, in the experiment summarised in Table II, 26 grams of NaCl had been taken on the previous day, and 13 at 9.30. Ten grams of NaHCO3 and three of NaCl were taken in 150 c.c. of water at 11.10, 12.10, 13.10, 14.10 and 15.10, also a little extra water at 13.45 and 16.00. Hours Volume TABLE IT. ending per hr. Cl HCO8 Cl + HCO3 CON2H4 A 11.40 62 *321.000 *321 *252 1.820 12.40 152 *246 *063 *309 *186 13.40 221 *185 *134 *319 *135-14.40 391 *150 *158 *308-117 15.40 294 *141 *177 *318 *089 1.400 16.40 335 *138 *171 *309 16.40-18.30 > 200 *143 *190 *333 *101 - Here the effect of the bicarbonate was to lower rapidly the chloride concentration, though more chloride was being ingested than excreted; but the sum of the concentrations remained steady within 8 p.c. It is noticeable that this value was quite independent of considerable variations in the concentration of urea or the depression of the freezing point. If bicarbonate be given without chloride the latter may almost disappear from the urine. In the experiment recorded in Table III, 25 grams of NaHCO3 were taken in 100 c.c. of water at 10.45, and TABLE III. Volume Gms. NaCi Time per hr. Cl HCO3 Cl + HCO3 CON2H4 per hr. 10-11 39-5 *212-003 *215 *489 11-12 55-5 *134 **135 *269 *420 *435 12-13 105.5 *078.209 *287 - *481 13-14 169 *043 *258 *301 *135 *425 14-15.05 155 *024 *269 *293 *217 15-05-16 123 *026 *280.306 *193 *187 16-17 134 *072 *242 *314 *564 17-17.30 143 *082 *220 *302 *178 *684 17.30-18 95 *090 *201 *291 B.5O 18-19 142*5 '085 '201 *286 *213 '708 19-20 144 '088 *208 *296-740 20-21 1345 '095 *146 *241 '202 *747
EXCRETION BY KIDNEY. 271 20 grams of NaCl with 5 of NaHCO3 in 400 c.c. between 15.20 and 16.15. A litre of water was drunk at 17.00 and again at 19.00. Here less salt was taken, so the maximum was lower. At first the chloride output was unaffected, but it fell sharply when the sum of chloride and bicarbonate reached *30 N. In presence of the bicarbonate even 20 grams of NaCl failed to raise the urinary chloride concentration to its normal value. Four other experiments gave results like those of Tables II and III. The maximum value of Cl + HCO3 reached was *334 N on two occasions. The antagonism between chloride and bicarbonate excretion also appears when the bicarbonate is being excreted as a result of forced breathing. In an experiment where H. W. D. over-breathed for 87 minutes, his mean alveolar C02 being 1-67 p.c., the urinary bicarbonate rose to -053 N, while the chloride fell from *120 N to *015 N, although the rate of water excretion was not doubled. This fall is the more remarkable since removal of C02 slightly increases the chloride content of the plasma. Not only is a simultaneous excretion of urea without effect on the kidney's capacity for concentrating chloride and bicarbonate, but urea ingestion, though it may lower the chloride concentration by promoting diuresis, considerably increases the output per hour. Thus, after taking 100 grams of urea the chloride output rose from *88 gram NaCl per hour to values which exceeded 1-2 grams per hour during five consecutive hours. On then taking 20 grams of NaCl, as in Table III, the chloride output at once rose to 2-4 grams per hour as compared to 0 75. Further experiments were undertaken to determine whether the constancy of the maximum of Cl + HCO3 was due to the existence of a maximum possible concentration in the urine of Na or total cations. Attempts made to increase the chloride concentration by taking NH4C1 failed, owing to the vomiting caused by strong solutions. The question was, however, settled by simultaneous ingestion of chloride and acid phosphate. The following were ingested: 24.15. 20 gm. NaCl + 500 c.c. water. 9.00. 16 gm. NaCl + porridge. 12.05. 20 gm. NaH2PO,. H20+4 gm. NaCl +220 c.c. water. 13.05. 20 gm. NaH2PO4. H10 +4 gm. NaCl +220 c.c. water. 16.05. 500 c.c. water. 17.05. About 1 litre tea. 19.15. About 1 litre various fluids +dinner. The urines produced are shown in Table IV. Though some of the salts were lost through diarrhoea the chlorides were but little depressed by the phosphates, and the sum of the two rose 18-2
272 H. W. DAVIES, J. B. S. HALDANE AND G. L. PESKETT. TABLE IV. Hours Volume ending per hr. Cl H2P 4 CON2H4 Cl +H2P04 11 124 *330-0048 -184 *335 12 145 *338 *0038 *342 13 142-329 -0120-341 14 165-308 -0397 *160 *348 15 139 *294-0696 -364 16 131 *293-0809 -147-374 17 129 *310 *0718 *151-382 17-18.32 96 *312 *0795-181 *392 18.32-20.32 77.5 *303 0662-221 *369 to a far higher value than was ever obtained for chloride, bicarbonate, or both together. Moreover, it reached a maximum at a time when there was little thirst, which always accompanied very high Cl + HCO3 concentrations. Hence the property which causes chlorides and bicarbonates to share a common maximum is neither that they share a common cation, nor that both are ionised. DISCUSSION. The fact that the Cl + HCO3 of the urine has a definite maximum which is unaffected by the urea or phosphate content of the urine or its total molecular concentration suggests strongly that the former salts are concentrated by a different part of the kidney from that which concentrates the urea, phosphates, and presumably other no-threshold bodies. This view is borne out by the fact that the dog can concentrate urea to 1-6 N, but its maximum for chlorides is apparently only -17 N. The limit is more probably set by the difference in salt concentration between plasma and urine than by the absolute concentration in the latter. Since J. B. S. H.'s normal colloid-free plasma contains about -115 N chloride and -025 N bicarbonate, or -14 N in all, this difference is about -17 N. The fluctuations in the maximum may then be explained as due to changes in the salt content of the plasma. It is clearly indifferent to the concentrating cells whether the difference in concentration is due to Cl or HCO3. The factor which limits their performance is presumably the osmotic leakage of water from the plasma into the concentrated urine, possibly a leakage of cations. Our results are quite consistent with Heidenhain's(7) theory that the glomerulus alone is responsible for the secretion of " water and those salts which everywhere accompany water in the organism." On this view the maximum is a measure of the glomerular concentrating power. If, however, we consider that the urine is concentrated by the tubules, we observe that chloride and bicarbonate agree with one another and. water, and differ from all the anions so far studied, except bromide, in
EXCRETION BY KIDNEY. 273 all the following properties: (1) they are present in large amounts in the plasma; (2) they possess high thresholds for the kidney; (3) their excretion is more interfered with than that of other urinary constituents by partial obstruction of the ureter [Cushny(s)] or renal artery [Marshall and Crane (9)]; (4) their excretion is less interfered with than that of any other urinary constituent by a short asphyxia of the kidney [Marshall and Crane(9)]. The last two facts are most easily explained on the view that all or most of the water, chloride and bicarbonate leave the blood by filtration through the glomerulus, while most other substances are in part actively excreted by the tubules. If this is the case bicarbonate must be reabsorbed from the filtrate under normal conditions, water whenever the urinary chloride or bicarbonate is higher than that of the plasma, and chloride when the urinary chloride is lower than that of the plasma. It may be that all are absorbed at once in constant proportions, as on Cushny's (lo) theory. If then the glomerulus is a filter the chlorides and bicarbonates are concentrated by a process of reabsorption, and the observed maximum is a measure of the limit to which this concentration can be carried in face of the tendency to osmotic diffusion of water in the opposite direction. But if the no-threshold bodies are also concentrated by reabsorption we should expect them to hinder the concentration of chloride and bicarbonate, which is not the case. And this hindrance would also occur if the no-threshold bodies had all been excreted into the tubules before the concentration of the chloride and bicarbonate. For the urea in the tubules would tend to hold back water from the reabsorbing cells. Hence excretion must take place lower down the tubules than reabsorption. It is true that Am bard and Papin found that the urinary chloride did not affect the urea maximum of the dog. But as the chloride concentration of the urine never exceeded that of the plasma in those of their experiments where the urea maximum was reached, this result was to be expected. Our experiments, therefore, are in harmony with Metzner' s(11) view that both reabsorption and excretion occur in the tubules. SUMMARY. 1. There is a maximum possible molecular concentration of chlorides in the urine. For J. B. S. H. this is about *33 N. 2. The maximum for bicarbonates has the same value. 3. When chlorides and bicarbonates are being excreted together the maximum possible sum of their molecular concentrations has this same value.
274 H. W. DAVIES, J. B. S. HALDANE AND G. L. PESKETT. 4. This maximum is independent, within wide limits, of the total molecular concentration of the urine, or those of urea and phosphates. 5. Chlorides and bicarbonates must be concentrated by the same part of the kidneys, which is probably reabsorptive, urea and phosphates a different one, which is excretory. REFERENCES. (1) Ambard and Papin. Arch. Intern. de Physiol. 8. p. 432. 1909. (2) Bailey and Bremer. Arch. Int. Med. 28. p. 773. 1921. (3) Davies, Haldane and Kennaway. This Journ. 54. p. 32. 1920 (4) J. S. Haldane. Journ. Path. and Bact. 23. p. 443. 1920. (5) M. Krogh. Ztsch. f. physiol. Chem. 84. p. 379. 1913. (6) Marshall. Journ. Biol. Chem. 14. p. 283. 1913. (7) Heidenhain. Hermann's Hdb. d. Physiol. 5. p. 361. (8) Cushny. This Journ. 31. p. 201. 1904. (9) Marshall and Crane. Amer. Journ. Physiol. 55. p. 278. 1921. (10) Cushny. The Secretion of Urine, p. 47. 1917. (11) Metzner. Nagel's Hdb. d. Physiol. 2. p. 291.