182 J. Physiol. (I948) I07, i82-i86 6I2.46I.62 PHOSPHATE CLEARANCES IN INFANTS AND ADULTS BY R. F. A. DEAN AND R. A. McCANCE From the Medical Research Council, Department. of Experimental Medicine, Cambridge, England, and Wuppertal, B.A.O.R. (Received 19 June 1947) Phosphate clearances in man have received comparatively little attention but the rate of excretion of P has been studied from time to time. Kleitman (1925) found that the excretion of P rose during sleep and was at its lowest during the forenoon. This was a confirmation of many previous observations (Fiske, 1921). Ollayos & Winkler (1943) investigated the excretion of P in relation to its serum level. Subjects were examined when they were asleep, at rest, fasting and after a meal. The authors found that the rate of excretion of P did not depend upon the level of P in the serum unless the latter had been raised by phosphate infusions. From their paper it appears that when the serum contained 34 mg. of inorganic P/100 c.c. the excretion rate varied widely and for unknown reasons from 0.1 to about 10 mg./min. This range would have given clearances for normal people of the order of 15 c.c./min. The data given by Blatherwick, Bell & Hill (1924) make it possible to calculate the phosphate clearances of their normal subjects, and they seem to have ranged from 5-8 to 13-3 c.c./min. and to have averaged about 8 c.c./min. This seems a low figure but the experiments were made on fasting subjects and probably during the forenoon when the phosphate clearances were likely to have been lower than at other times of the day or night (Fiske, 1921; Kleitman, 1925, and see below). According to Pitts & Alexander (1944) there is a sharp limit to the rate at which the tubules can reabsorb phosphates. This Tm for phosphates can be depressed by raising the plasma glucose but it is not affected by phloridzin. No work appears to have been done on babies. METHODS Urines were obtained from healthy British and German men and women. The times over which urine had been allowed to collect in the bladder were carefully noted. Specimens were obtained at any convenient time; some were passed on rising and others during the forenoon, afternoon or evening. Several specimens were obtained from most of the subjects, rarely only a single one. Blood was withdrawn from an anticubital vein and centrifuged quickly without the addition of any anticoagulant. So far as possible the blood was taken in the middle of the time over which urine was being collected, and in a few instances a second sample ofblood was withdrawn.
PHOSPHATE CLEARANCES IN INFANCY 183 The 'newborn' infants used for this investigation were mongols or suffered from inoperable meningomy'eloceles. The older child had an advanced degree of hydrocephalus. Urine was collected by catheter; blood was withdrawn from the anterior fontanelle in almost every case, and rapidly separated without the addition of any anticoagulant. The exact techniqu* of this work has been described by Dean & McCance (1947). The longer experiments on babies 1 to 4 lasted 6 or 8 hr., and during this time no food was administered by mouth. The tests on the other infants were made between one feeding time and the next, and never lasted more than 3 or 4 hr. Some of the babies were tested on two separate occasions, others only once, and the number of samples of urine and blood which were taken also varied from child to child. The infants appeared to suffer no inconvenience or harm as the result of these studies. The inorganic phosphate in the serum was determined by Fiske & Subbarow's (1925) method, and in the urine by the same method, or by that of Briggs (1922). RESULTS Tables 1 and 2 show the results which have been obtained in adults and children respectively. The clearances shown in the tables are averages of the clearances found in the separate experimental periods. The clearances in adults varied from 8-9 to 38-4 c.c./min., and the average for all the adults taken together was 18*0 c.c./min. These figures are of the same order as those obtained by Ollayos & Winkler (1943). In the same person the clearances sometimes varied considerably from one tile of day to another, and no satisfactory explanation can be advanced. In six out of the fifteen adult subjects it has been possible to compare the phosphate clearances during the forenoon with those during the afternoon, evening or night. In every instance the forenoon clearance has been the lowest, sometimes very much the lowest. Thus, the two forenoon clearances of no. 15 averaged 6-6 c.c./min. His afternoon clearance was 16*7 c.c./min. and his overnight clearance 201. No. 14's forenoon clearance was 6-5 c.c./min. and his evening clearance 19-5. The clearances of nos. 4 and 5 differed by similar amounts and those of the other two by smaller amounts. In this respect, therefore, the observations now being reported confirm those of Fiske (1921) and of Kleitman (1925). The clearances of the newborn infants (Table 2) varied from 002 to 0O81 c.c./min., and if these figures are expressed per 1-73 sq.m. of surface area to make them comparable with those of the adults, the variations were from 0O18 to 6-64 c.c./173 sq.m./min. Thus, as in adults, the clearances showed great individual variations, but they were all lower than any of the adults and most of them were of quite a different order of magnitude. A reference to the way in which clearances are calculated shows that the higher serum levels in infancy as well as the lower urinary excretions combined to produce these differences. There is a suggestion from these results that the phosphate clearances may rise within a relatively short time of birth. Thus, no. 6's clearance rose from 077 c.c./1.73 sq.m./min. on the second day of life to 1'95 c.c. on the seventh, no. 7's from 1-67 c.c./1.73 sq.m./min. on the third day of life to 6-64 c.c. on the tenth day, and no. 9's from 0*18 c.c./1.73 sq.m./
184 R. F. A. DEAN AND R. A. McCANCE mi. on the fifth day to 2-93 c.c. on the fourteenth day. No. 10, who was 5 months old, had a clearance of 13-0 c.c./1.73 sq.m./min. which is close to the average figure for adults. TABLE 1. The phosphate clearances of adults Urine No. of Blood P - A a periods (mg./100 Volume Clearance No. averaged c.c.) P (mg./100 c.c.) (c.c./min.) (c.c./min.) 1 1 2-6 37.0 1418 16-8 2 5 4.7 106*0 3 03 21*0 3 6 3.7 30 3 3-78 17*6 4 2 3-1 22-1 1-77 11-7 5 2 3-1 23-0 1-44 8-9 6 2 2*3 30'5 2-16 28*1 7 1 3*6 87-0 0 70 17-0 8 2 3.4 66-5 1-14 20-5 9 1 4-1 39-0 1-14 10.9 10 1 4-6 112-0 1-33 33 0 11 1 3*8 33 0 4-46 38-4 12 1 3-2 80-0 0.95 23.6 13 4 4-8 48.3 1-66 16-2 14 3 4.4 65.0 1.1 14-7 15 4 4-2 37*4 1.21 12*5 Average = 18-0 When data from more than one period have been available the figures given for the inorganic P in the urine, for the urine volume and clearance were all obtained by adding together the figures for the separate periods and dividing by the number ofperiods. The average figure shown atthe bottom of the table was obtained in the same way. TABLE 2. The phosphate clearances of infants Clear~ance Wt. at No. of Blood P Urine vol.,_-_- birth Age periods (mg./100 (c.c./1.73 c.c./1.73 No. (g.) (days) averaged c.c.) sq.m./min.) c.c./min. sq.m./min. 1 3250 4 6 6-8 3-71 0-68 5B25 2 3800 2 4 4-7 1-07 0 37 2-40 3 3200 11 4 6-4 2-56 0-21 1*77 4 2800 14 5 5.7 4.10* 0 53 4.28* 5 2950 4 1 3.9 0-24 0-29 2-41 6 3160 2 1 5.5 0-16 0.10 0-77 7 1 6-9 0-98 0-26 1*95 7 2880 3 1 7-8 0-25 0-20 1-67 10 1 6-7 0-36 0-81 6-64 8 2600 4 1 8*3 0*84 0.35 3-14 9 2650 5 1 6-2 0 75 0-02 0-18 14 1 5.7 1-06 0 34 2-93 10 153 1 7-1 0-58 1.99 13*00 * The diuresis in this experiment was produced by giving 5 % glucose intravenously. Although no glucose appeared in the urine, the clearance of phosphate may have been reduced because the tubules were actively engaged in the reabsorption of glucose (Pitts & Alexander, 1944). It is worth drawing attention to the very small quantities of P in the urine of some infants. 100 c.c. of no. 9's urine, for instance, contained only 1.22 mg. of inorganic P, and this is not a highly exceptional figure, for McCance & von Finck (1947) found that out of the seventy-two infants' urines, which were
PHOSPHATE CLEARANCES IN INFANCY 185 examined by them, three contained less than 0.1 mg./100 c.c. and twenty-five less than 1 mg./100 c.c. In comparison with these figures the present series of urines seem rich in phosphates and a more extended investigation might lower the average phosphate clearance for newborn infants very considerably. Walker & Hudson (1937) drew attention to the fact that the glomerular filtrates of Amphibia contained the same concentration of inorganic P as the plasma, but that the formed urine might occasionally contain a smaller one. This is evidently a common phenomenon in human infants, but it must be extremely rare or unknown in adults except perhaps after large doses of insulin when the excretion of P has been found to fall to levels as low as 0 7 mg./hr. (Blatherwick et al. 1924). TABLE 3. The effect of urine flow upon the phosphate clearance Lowest minute Clearance Highest min. Clearance volume (c.c./ (c.c./min./ volume (c.c./ (c.c./min./ No. 173 sq.m.) 1-73 sq.m.) 1X73 sq.m.) 1-73 sq.m.) Infant 1, 1st exp. 0*45 2.30 2-46 7*05 Infant 1, 2nd exp. 4-60 5 40 6-60 6.00 Infant 2 0-61 2-30 1-85 3 70 Infant 3 0.11 0.51 8-60 4-80 Infant 4 0*80 2-00 9-72 6-35 Adult 2 0.50 16-50 10.00 24-00 Adult 3 1P00 14-20 8-90 19 00 Ollayos & Winkler (1943) found no correlation between the rate of formation of urine and the rate of excretion of P. The present results bearing upon this question have been assembled in Table 3, and they suggest that a correlation between these two variables certainly exists in infants, and may exist in adults. It is impossible to be more definite with the limited amount of data available. DISCUSSION The inulin clearances, i.e. the glomerular filtration rates, are now generally recognized to be much lower in infants than in adults (McCance, 1946). Hence the clearances of all substances such as urea which depend for their clearance upon the glomerular filtration rate must be expected to be lower in infants than in adults, and for urea this has been shown with certainty to be the case. Phosphates, sodium and chloride, however, are actively reabsorbed by the tubules. The glomerular filtrates always contain far more of these ions than the formed urine, and consequently the amounts excreted per unit of time depend largely upon the reabsorptive activity of the tubules. This may not be very great in infancy, for in some respects the tubules are known to be less effective at that age than they are in adult life (Dean & McCance, 1947). Owing to the low glomerular filtration rates, however, the tubules need not be so effective and are certainly effective enough in most instances, for it is truly remarkable how little P may remain in the urine after its passage through an infant's tubules. The same is true of sodium and chloride. Looked at it in one
186 R. F. A. DEAN AND R. A. McCANCE way, the low P clearances in infancy may be an indication of ill-matched tubular and glomerular function, i.e. of overactive tubular reabsorption, but it is quite evident that a great deal more work will have to be done before these problems can be regarded as solved. SUMMARY 1. The phosphate clearances have been found to be much lower in newborn infants than in adults. The range in infants was from 0O18 to 6-64 c.c./173 sq.m./min., and in adults from 8-9 to 38-4 c.c./min. 2. The phosphate clearances in infancy probably vary with the rate of urine flow, and may rise to adult levels within a few weeks or months of birth. 3. In confirmation of previous work the phosphate clearances of adults were found to be at their lowest during the forenoon. Most of the infants used for this investigation were born at the Landesfrauenklinik, Wuppertal, and the authors are very grateful to Prof. K. J. Anselmino and his staff for their help and cooperation. Four babies were obtained through other German hospitals and Prof. E. Thomas, Duisburg, Dr F. W. Koenen, Krefeld, and Dr J. Gehrt of Elberfeld have been particularly helpful. The oldest child was investigated at Cambridge through the co-operation of Dr Margaret Sutton. REFERENCES Blatherwick, N. R., Bell, M. & Hill, E. (1924). J. biol. Chem. 61, 241. Briggs, A. P. (1922). J. biol. Chem. 53, 13. Dean, R. F. A. & McCance, R. A. (1947). J. Phy8iol. 106, 431. Fiske, C. H. (1921). J. biol. Chem. 49, 171. Fiske, C. H. & Subbarow, Y. (1925). J. biol. Chem. 66, 375. Kleitman, N. (1925). Amer. J. Phy8iol. 74, 225. McCance, R. A. (1946). Schweiz. med. W8chr. 76, 857. McCance, R. A. & von Finck, M. A. (1947). Arch. Di8. Childh. 22, 200. Ollayos, R. W. & Winkler, A. W. (1943). J. clin. Invest. 22, 147. Pitts, R. F. & Alexander, R. S. (1944). Amer. J. Phy8iol. 142, 648. Walker, A. M. & Hudson, C. L. (1937). Amer. J. Physiol. 118, 167.