Acta Pzdiatr Scand 64: 393-398. 1975

DEVELOPMENT OF RENAL CONTROL O F SALT AND FLUID HOMEOSTASIS DURING T H E FIRST YEAR OF LIFE A. APERIA, 0. BROBERGER, K . THODENIUS and R. ZETTERSTROM From the Depcirtment of Purdiarrics. Ktrrolinsker Institutet, St Giircin's Hospitul,for Children, Stockholm. Susrden

ABSTRACT. Aperia, A., Broberger, O., Thodenius, I(. and Zetterstrom, R. (Department of Paediatrics, Karolinska Institutet, St Goran's Hospital for Children, Stockholm, Sweden). Development of renal control of salt and fluid homeostasis during the first year of life. Acta Paediatr Scand, 64:393, 1975.-This study describes the development of renal control of salt and water homeostasis. Twenty-three infants aged 3 weeks to 13 months were studied with respect to glomerular filtration rate (GFR) using single injection technique, ability to excrete an oral salt load, ability to excrete water, and diluting capacity. GFR developed exponentially, salt excretion linearly, water excretion was unchanged and diluting capacity actually decreased. A hypothesis is presented for the theoretical basis of this functional development taking into account the interdependence of the functional parameters studied. This theory might well explain the high incidence of hypernatremic dehydration in infants.

.

KEY WORDS: Infants, renal function, glomerular filtration rate, sodium excretion, water excretion, diluting capacity

It is well documented that renal function is low in relation to the size of the organism in most newborn mammals ( 1 I , 19). In man, glomerular filtration rate (GFR) related to body surface is generally considered t o reach a relatively constant level at the age of 2 years (20). Little is known, however, about the pattern of the postnatal development of the various homeostatic functions of the kidney. The homeostatic properties will of course depend on both glomerular and tubular function. The question whether the balance between glomerular and tubular function is the same in the immature as in the mature kidney has been much discussed and is as yet not settled (9, 11, 19). Supported by grants from the Swedish Medical Research Council (3644), Research Funds of the Karolinska Institute, Semper Fund for Nutritional Research and Foreningen Mjolkdroppen. 26-752873 Acta Pzdiatr Scand 64

The purpose of this study has been to follow the development of some homeostatic functions of the kidney, namely salt and fluid excretion and diluting capacity, during the first year of life in man. Previous studies from this laboratory have described those functions in the neonatal period (4, 5). MATERIAL AND METHODS Twenty-three infants from 3 weeks to 13 months of age have been included in the study. The ages of the infants are shown in Fig. 1. All infants had normal deliveries and were of appropriate length and weight for gestational age according to Swedish standards (12). They were hospitalized for illnesses which had no influence on the general conditions and no one had any type of renal disease or other disorder that might affect water and electrolyte metabolism. Arterial blood pressure recorded by sphygmomanometry was normal for age according to the standards given by Haggerty et al. (15). All infants were normothermic and had no signs of intestinal malabsorption. Before the study all infants reAcra Pzddiarr Scand64

-

5 Numbers 4-

3-

-

-

2I-

ceived a standardized food intake recommended by the Child Health Centers (BVC) (24). A detailed history of food intake was obtained in each case. No infant with special diet o r abnormal salt intake was included. During the first month after birth when the infants were fed only breast milk o r cow milk's formula.' they had a daily sodium intake of about 1.2 mEq/kg body weight. Infants between 4 and I?, months of age were fed industrially prepared mixed food which should give a daily sodium intake of 5-6 mEq/kg and day (24). All studies were carried out in the nursery, and the infants were kept in their own cots. No signs of discomfort were noticed except in one 9-month-old baby who vomited during the salt load. This study was interrupted and is not included in the report. The following aspects of renal funcfion were studied: ( u ) The renal response to an oral salt and fluid load; and ( h )the glomerular filtration rate (GFR). In I ? infants only the salt load was performed and in one infant only t h e GFR was estimated. In the remaining 10 infants both parameters were studied. Informed parental consent was obtained in each case studied. Rcntrl response to

Lin or111 stilt loud At about 7 a.m. the infants received their ordinary formula appropriate for age. At 9 to I0a.m. the study was started by induction of water diuresis. For this purpose the infants received breast milk o r cow milk's formula (Baby S e m p I ) diluted 1 : 3 with water in an amount of 2 % of body weight during the first hour and thereafter by 0.5 % of the body weight every half an hour during the entire study. At least 14 hours after the high fluid intake was started, an oral salt load ofO.13gsodiumchlorideper kg bodyweight(2.2mEq Na+/kg) was given. The sodium chloride was added to the diluted formula, yielding a I % NaCl solution. It was generally administered by stomach tube. I n infants older than 8 months it was administered by a feeding bottle. For that purpose the cow milk's formula had been diluted with salt-free fruit juice instead of water. Sodium chloride was then added, yielding a 1 % NaCl solution. N o ordinary food was givenduring the study. Capillary blood samples were taken with heel puncture o r fingerprick for determination of hematocrit, serum concentration of sodium, albumin and osmolality 30 minutes before and 120-240 minutes after the salt load. The glornerular filtration rate (GFR) was estimated as inulin clearance by following the disappearance curve after a single injection of this substance (10% inulin, Laevasar

Baby Semp no. 1 (Semper) sodium content 6.6 mEq/l. Milkotal (Findus) sodium content 8.7 mEq/l, human breast milk sodium content 7 mEq/l. Actu Pzdiutr S a n d 64

Gesellschaft). For this purpose 0. I ml blood was obtained in capillary samples %I0 times during 80 minutes. Details of this method have previously been described (4). A nulytictr 1 methods

The sodium concentration in serum and urine was analysed by flame photometer (Eppendorff). Inulin in blood was determined with the Anthron method (16). Osmolality in blood and urine was determined cryoscopically with the aid of a Knauer osmometer. Serum albumin was determined refractrometrically. Hematocnt was estimated in glass capillaries which were centrifuged at 10000 rpm for 5 minutes. Culc~ul~itions The average urinary sodium excretion ( U N a V ) per hour between 1-5 hours after the salt load was calculated. Urinary water excretion ( V ) during high fluid intake was also calculated a s mean value per hour. The glomerular filtration rate (GFR) was calculated from the plasma disappearance curve of inulin accordifig t o the formula of Sapiistein ( 9 2 ) .All values have been related t o 1.73 m2 body surface which has been regarded to be the most reliable reference when comparing renal function parameters during growth (20). Student's t-test has been used in statistical analysis.

RESULTS T o demonstrate the development of renal function from birth, data have been included from 8 full term infants reported in previous studies (4, 5 ) . The development of the glomerular filtration rate (GFR) during the first year is demonstrated in Fig. 2 a and 6. All values are related to 1.73 m 2 body surface. During the first 2 months after birth there is a steep increase in GFR. The GFR then increases more slowly and towards the end of the first year reaches values found in older children (6). When the GFR is related to the logarithm of age (Fig. 2 b ) the relationship is more linear. The renal response t o an oral sodium load is shown in Fig. 3 a and b. Fig. 3a demonstrates the increase in the natriuretic response to the oral salt load. Again the values are related to body surface. The natriuresis is given as the average urinary sodium excretion (UNaV) per hour. In contrast to the GFR the development of the natriuretic response is more linear. During the first year UNaV increases about 10 times. The values found at 10 to 13 months are in accordance with values earlier found in older children i.e. about 16 mEq/hour/l.73 m2 (6).

Renal control of salt and fluid homeostasis b

150.

100-

50

395

150.

.... ..

1

..' ..

100-

I

Fig. 2. ( u )Glomerular filtration rate

. . . *

* * *

' Age,

2

The increase in the natriuretic response is out of proportion to the GFR as demonstrated in Fig. 3b. The studies were carried out under standardized and "maximal" hydration, sufficient to maintain a water diuresis throughout the study. It thus seemed justified to compare the water excretion among the infants studied. In contrast to GFR and the natriuretic responses urinary water excretion ( V ) is fairly stable during the first year of age. This is demonstrated in Fig. 4. It should, however, be noted that there are fairly large individual variations. Fig. 5 a and b demonstrate the diluting capacity in younger and older infants. The diluting capacity is measured as free water clearance. A characteristic relationship normally exists between the diluting capacity and the distal tubular sodium delivery which can be given as the sum of free water clearance (CH20)and sodium clearance (CNJ ( I ) . Results obtained from our laboratory in 4 older children aged 7-12 years are included in the figure. Newborn full-term infants have a supernormal diluting capacity when compared with older children. Fig. 5a shows that the ability to dilute the urine re-

0 3 , UNoV/iOOml GFR

3

mms

i5 6 i68'i"~

(GFR) during first year of life. The scale i s lin-lin. ( 6 )Glornerular filtration rate (GFR) during first year of life related to the logarithm of age.

mains supernormal during the first 5 months of life; 5 b demonstrates the diluting capacity in 6-13 months old infants. The results from the older infants are more in accord with those found in older children. Serum concentrations of sodium and albumin and hematocrit did not change by the fluid and salt load and were also independent of age. The mean sodium value was 136 mEq/l. Serumalbumin 6.2 g/100 ml. Hematocrit ranged from 3 1-53 %, mean value 38 %. The highest hematocrit values were found during the first month after birth, the lowest values at 2-3 months of age. DISCUSSION The developmental pattern of various parameters of renal function is very heterogenous during the first year of life. None of the homeostatic functions studied, i.e. Naf excretion, water excretion, and diluting capacity, follow the development of the GFR. The GFR increases exponentially, the ability to excrete Naf load increases linearly, the ability to excrete water appears to have reached a level

. b

Fig. 3. ( a )The average hourly uri-

nary sodium excretion (UNaV) during first year of life. The correlation coefficient (r=0.764) is highly significant @p>0.001). Acta Psediatr Scand 64

396

A . Aperia et al.

.

. 0

, . . .

,

,

l

.

.

.

10

Age, mths , . l , 15

FIR 4 The average hourly water excretion dunng wnter diurew i n infant\ from birth to 13 months of age

already during the first month of life and the ability to dilute the filtered load actually decreases. A hypothesis for the mechanism of development of these homeostatic functions, taking in account their dependence on each other, will now be presented. Since the anatomical developments of the glomerulus and the tubule do not appear to follow each other closely (13), it has often been suggested that the functional development of those structures will also proceed at different rates ( I 1 , 13, 19). The renal tubule is, however, composed of a series of different functional units, the proximal tubule, the descending loop of Henle (DLH), the medullary thin and thick ascending loop of Henle, the distal tubule consisting of the diluting segment, the

0

distal convolution and the cortical and papillary part of the collecting duct. The work carried out in each unit will depend not only on the functional capacity of the unit, but also on the load which in turn depends on the filtration rate and the work in the preceding tubular units. Thus the functional balance between various tubular segments is just as important as the balance between glomerular and tubular function for the homeostatic efficiency of the kidney. The handling of Na+ and water differs markedly in different parts of the tubule. In the proximal tubule Naf is presumably reabsorbed both by active transport mechanisms and as a result of solvent drag (27). Water reabsorption follows Na+ reabsorption and the Na+ concentration of the tubular fluid does generally not change along the length of the proximal tubule (27). Pressure gradients between the peritubular capillaries, interstitium and tubular lumen will to a large extent determine the Na+ reabsorption (18). Those physical forces are among other things determined by the arterial blood pressure (3) and hematocrit (7, 23). In DLH Na+ transport out of and into the lumen is negligible (17). The tubular fluid is concentrated during the passage through DLH by a mostly urea-dependent osmotic withdrawal of water (17, 21) and the addition of urea (21). It

0

0

61

I

0

0

0 0 : . 00

:

Fig. 5. The relationship between free water clearance and

the sum of sodium and free water clearance ("distal tubular Na+ delivery") during first year of life. 0,newborn fullterm infants. A, older children aged 7-12 years. Arta Pzdiatr Scand 64

(0)0 , Infants 3 weeks Infants 6 1 3 months of age.

Fig. 5 .

-

5 months of age. ( h ) 0 ,

Renal control of salt and fluid homeostusis

has been calculated that withdrawal of water will account for 60-70% of the concentration of fluid in the DLH ( 2 1). Withdrawal of water will result in the concentration of Na+ creating a steep lumen interstitial Na+ gradient (17). This gradient will promote the Na+ reabsorption in the ascending loop of tubule and in turn create the optimal conditions for a very pronounced dilution of the urine. If the osmotic concentration of the fluid in DLH were t o -be accomplished mainly by urea addition, the concentration gradient of lumen interstitium Na+ would be less steep and the net effect of Na+ reabsorption in the ascending loop of Henle and the diluting segment would be less, resulting in a less diluted urine under the condition of water diuresis. It has recently been suggested from this laboratory that urea addition to the DLH will increase with increasing urea availability in the interstitium ( 2 ) . The urea availability of the renal medulla in the newborn infant is most likely low and has been regarded as responsible for the low concentrating capacity of the newborn infant (10,26). In fact, it has been shown that the concentrating capacity of the infant can be increased considerably with high protein intake (10). It is therefore suggested that the fluid concentration in the DLH in the immature kidney is accomplished by water withdrawal. Thereby optimal conditions for Na+ reabsorption in the ascending loop of Henle and the distal segment are created, resulting in a high degree of urine dilution and Na+ retention. The hypothesis is supported by the observation in this study and in previous studies from this laboratory that in the very young infants, which are unable to excrete an acute Na+ load, the diluting capacity is supernormal (4,5 ) . In the older infants the diluting capacity as well as the ability to excrete a salt load appraoches normal adult values. Na+ reabsorption in the proximal tubule of the immature kidney is unpredictable as long as micropuncture data with identified puncture sites are not available. The load to the proximal tubule is determined only by the filtration rate.

397

Anatomical observations suggest that the growth of the glomerulus precedes the growth of the proximal tubule in the first period of life (13). This would imply an inadequate reabsorption of the filtrate in this segment. On the other hand, the physical forces controlling proximal Na+ reabsorption should by the low arterial blood pressure and the high hematocrit found in the newborn infant act to promote Na+ reabsorption. T o sum up the above presented hypothesis of the handling of Na+ and water in the immature kidney, proximal tubular Na+ reabsorption could be low, normal or in case of high hematocrit slightly increased. The Na+ reabsorption in the distal tubule is always enhanced. This enhancement is reflected by the high diluting capacity. It is most likely secondary to the low availability of urea in the renal interstitium. Therefore the development of the ability to excrete a Na+ load and the ability to concentrate urine will parallel each other. This hypothesis will explain the high incidence of hypertonic dehydration (14) in infants. Due to the inability to concentrate the urine, fluid cannot be retained adequately despite large losses. The reabsorption of Na+ is, however, unchanged and enhanced. This will result in a more pronounced Na+ than water retention, which in itself will predispose to a hypertonic situation. If in addition the diet is high in Na+, the effect of the disproportionate urinary excretion of water and Na+ will be potentiated. It has also been shown that the incidence of hypertonic dehydration in infants on a high-salt diet is increased (8, 25).

REFERENCES 1. Aperia, A , , Broberger, 0. & Feychting, H.: The effect

of hypotonic mannitol and saline load on diluting capacity in man. Acta Physiol Scund, 80: 145, 1970. 2. Aperia, A , , Broberger, 0. & Snellman, K . : Tubular urea secretion during arginine infusion in dogs. To be published. 3. Aperia, A , , Broberger, 0. & Soderlund, S.: Relationship between renal artery perfusion pressure and tubu-

-

Acta Pediatr Scand 64

398

A . Aperia et a / .

lar sodium reabsorption. A m J Physiol, 220: 1205, 1971. 4. Aperia, A . , Broberger, O., Thodenius, K . & Zetterstrom, R.: Renal response to an oral sodium load in newborn full term infants. Actci Poeditrtr Scand, 61: 670. 1972. 5 - Developmental study of the renal response to an oral salt load in preterm infants. Acta Porditrtr Sccmd, 6.?: 5 17. 1974. 6. Berg, u.: Urineeliminationofanoral saltandfluid load in healthy children. Actu Paediatr Scund, 62: 505, 1973. 7. Burke, T. J . , Robinson, R. R. & Clapp, J. R.: Effect of arterial hematocrit on sodium reabsorption by the proximal tubule. A m J fhysiul, 220: 1536, 1971. 8. Colle, E., Ayoub, E. & Raile, R.: Hypertonic dehydration (hypernatremia): The role of feedings high in solutes. Pediutrics. 22: 5, 1958. 9. Edelmann. C. M., Jr: Pediatric Nephrology. E. Mead Johnson Award Address 1972. Pediutric.s, .51:854, 1973. 10. Edelmann, C. M., Jr, Barnett, H . L. & Troupkou, V.: Renal concentrating mechanism in newborn infants. Effect of dietary protein and water content, role of urea, and responsiveness to antidiuretic hormone. J Clin Invest, 39: 1062, 1960. I I Edelmann, C. M., Jr & Spitzer, A.: The maturing kidney. A modern view of well-balanced infants with imbalanced nephrons. J f e d i a t r , 75: 509, 1969. I2 Engstrom, L., Karlberg, P. & Selstam, U.: Neonatal lungdlvikt i fiirhdllande till gruvidiretstid. 1 97 1. Copyright. 13. Fettermann, G. H.. Shuplock, N. A,, Philipp, F. J. & Gregg, H. S.: The growth and maturation of human glomeruli and proximal convolutions from term to adulthood: Studies by microdissection. Pediatrics, 35:601. 1965. 14. Finberg, L.: Hypernatremic (hypertonic) dehydration in infants. N Engl J M e d , 289: 196, 1973. 15. Haggerty, R. J., Moroney, M. W. & Nadas, A. S . : Essential hypertension in infancy and childhood. A m J Dis Child, 92: 535, 1956. 16. Hilger, H. H . , Klumper, J. D. & Ullrich, K.J.: Wasserrucksresorption und Ionentransport durch die Sam-

Acru P z d i u b Scand 64

17. 18.

19. 20. 21.

22.

23.

24.

25.

26.

27.

melrohrzellen der Saugetierniere. Arch ges Physiol, ,767: 218, 1958. Kokko, J . P.: Membrane characteristicsgoverning salt and water transport in the loop of Henle. Fed Pr(ic. 33.35, 1974. Lewy, J. E. & Windhager, E. E.: Peritubular control of proximal tubular fluid reabsorption in the rat kidney. Am J Physiol, 214: 943, 1968. McCrory. W. W.: Developmentul Nephrulogv. Harvard University Press, Cambridge, Massachusetts, USA, 1972. - D r ~ ~ e l o p m e n t aNephrology. l p. 90-108, Harvard University, Cambridge, Massachusetts, USA, 1972. Pennell, J. P., Lacy, F. B. & Jamison, R. L.: An in vivo study of the concentrating process in the descending limb of Henle’s loop: Kidney I n t , 5 : 337, 1974. Sapirstein, L. A., Vidt, D. G., Mandel, M. J. & Hanusek, G.: Volumes of distribution and clearances of intravenously injected creatinine in the dog. Am J fhysiol, 181: 330, 1955. Schrier, R. W. & Earley, L. E.: Effects of hematocr;t on renal hemodynamics and sodium excretion in hydropenic and volume expanded dogs. J Clin Invest, 49: 1656, 1970. Socialstyrelsens medicinska expertgrupp for kost och fysisk aktivitet i barnasldern 0-18 ?ir(MEK-B). Socialstyrelsen redorzisar nr 33, 1973. Taitz, L. S. & Byers, H. D.: High calorie/Osmolar feeding and hypertonic dehydration. Arch Dis Child, 47: 257, 1972. Winberg, J.: Determination of renal concentrating capacity in infants and children without renal disease. Acta Paediatr Scand, 48.318, 1959. Windhager, E. E.: Some aspects of proximal tubular salt reabsorption. Fed Proc, 33: 21, 1974.

Submitted Sept. 5, 1974 Accepted Oct. 16, 1974

(K.T.) Dept. of Paediatrics S:t Gorans Sjukhus Box 12500 S-I12 81 Stockholm Sweden

Development of renal control of salt and fluid homeostasis during the first year of life.

This study describes the development of renal control of salt and water homeostasis. Twenty-three infants aged 3 weeks to 13 months were studied with ...
439KB Sizes 0 Downloads 0 Views