The role of the kidney in sodium homeostasis during maturation

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1 Kidney International, Vol. 21 (1982), pp EDITORIAL REVIEW The role of the kidney in sodium homeostasis during maturation Although more studies have been performed and articles have been published about sodium homeostasis in the newborn than about any other aspect of electrolyte metabolism during early life, an understanding of the mechanism by which the kidney maintains the positive sodium balance intrinsic to the process of growth is just emerging. The purpose of this article is to present pertinent information that led us to propose a hypothesis relating the special features of renal handling of sodium to the maintenance of homeostasis during development. There are two well established characteristics of sodium metabolism in the growing organism: (1) the existence of a positive balance, and (2) the limited ability to excrete a load. The accretion of body tissue, particularly bone, is associated with the retention of sodium. Breast-fed puppies excrete in the urine only about 3% of the sodium provided by milk [1]; healthy premature infants, fed a variety of formulas, retain about one third of the salt present in the diet [2]. Interestingly, the magnitude of this positive balance remains relatively constant within a wide range of sodium intakes [1 4] and despite the fact that salt intake per unit of body surface area is generally smaller in a baby than in an adult. Thus, the developing kidney is able to conserve sodium efficiently, a condition essential for growth. While chronic retention of sodium, within certain limits, is a natural phenomenon in the growing child, the inability to excrete an acute sodium load is not appropriate obviously to the needs of the organism. Goldsmith et al [5] subjected 1-, 2- and 3- week old puppies and adult dogs to the administration of an isotonic sodium solution equal to 1% of their body weight. The limited diuretic response of the one-week-old puppies was striking (Fig. 1). Two hr after administration of the saline, the puppies excreted less than 1% of the administered load, as compared to about 5% by the adult dogs. An almost identical response was observed by Dean and McCance in humans [6]. Because GFR has been well documented as lower in the neonate than in the adult, even when corrected for body weight or surface area [71, it was reasonable to consider this factor as a cause of the sodium retention. It should be readily apparent, however, that a low GFR per se cannot explain the limited capacity of the newborn to dispose of an extra load of sodium. Even at a GFR of 5 ml/min, such as encountered in a 25 g infant, the 42 meq of sodium filtered in 1 hr exceeds by a substantial margin the amount of sodium contained in a load of isotonic saline equal to 1% of body weight. One is on firmer grounds when referring to the duration of the change in GFR 539 that occurs in association with the volume expansion; whereas in the adult animals the glomerular filtration remained at a high level throughout the entire experimental period, in the puppies the GFR returned to baseline while the saline solution was still being infused at rapid rates [5]. Unfortunately, these and similar observations do not allow us to assess the relative importance GFR plays in the blunted response of the newborn to sodium loading because it is well recognized that factors influencing GFR also might have a direct effect upon tubular reabsorption [8 1]. However, we [5] and others [11] have observed that substantial differences in sodium excretion between puppies and adult dogs persist even when correction is made for GFR. This difference suggests that factors related to tubular reabsorption play an important role in limiting the excretion of sodium by the puppy. The first and quantitatively the most important step in the process of sodium reabsorption occurs in the proximal tubule. This segment of the nephron has never been implicated in the sodium retention of early postnatal life. Actually, the demonstration of a morphological preponderance of the glomerulus upon the tubule in the newborn of several species [12, 13] and functional data obtained by clearance techniques [14 16] have been used as evidence of glomerulotubular imbalance, whereby, at this stage of development, the capacity for proximal tubular reabsorption lags behind the capacity for glomerular filtration. Evidence obtained from micropuncture studies done in puppies [171 and newborn guinea pigs [18] has prompted us to surmise that the increase in GFR proceeds pan passu with the increase in fluid reabsorption by the proximal tubule, which, in turn, appears related to the increase in the relative basal and lateral surface area of the proximal tubule cells [19]. An impressive body of literature has been devoted to the evaluation of the factors that modulate the reabsorption of solute and water in the proximal tubule under various conditions [2, 21]. Because the juxtamedullary nephrons appear to have a higher capacity than the superficial ones to reabsorb sodium [22, 23], it was postulated that a redistribution of blood flow between these two populations of nephrons might serve as a regulatory mechanism for sodium excretion [24, 25]. Concordant with this hypothesis, the better development of the juxta- Received for publication June 9, 1981 and in revised form October 23, /82/ $ by the International Society of Nephrology

2 54 Spitzer C a' C., 'C E > E C) 6 O Adults o a 9-15 Days A Days o.- o 2-6 Days 3 6 Saline infusion Time, rn/n Fig. 1. The effect of acute administration of an isotonic saline solution equal to 1% of body weight on the excretion of sodium in dogs of various ages [5]. medullary nephrons in early postnatal life [26 28] should enable the newborn to conserve sodium and, under conditions of continuous stimulation, it may make him less capable of disposing an increased load. Measurements that we made show that no redistribution of renal blood flow occurs in puppies as a result of acute loading with isotonic saline [5]. Moreover, no differences were observed in the degree of natriuresis related to the nature of the infusion when puppies between 1 and 6 weeks of age were subjected to similar degrees of volume expansion with either a saline or an albumin solution (Aladjem, Spitzer, and Goldsmith, to be published). The fact that changes in the response to these two kinds of infusion closely parallel each other over the entire age span covered by the observations indicates that the age related differences in response are not dependent upon the presence of mature superficial nephrons. Finally, the contention that redistribution of glomerular blood flow is causally related to natriuresis remains tenuous. For instance, researchers have found that certain natriuretic states are associated with an increase in blood flow to the inner rather than outer cortical nephrons [29, 3], whereas in at least one model of antinatriuresis there were no alterations in intrarenal distribution of blood flow [311. In recent years evidence has been presented in support of a relationship between physical forces in the peritubular space and the rate of fluid reabsorption by the proximal tubule [ It has been proposed that the balance of hydrostatic and colloid-osmotic pressures across the peritubular capillary membranes affects the net transtubular reabsorption rate. According to this theory, a rise in the colloid-osmotic pressure or a fall in the hydrostatic pressure of the blood in the peritubular capillary enhances transtubular movement of fluid and vice versa. In addition, a small hydrostatic pressure gradient, favoring the outward movement of fluid, has been documented in adult animals [36, 37]. This gradient appears to be significantly higher Table 1. Pressure differences across proximal tubular epithelium in the dog (mm Hg)a b,pc Newborn Adult Calculated from data of Horster and Valtin [17]. b = oncotic pressure difference. = hydrostatic pressure difference. in the newborn, accounted for quantitatively by a lower pressure in the peritubular capillaries [17, 38]. Yet another factor that might favor reabsorption during the first few weeks of extrauterine life is the high hematocrit. Other documented clinical and experimental observations reveal that polycythemia is associated with enhanced reabsorption of sodium [39]. In addition, Aperia et al [4] show that in full-term infants with high hematocrit values subjected to isovolemic hemodilution, an inverse correlation between sodium excretion and hematocrit is obtained. While the high hydrostatic pressure gradient and the high hematocrit observed in the newborn should enhance tubular reabsorption, the low colloid osmotic pressure generated by a low protein concentration in the peripheral blood [17, 41] should have an opposite impact. Compounding this effect is the low filtration fraction prevailing at this early age [17, 42, 43] which should dampen the rise in the colloid osmotic pressure of the blood reaching the peritubular capillaries. By using this information [17] and the Landis-Pappenheimer equation [44], one can calculate that in the 3-week-old puppy, the sum of forces favoring peritubular uptake of fluid was about 8 mm Hg lower than in the adult dog (Table 1). Furthermore, a higher permeability of the neonatal proximal tubule to macromolecules was documented by recent ultrastructural studies performed on the rat kidney tissue by Larsson [45] and by in situ microperfusions performed in guinea pigs by Lockhart and Spitzer [46]. In this latter group of experiments, known amounts of metabolically inert radioactive substances of various molecular weights were injected into the proximal tubule near the glomerulus and collected in the final urine. Simultaneously injected 3H-inulin served as a reference substance. Whereas creatinine (molecular weight 113, Stokes-Einstein radius 3 A) leaked at a constant rate of about 7% over the entire age span studied, the urinary recovery of mannitol (molecular weight 183, Stokes-Einstein radius 4 A) rose from about 92% at birth to 1% at 4 days of extrauterine life. This finding is interpreted to reflect a narrowing of the "tight junctions" that may account for the decrease in hydraulic conductance during postnatal development [47]. It would appear, therefore, that the low hydro-oncotic force promoting the absorption of fluid across the proximal tubule of the immature animal is compensated by a higher permeability, resulting in preservation of the glomerulotubular balance. Because the fractional reabsorption of sodium in the proximal tubule is either similar to or lower than that of the adult, but certainly not higher, the retention of sodium observed in infancy must be caused by enhanced reabsorption in more distal segments of the nephron. That this might be the case was suggested by clearance experiments performed by Kleinman in 1- to 23-day-old puppies [48]. When blockers of distal tubular

3 Sodium homeostasis during development Days A Days U Days Table 2. Fractional reabsorption of sodium (%, mean SEM) associated with intravenous infusion of an isoncotic albumin solution equal to 5% of body weighta Age, days Control Experimental 2.2 C, C E. x 1.8. U- I- A U ito to to There was a significant decrease in fractional sodium reabsorption in response to isoncotic volume expansion in all groups (P <.5). The fractional sodium reabsorption after volume expansion in the oldest group was significantly less (P <.1) than that in the other two age groups [52] TF/P1, Control Fig. 2. TF/P,, ratios obtained by the recollection technique in three dtfferent age groups of guinea pigs before (control) and after (expenmental) infusion of an isoncotic albumin solution equal to 5% of body weight. Each point represents the mean of 2 to 4 individual measurements made in the same animal [52]. reabsorption (chiorothiazide and ethacrynic acid) were administered to hydropenic animals, a decrease in fractional reabsorption of about 3% ensued, with a further drop of a similar magnitude occurring when a load of isotonic saline, corresponding to about 3% of body weight, was superimposed upon the diuretics. Because of the distal blockade, the second decrease in fractional reabsorption, from about 7 to 5%, had to result in large part from proximal inhibition of sodium reabsorption, induced by saline loading. When distal tubular sodium reabsorption was not blocked, saline expansion produced only an insignificant decrease in fractional sodium reabsorption, suggesting that the effect of a proximal inhibition was mitigated by increased reabsorption at more distal sites. Because newborn dogs excreted less of their filtered sodium than did adult animals during saline expansion and because the change in proximal fractional reabsorption appeared to be similar in animals of all ages, the distal segments of the newborn nephron must have absorbed a greater fraction of the filtered load than the nephron of the adult dog. Aperia et al [491 arrived at a similar conclusion from a study of 23 infants 3 weeks and 13 months of age who were found to have a higher capacity to form free water than children between 7 and 12 years of age, at comparable rates of distal sodium delivery (approximated by adding the clearance of sodium to the clearance of water). However, these later findings are difficult to reconcile with the results of the micropuncture studies of Zink and Horster [51 which indicate that the ability of the loop of Henle to generate a hypotonic fluid is attained only gradually during ontogeny. A more detailed exposition of the behavior of various segments of the nephron during development is provided by micropuncture experiments that we performed on guinea pigs [51]. The recollection technique was used to obtain proximal tubule fluid under hydropenic conditions and following expansion with an iso-oncotic albumin solution corresponding to 5% of body weight. The amount of sodium reabsorbed in the proximal tubule was estimated from changes in TF/P1, and the renal fractional reabsorption of sodium was calculated from the urinary to plasma ratio of sodium and inulin. There was a marked decrease in proximal reabsorption of fluid following infusion of albumin solution at all ages, but the magnitude of the change did not vary from one age group to another (Fig. 2). However, the excretion of sodium was significantly less in the younger than in the older animals (Table 2) suggesting differences in reabsorption in nephron segments located beyond the proximal tubule. That this is indeed the case was demonstrated by Aperia and Elinder in a micropuncture study performed on growing rats [52]. Sodium delivery into and sodium reabsorption by the distal convoluted tubule were measured in 24- and 4-day-old hydropenic and volume-expanded rats. Under both these experimental conditions, the fractional reabsorption of sodium along this nephron segment was substantially larger in the younger than in the older animals. In hydropeni the TF/PN&Ifl ratio fell between the early and the late distal tubule by 12-fold in the 24-day-old rats and by only 3-fold in the 4-day-old rats. In volume expansion the decrease was of about 7-fold in the younger animals and of only 2-fold in the older group. Thus, the enhanced reabsorptive capacity of the distal convoluted tubule appears to contribute to the retention of sodium and to the blunted response to saline loading. Whether or not a similar phenomenon occurs at the level of the collecting duct is yet to be determined. Knowledge regarding the mechanisms controlling sodium reabsorption by the distal segments of the nephron is sparse. The prevailing evidence speaks against a significant impact of physical forces at this level [2, 21]. On the other hand, there is compelling evidence that adrenocortical steroids exert a specific regulatory effect on the distal tubular transport of both sodium and potassium [53 55]. Mineralocorticosteroids are thought to enhance the reabsorptive transport mechanism, either by providing more energy to the active transport pump [56] or by increasing the number of receptor sites [57]. The renin-angiotensin-aldosterone system is very active in early postnatal life. Kotchen et al [58] documented high levels of renin in plasma of infants. Similar findings have been reported by Drukker et al [59] in puppies. The high plasma renin activity (PRA) levels observed during infancy may be due to the presence of stimuli that enhance the synthetic rate of this enzyme or it might be the result of a poorly developed feedback mechanism. Among the stimulatory factors that have been

4 542 Spitzer Days 11 Days 21 Days Fig. 3. Plasma renin activity (PRA) in puppies of various ages prior to (first of each pair of bars) and following loading with an isotonic saline solution equal to 1% of body weight [61. proposed are a low BP [581, enhanced activity of the sympathetic nervous system [61, and increased sensitivity of the neonatal vasculature to the pressor effect of catecholamines [61]. The lack of maturation of the feedback mechanism is suggested by the measurements of PRA [59] performed in the puppies we investigated for their response to infusion of isotonic saline (Fig. 3) [5]. In all three age groups studied a significant fall in PRA was noticed following volume expansion. The decrease was 6% in the youngest puppies, 7% in the 2-week-old animals and 8% in the oldest group. Similar changes were described to occur as a result of administration of furosemide [62] and peritoneal dialysis [63]. Thus, in the newborn, PRA changes appropriately in response to various stimuli. However, the suppression is incomplete and rises with age, reflecting probably some degree of immaturity of the feedback system. This incomplete suppression, if attended by parallel changes in plasma aldosterone, might explain not only the less efficient excretion of a sodium load by the newborn but also the absence of the escape phenomenon at this age. Aldosterone excess leads to a decrease in salt excretion, a positive sodium balance, and an increase in the volume of the extracellular fluid compartment. Sodium excretion gradually returns to its former level, as progressive expansion of the extracellular fluid compartment ensues, but the excess of salt and water already accumulated is not disposed of until aldosterone levels return to normal [64, 651. In the growing individual the expansion of the extracellular fluid compartment does not occur, presumably because most of the sodium retained is deposited in newly formed cells. This is reflected in a larger increase in body mass than in extracellular volume [66]. Under these circumstances the escape fails to occur even when supplemental amounts of mineralocorticoids are administered for as long as 1 days [67]. Kotchen et al [58] and Aperia et al [68] considered aldosterone among the factors responsible for the retention of sodium during infancy, but they discarded it based on evidence available at the time, which suggested low secretory rates of this hormone in early life. Subsequently, Kowarski, Katz, and Migeon [69] demonstrated that aldosterone secretion in the newborn is actually elevated when considered relative to body surface area. Moreover, Beitins et al documented high plasma aldosterone concentrations at an early age, presumably due to the combination of high secretion rates and low metabolic clearance rates relative to body size [7]. Indirect evidence for enhanced aldosterone activity in the neonate is derived from data of Pasqualini, Sumid and Gelly [71] who found greater binding of radiolabelled aldosterone to fetal rather than to maternal guinea pig kidney. Recently, Aperi Larsson, and ZetterstrOm [72] have demonstrated that the proximal tubule cells of the immature rat but not those of the adult animal respond to the administration of aldosterone with a substantial rise in the Na-K-ATPase and that this effect is mediated via common steroid receptors. The observation that the sodiumlpotassium concentration ratio decreases during the development of the guinea pig prompted Merlet-Benichou and de Rouffignac to speculate that a high fractional reabsorption of sodium and water in segments of the renal tubule stimulated by aldosterone accounts for the blunted response of the newborn animal to saline loading [73]. A causal link between the renin-angiotensin-aldosterone system and the positive sodium balance characteristic of the growing infant is suggested by the close relationship between the drop in PRA [Fig. 31 and the amount of sodium excreted in the urine observed in our experiments (Fig. 1). It should be noted that the 2-week-old puppies excreted more sodium than the 3-week-old animals, showed the highest levels of renin prior to loading, and underwent the largest absolute drop in PRA following infusion of saline. Since the experiments lasted about 2 hr and changes in plasma aldosterone concentration can occur within 15-3 mm [56], the time framework is consistent with this hypothesis. The status of the renin-angiotensin-aldosterone system can also explain the inappropriate sodium loss observed to occur in 2- to 4-week-old, healthy premature infants [75 77]. Sulyok et al [78] performed simultaneous measurements of PRA, plasma aldosterone concentrations, and urinary excretion of aldosterone, along with determinations of sodium and potassium balances in 1-week-old neonates with gestational ages of 3 to 41 weeks and birth weights of 116 to 467 g. The urinary sodium excretion was the highest in the infants born between 3 to 32 weeks of gestation, who were found to be in a negative sodium balance. As expected, PRA was directly related to the urinary sodium loss and inversely related to the sodium balance. However, there was an inverse correlation with age between PRA and urinary aldosterone excretion and a positive correlation between the latter and sodium balance. These observations indicate that in response to salt wasting, premature infants can augment their PRA, but their adrenals fail to respond adequately to this stimulation. The result is an inability

5 II Sodium retention C?A1oneAngiotensin Sodium homeostasis during development 543 Sodium utilization Rin Fig. 4. Schematic representation of the relationship between sodium reabsorption and the renin-angiotensin-aldosterone system during three successive periods of postnatal development. The size of the nephron segments and of the arrows is intended to mirror functional as well as morphological changes (for details see text). to conserve sodium, manifested clinically by loss of weight and hyponatremia. Alternatively or concurrently, a partial unresponsiveness of the distal nephron to aldosterone may account for the sodium loss and the hyponatremia of prematurity. An increase in sodium reabsorption by the distal tubule from % to % of the amount delivered was observed between the first and the second week of life. This increase occurred concomitant with a rise in plasma aldosterone concentration and urinary aldosterone excretion from the already high values of nglml and p.g/day, respectively, to the exceedingly elevated levels of nglml and p.g/day [79]. Of note is the fact that even this degree of stimulation was insufficient to maintain the external sodium balance: Hyponatremia ensued in these infants by 3 weeks of age. Altogether, these observations allow us to postulate that the positive sodium balance implicit to growth and the tendency to retain sodium under conditions of sodium loading observed during infancy are consequent to the sequence of events portrayed in a diagrammatic fashion in Figure 4. The deposition of sodium, particularly in bones, creates a state of continuous stimulation for renin release. This, in turn, increases the amount of circulating angiotensin, which stimulates the production of aldosterone, thereby enhancing the tubular reabsorption of sodium. It is reasonable to assume that during a second period of extrauterine development, the rapid rise in GFR of the superficial nephrons [18], creates a tendency toward sodium loss. This could lead to the further stimulation of the reninangiotensin-aldosterone system observed to occur around 2 to 3 weeks of age [59, 79]. When the rise is insufficient or the distal tubule is unable to respond adequately to this stimulus, renal loss of sodium and hyponatremia ensue. During a third period of postnatal development, the absolute reabsorption of sodium in the proximal tubule and the intrinsic capacity for reabsorption of the distal tubule rise, resulting in a progressive diminution of the stimuli for renin release and consequently, in a decrease in aldosterone production. Acceptance of this hypothesis should not be construed to imply that other adaptive mechanisms whether hormonal, neural, or physical in nature, do not play a role in the maintenance of sodium homeostasis during development. Summary. Evidence is presented that the retention of sodium observed during development is consequent primarily to enhanced tubular reabsorption rather than to low rates of glomerular filtration. The enhanced transport of sodium occurs in nephron segments located beyond the proximal tubule, apparently under the stimulation of the high plasma concentration of aldosterone. This adaptive mechanism may account for the fact that the infant thrives on a rather low intake of sodium, as prevails during the period of breast-feeding. The renin-angiotensin-aldosterone system cannot be fully inhibited even by intravascular volume expansion and this may account for the blunted natriuretic response of the developing animal and human to the acute infusion of saline or albumin solutions. Conversely, the renal sodium loss and the hyponatremia often encountered in premature babies appear to be due to an insufficient rise in aldosterone secretion or to a limited responsiveness of the distal tubule to aldosterone stimulation. ADRIAN SPITZER Bronx, New York Acknowledgments This work was supported in part by the National Institutes of Health Research Grant AM25291 and the New York State Research Council Grant 118. The author would like to recognize Mrs. S. Berkower for her technical assistance and Mss. W. Brooks, V. Mimnaugh, and F. Maniscalco for their secretarial help. Reprint requests to Dr. A. Spitzer, Department of Pediatrics, Division of Nephrology, Albert Einstein College of Medicine, Bronx, New York 1461, USA References 1. MCCANCE RA, WIDDOWSON EM: The response of the newborn puppy to water, salt and food. J Physiol 141:81, GORDON HH, LEVINE SZ, MARPLES E, MCNAMARA H, BENJAMIN HR: Water exchange of premature infants. 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