Chapter 465. Development of Renal Function

In the perinatal period, kidney function, as it relates to fluid and electrolyte homeostasis in the premature and full-term neonate, is predominantly influenced by (1) anatomical kidney development at the time of birth, (2) physiologic adaptations that occur during the transition from intrauterine to extrauterine environment, and (3) diminished capacity of the newborn kidney to respond to increased fluid, electrolyte, or acid load. Their combined effects on renal function in the newborn infant are in indirect proportion to gestational age such that premature infants are most vulnerable to effects of anatomical immaturity, changes in renal blood flow, and limited functionality of hormonal regulatory mechanisms. Consequently, a clear understanding of changes in glomerular and tubular function and renal hemodynamics in the perinatal period is crucial for appropriate management of fluid and electrolyte problems in the sick neonate. In this chapter, general and specific aspects of renal function as they relate to the antenatal and postnatal periods are reviewed to provide a framework for evaluating renal function in the healthy and sick newborn infant. Diagnostic and therapeutic aspects regarding normal and abnormal renal function are discussed elsewhere.

Morphologic aspects of human kidney development are discussed in detail in Chapter 464. Here, attention is given to spatiotemporal relationships between anatomical and functional development of renal structures. Table 465-1 provides a summary of relationships between anatomical and functional kidney development.

Human kidney development begins at the fifth week of gestation (Fig. 465-1).1,2 The first functioning nephrons are formed by week 9 and excrete urine by week 12. By 32 to 34 weeks, nephrogenesis is completed, following which no new nephron units are formed.3,4 In humans who suffer fetal or perinatal renal injury, the developing kidney is incapable of compensating for irreversible nephron loss by either accelerating the rate of nephron formation ex utero in infants born prematurely, or by de novo generation of nephrons once nephrogenesis is completed.3,5

There is increasing evidence that the number of functioning nephrons formed at 32 to 34 weeks’ gestation may have important implications for short-term and long-term renal function. This concept is supported by the association of renal failure in humans with oligomeganephronia, a severe form of renal hypoplasia characterized by small kidneys and disproportionately reduced nephron number.6,7 Additional support is given by the demonstration of reduced glomerular number in humans with primary hypertension and chronic kidney disease.8,9 Quantitative analyses of glomerular number in humans and rodents using stereological methods of glomerular counting in renal autopsy or necropsy specimens have revealed a direct relationship between birth weight and glomerular number.10,11 The latter data are consistent with the Barker hypothesis, which proposes that adult disease has fetal origins and is based on epidemiological studies showing a correlation between birth weight and the incidence of cardiovascular disease.12,13

It is traditionally held that nephron number (and by extension, glomerular number) is a direct function of the number of ureteric bud or collecting duct branch generations, which iteratively induce new nephrons at their advancing tips throughout nephrogenesis.14,15 Consequently, ureteric bud branching morphogenesis (also termed renal branching morphogenesis16) is considered a critical determinant of nephron number.17 This concept is furthered by genetic evidence of inborn nephron deficits in genetic mutant mice exhibiting defective renal branching morphogenesis.18-20 Recently, several morphometric studies analyzing renal branching morphogenesis and nephron number during mouse kidney development have revealed variability in the branching patterns of ureteric bud segments and nephron induction, which may account for the broad range of glomerular counts quantified by stereological methods in human kidneys.10,11,21 In one study, nephron induction in developing mouse kidneys showed a 10-fold increase in nephron number during the final days of organogenesis when ureteric bud branching had increased only 2.7-fold, suggesting that the mathematical relationship between ureteric bud branching and nephron induction is not linear during gestation.22

Between the 22nd and 34th weeks of human fetal gestation,3 or gestation day 15.5 to postnatal day 7 in mice,14 the peripheral (ie, cortical) and central (ie, medullary) domains of the developing kidney are established. The specification of cortical and medullary domains is essential to eventual function of the mature collecting duct system. During embryonic life, the developing renal cortex and medulla exhibit distinct axes of growth. The renal cortex grows along a circumferential axis, resulting in a 10-fold increase in its volume while preserving relative spatial organization of developing structures within the expanding renal cortex.22 In this manner, differentiating glomeruli and tubules maintain their relative position in the renal cortex with respect to the external surface of the kidney, or renal capsule, throughout development and into postnatal life. The preservation of this spatial relationship between developing nephrons and the renal capsule appears to be crucial, as revealed by defective nephron development in mice that fail to form a renal capsule.23

In contrast to the circumferential pattern of growth exhibited by the developing renal cortex, the developing renal medulla expands 4.5-fold in thickness along a longitudinal axis perpendicular to the axis of cortical growth.22 This pattern of renal medulla growth is largely due to elongation of outer medullary collecting ducts.22 Longitudinal growth of the medulla contributes to lengthening of the loops of Henle such that all but a small percentage of the loops of Henle extend below the corticomedullary junction in full-term newborn infants.3 As the kidney increases in size postnatally, the loops of Henle further elongate and reach the inner two thirds of the renal medulla in the mature kidney. In the mature kidney, the loops of Henle contribute to the kidney’s urine-concentrating mechanism by generating an interstitial medullary tonicity gradient as a consequence of sodium and urea transport along its thick ascending limb (TAL) into surrounding interstitial tissue. Maintenance of this medullary interstitial tonicity gradient is functionally coupled to urine concentration by rendering a favorable environment for water reabsorption from collecting ducts. During kidney development, renal concentrating capacity is dependent on elongation of the loops of Henle, since the magnitude of sodium and urea transport along the proximal-distal length of the TAL is greatest in longer loops. Consequently, longer loops are more capable of generating steeper medullary tonicity gradients, which favors urine concentrating capacity. In the extremely premature fetus, the loops of Henle are short owing to the relative distance between the renal capsule and the renal papilla. Consequently, the urine concentrating capacity of the premature kidney is limited by generation of a shallow medullary tonicity gradient.

All parts of the developing nephron increase in size as they mature. However, the most striking changes exist in the proximal convoluted tubule, which shows increased tortuosity with maturation, and in the loop of Henle, which undergoes elongation.3Cellular maturation of the proximal tubule involves a transition from columnar to cuboidal epithelium and elaboration of apical and basal microvilli and a gradual increase in tubular diameter and length.24 The human kidney at birth shows marked heterogeneity in proximal tubule length from the outer cortex to the inner cortex.25 Uniformity in proximal tubule length is achieved by 1 month of life, and the proximal tube continues to lengthen at a uniform rate into early childhood. Increasing proximal tubule length during kidney development correlates strongly with increased absolute sodium reabsorption.26

Glomerulogenesis, which describes formation of the glomerular capillary tuft and differentiation of podocytes, mesangial cells, and glomerular capillary endothelial cells,27 is completed in humans by 32 to 34 weeks’ gestation with cessation of nephrogenesis. Subsequently, factors affecting maturation of the glomerular filtration barrier influence glomerular function in the newborn term and preterm infant. The glomerular filtration barrier is a physiologic module composed of fenestrated glomerular capillary endothelial cells, slit diaphragms that form between adjacent podocyte foot processes, and the glomerular basement membrane, which lies interposed between podocytes and glomerular capillary endothelium (reviewed in Kreidberg27 and Pavenstadt, Kriz, and Kretzler28). Studies in rats show that the glomerular basement membrane surface area increases 3.5-fold between birth and adulthood.29 In dogs, glomerular capillary cross-sectional area increases 8-fold during development between 3-week-old pups and adult dogs.25 In humans, glomerular diameter increases by 40% between birth and 18 years of age.25 These factors are likely to contribute to a maturational increase in glomerular filtration rate that occurs after birth.

Development of Renal Blood Flow

Classic studies of fetal renal hemodynamics in nonhuman species employing radiolabeled microsphere perfusion techniques have served as the foundation for our understanding of renal blood flow changes during human kidney development.30-33 In fetal lambs and primates, the kidney receives approximately 2.5% to 7% of combined ventricular output during the last trimester of gestation, whereas the newborn kidney subsequently receives 15% to 18% of total cardiac output after birth.33,34 Recent studies employing noninvasive Doppler echocardiography to estimate human fetal renal blood flow have confirmed animal data by showing that renal blood is 3% to 4% of total fetal cardiac output in newborn infants and increases to 12% to 16% in the first year of life.35,36 The mechanism responsible for the age-related increase in renal blood flow at birth is largely attributed to a postnatal drop in renal vascular resistance.37 To a lesser extent, increased cardiac output and renal perfusion pressure in the neonate may also contribute to increased renal blood flow during fetal to neonatal transition.38

Factors affecting the drop in renal vascular resistance include changes in intrarenal blood flow distribution during the transition from fetal to postnatal life. During fetal life, the relative distribution of intrarenal blood flow to glomeruli situated in the outer renal cortex is significantly lower when compared with juxtamedullary glomeruli located in more central regions of the cortex. Studies of intrarenal blood flow distribution in late fetal lambs have shown that 100% of juxtamedullary glomeruli situated in the inner regions of the renal cortex receive blood flow, whereas less than 25% of glomeruli located within the outer renal cortex are perfused.30 At birth, however, the proportion of perfused outer glomeruli abruptly increases to 77% and reaches 98% within 3 days. Similar changes in the characteristics of blood flow to inner and outer glomeruli have been observed in the newborn dogs (eFig. 465.1),39 although the time to achieve uniform perfusion throughout the renal cortex is longer (14 days). In contrast, longitudinal analysis of human intrarenal blood flow using noninvasive Doppler have indicated that most of the maturational changes in renal blood flow were related to changes in renal artery diameter and not redistribution of intrarenal blood flow, suggesting that mechanisms affecting changes in renal vascular resistance in the perinatal period may not be as conserved across mammalian species as previously believed.

Regulation of Fetal and Neonatal Renal Blood Flow

Increased neuroadrenergic system activity likely contributes to increased fetal and neonatal renal vasomotor tone. Immediately following birth in sheep and swine, renal sympathetic nerve activity is high and plasma epinephrine and norepinephrine levels rise severalfold.40,41 Higher levels of α1- and α2-adrenoreceptor expression in fetal sheep renal cortex may partly account for the increased sensitivity of fetal vessels to neuroadrenergic activation.42,43 Renal denervation in maturing piglets has been shown to increase renal blood flow,41 further demonstrating the importance of the nervous system in controlling renal vascular resistance. In addition, renal nerve stimulation has been shown to induce renal vasodilation exclusively in fetal lambs following α-adrenoreceptor blockade, and to a significantly lesser extent in newborn lambs.44 This vasodilatory effect may be prevented by selective β2-adrenoreceptor antagonists, providing evidence in mammals for an age-dependent, β2-neuroadrenergic-mediated renal vasodilatory mechanism. Studies in sheep have shown, however, that neither surgical nor pharmacological renal denervation is associated with significant changes in renal blood flow during fetal life,40,45 suggesting that additional mechanisms likely contribute to regulation of fetal renal vasomotor tone.

In addition to its importance in adult life for regulating systemic vascular resistance, the renin-angiotensin system appears to play an important role in regulating fetal renal blood flow. Plasma renin, angiotensin II, and angiotensin converting enzyme (ACE) levels are higher in the first 2 weeks of life than in adulthood.46-48 Expression studies of angiotensin receptors in fetal and newborn sheep kidneys reveal that angiotensin I receptors are upregulated during fetal maturation and are increased 2-fold above adult levels at 2 weeks of age in rats.47 Maturational changes in angiotensin receptor expression may explain the enhanced renal vasoconstrictor response to angiotensin II in newborn fetal sheep as compared to fetal sheep.49

In the early postnatal period, levels of endothelin-1 (Et1), a potent vasoconstrictor, are high in term and preterm newborns and are subsequently reduced after the first week of life.50 Similarly, increased levels of high-affinity Et1-binding sites have been described in 1-day-old rat kidney.51 Lower levels are detected at 30 days of postnatal life,51 suggesting that the vasoconstrictor effect of Et1 on renal blood flow becomes attenuated with advancing postnatal age. Further characterization of Et1 receptor subtypes in newborn rat kidneys from day 1 to day 30 revealed diminished binding capacity over time for Et1-A receptors, which mediate the vasoconstrictor effects of Et1.51 In contrast, the binding capacity of Et1-B receptors, which induce a nitric oxide–dependent vasodilatory response, remained constant over a similar time interval, suggesting that developmental regulation of Et1 receptor subtype expression may account for decreased Et1-mediated vasoconstriction in the newborn.52,53

Prostaglandins, which exert vasodilatory effects on renal blood flow,54 may be involved in counterbalancing vasoconstrictor effects of neuroadrenergic, angiotensin, or Et1-A receptor activation in the kidney during the transition from fetal to postnatal life. Newborns are shown to exhibit elevated circulating levels of prostaglandins and demonstrate high synthetic activity of renal prostaglandins with advancing gestational age.55 The role of prostaglandins in maintaining renal blood flow is suggested by the demonstration of a transient reduction in renal blood flow following administration of the prostaglandin synthetase inhibitor indomethacin to fetal and newborn animals.56,57 The importance of prostaglandins in preserving renal blood flow in humans is further underscored by the demonstration of severe renal impairment in fetuses and newborns following administration of prostaglandin synthesis inhibitors during pregnancy.58,59

Additional mechanisms that may promote the drop in renovascular resistance observed at birth include the kallikrein-kinin system, which generates bradykinin, a potent local vasodilator, through proteolytic cleavage of high molecular weight kininogen.60 Renal expression of kallikrein rises rapidly in the immediate postnatal period, and urinary excretion of kallikrein is shown to correlate closely with the rise in renal blood flow observed in the newborn period.61,62 The possibility that bradykinin promotes renal blood flow in the newborn kidney is suggested by the demonstration in newborn rabbits that bradykinin-2 receptor blockade induces renal vasoconstriction.63

Development of Glomerular Filtration Rate

Glomerular filtration refers to the formation of a plasma transudate across the glomerular filtration barrier, which ultimately produces urine. Glomerular filtration rate (GFR), the volume of plasma filtered by the kidney per unit of time, provides a measure of the kidney’s filtrative capacity. In clinical practice, GFR is considered the sum total GFR of all functioning nephrons in the kidney (individually referred to as single nephron GFR, or SNGFR). Consequently, during fetal development, the number of perfused, functioning nephrons is a critical determinant of GFR.

During human fetal development, onset of glomerular filtration corresponds with the initial demonstration of urine production at approximately 9 to 12 weeks of gestation.64 A progressive increase in fetal GFR is suggested by the gradual increase in fetal urine production from 5 mL per hour at 20 weeks’ gestation to 40 mL per hour at 40 weeks’ gestation.65 Indeed, measurement of GFR during fetal lamb gestation increases with body mass; however, when corrected for body mass, studies in fetal lambs show that GFR is constant throughout gestation and remains at 30% to 50% of adult values until birth.65 Glomerular filtration refers to the formation of a plasma transudate across the glomerular filtration barrier, which ultimately produces urine. Glomerular filtration rate (GFR), the volume of plasma filtered by the kidney per unit of time, provides a measure of the kidney’s filtrative capacity. In clinical practice, GFR is considered the sum total GFR of all functioning nephrons in the kidney (individually referred to as single nephron GFR, or SNGFR). Consequently, during fetal development, the number of perfused, functioning nephrons is a critical determinant of GFR.

At birth, GFR, whether expressed per unit of body weight or surface area, is low in mammalian species and correlates closely with gestational age.38,66 In humans, GFR as determined by creatinine clearance is approximately 4 to 8 mL/min/1.73 m2 in newborns of 28 weeks’ gestation and 12 to 40 mL/min/1.73 m2 in newborns born at 40 weeks’ gestation (Fig. 465-2).67,68 Immediately following birth, GFR as determined by creatinine clearance increases 2-fold to 3-fold in term infants in the first months of life.66,69 The sharp postnatal rise in GFR is largely attributed to increased mean arterial blood pressure, increased renal blood flow, and redistribution of intrarenal blood flow32,35,70 (eTable 465.1).

Single nephron GFR (SNGFR) is influenced by hydrostatic and oncotic pressure gradients across the glomerular filtration barrier. Newborn rats exhibit a low glomerular capillary hydrostatic pressure, which results in a lower hydrostatic pressure gradient across the glomerular filtration barrier.71,72 In the adult, changes in glomerular hydrostatic pressure rarely play a significant role in alteration of SNGFR because autoregulatory mechanisms sustain intraglomerular hydrostatic pressure during periods of mild to moderate systemic hypotension.73 In contrast, SNGFR in the neonate is more sensitive to changes in systemic blood pressure than in the adult, since newborn rats exhibit systemic blood pressure that is below the threshold for autoregulation.71,72 This is evident in premature infants who exhibit lower creatinine clearance rates and lower systemic blood pressures than infants born at term.74,75 Similarly, SNGFR in newborn infants is likely to be affected by lower plasma protein concentrations as measured in neonates, which ultimately results in a reduced oncotic pressure gradient across the glomerular filtration barrier. In addition to net effects of hydrostatic and oncotic pressure on filtration, SNGFR is influenced by glomerular filtration barrier surface area and the hydraulic permeability of the glomerular capillary. Although glomerular capillary hydraulic water permeability does not change significantly after birth, glomerular filtration barrier surface area increases significantly in the first year of life as glomeruli undergo hypertrophy.29 Since hypertrophy is the main process for continued glomerular development following cessation of nephrogenesis, glomerular hypertrophy likely plays an important role in GFR maturation in term infants who have completed kidney development and enter postnatal life with their full complement of glomeruli. In contrast, the overall effect of glomerular hypertrophy on GFR maturation is less crucial in extremely preterm neonates, who continue to form new glomeruli ex utero until 34 weeks’ gestation, since the principal determinant of postnatal GFR in these infants is the number of functionally capable glomeruli. As a result, the rate of rise in creatinine clearance is frequently lower in preterm infants than in term newborns over similar postnatal time intervals.76

Assessment of fetal glomerular function is possible by simultaneous measurement of fetal serum cystatin C and β2-microglobulin. In a series of 54 fetuses without evidence of kidney disease, fetal serum cystatin C was shown to be independent of gestational age and had a higher specificity (92%) than β2-microglobulin (86%) for predicting postnatal kidney dysfunction.77 In contrast, β2-microglobulin levels decreased with advanced gestational age and demonstrated a higher sensitivity than cystatin C (90% vs 64% respectively) for predicting renal dysfunction. The combined use of these tests may be useful for antenatal evaluation of renal function; however, further studies are required to validate use of these tests for evaluating renal function in fetuses diagnosed antenatally with evidence of renal disease.

Within the first 48 hours of life, plasma creatinine concentration reflects maternal rather than newborn concentrations.68 By 7 days of age, plasma creatinine in term neonates is normally less than 45 µmol/L (0.5 mg/dL).78 In preterm neonates, levels can be, on average, as high as 50 to 60 µmol/L throughout the first month of life78 (Table 465-2). A progressive rise in serum creatinine over time in the neonate suggests a reduction in GFR regardless of gestational age.

Fetal Water Homeostasis

Water conservation is one of the most important functions of the mature mammalian kidney.79 For the developing fetus, regulation of water balance is crucial because total body water may account for up to 70% to 90% of total body mass.79 During gestation, the placenta, not the fetal kidney, serves as the principal regulator of fetal fluid homeostasis.80 Within the conceptus, which includes the developing fetus, fetal membranes, and the amniotic sac, water circulates among several compartments, including the fetal vascular and extravascular spaces, and amniotic fluid.81,82 Amniotic fluid volumes change dramatically during human pregnancy, with mean values increasing progressively from 20 mL at 10 weeks gestation to 630 mL at 22 weeks, reaching a plateau around 770 mL at 28 to 39 weeks (eFig. 465.2).83 During the latter half of gestation, the primary source of amniotic fluid is fetal urine production, although secretion of fluid generated by the fetal lung may account for up to 25% of amniotic fluid production in the term infant.83 In contrast, major routes of fluid reabsorption include fetal swallowing (approximately 500–1000 mL/day) and intramembranous flow of fluid across the fetal amniotic membranes into the fetal circulation (approximately 200–500 mL/day).83 Minor routes of fluid absorption may include transmembranous flow (from amniotic fluid cavity to maternal circulation), which has been measured in sheep to account for less than 0.6% of amniotic fluid efflux.84 Abnormalities of conceptus water flow can significantly impact neonatal morbidity and mortality as a consequence of decreased amniotic fluid volume, or oligohydramnios, when net water loss occurs, or increased amniotic fluid volume, or polyhydramnios, when net water gain is evident.85,86

Neonatal Water Homeostasis

For the developing fetus, regulation of water balance is crucial because total body water may account for up to 70% to 90% of total body mass.79 During gestation, the placenta, not the fetal kidney, serves as the principal regulator of fetal fluid homeostasis.80 Similar to the adult scenario, water homeostasis in the term and premature newborn is determined by factors affecting water intake and output (Table 465-3). In the critical care setting, fluid intake from intravenous solutions, total parenteral nutrition, infusions, and medications can comprise a substantial fraction of total fluid intake and must be considered in the context of the sick newborn’s capacity to excrete water. Factors affecting insensible fluid loss in the preterm and term infant include gestational age, ambient temperature, ambient humidity, and air circulation. Figure 465-3 illustrates the inverse relationship between gestational age and transdermal water loss,87 signifying that the principle determinant of water balance in the first days of life for extremely premature infants (ie, ⩽ 30 weeks) is the magnitude of insensible fluid losses.

The first days of life are characterized by a physiological state of negative water balance with significant changes in body compartment water content (see Table 465-4).79,88 Water loss is reflected by a 1% to 2% loss in total body weight per day over the first 5 days of life in newborn term infants89 and is greater and more sustained in premature infants.90 Volume contraction during this phase is isotonic and originates from the extracellular fluid compartment without compromising plasma volume.79,91 Atrial natriuretic peptide has been implicated in the immediate postnatal diuresis observed in term as well as preterm infants, although the precise mechanisms of isotonic volume contraction during this period are not clearly understood.92

The renal control of water balance is not fully developed at birth.93 Although full-term and preterm neonates can respond to hypotonic fluid challenge by appropriately producing hypotonic urine, newborns are at risk of fluid overload with hyponatremia in the immediate postnatal period as a consequence of delayed excretion of free water due to low GFR at birth.93 Moreover, the concentrating capacity of the newborn kidney is limited. In the first weeks of life, maximum urine concentrations achieved by preterm and term infants following fluid restriction are 600 mOsm/kg and 800 mOsm/kg respectively94; adult levels (1200 mOsm/kg) are not reached until 6 to 12 months of age95 (eFig. 465.3). The ability of the newborn kidney to concentrate urine is highly dependent on development of the loops of Henle. In the mature kidney, the loops of Henle originate in the renal cortex at their junction with the distal end of the proximal convoluted tubule, project deep into the renal medulla, and loop back to the cortex to join the proximal end of the distal convoluted tubule. By exploiting differential permeabilities to water and solute in its descending and ascending limbs, respectively, the loop of Henle of the fully developed kidney transports sodium and urea out of its thick ascending limb (TAL) and into the surrounding interstitium, which generates an interstitial medullary tonicity gradient for favorable reabsorption of urinary water in the collecting duct.96 The relationship between the length of the loops of Henle and the magnitude of the interstitial tonicity gradient is such that long loops generate a steeper gradient.97,98 Consequently, it is generally held that maturation of urine concentrating ability is functionally coupled to elongation of the loops of Henle that occurs during postnatal kidney growth. In addition, lower rates of sodium and urea delivery and uptake have been described in the TAL of newborn infants68,99-102 (eTable 465.2).

The response of collecting duct cells in the newborn kidney to antidiuretic hormone (ADH, or arginine vasopressin) is an important determinant of urine concentration in the postnatal period. ADH plays a pivotal role in maintaining water balance in the adult by inducing expression of the water channel, aquaporin-2 (AQP-2), on collecting duct cells via a cyclic adenosine monophosphate (cAMP)-dependent signaling mechanism.103,104 Despite adequate ability to secrete ADH in response to diverse stimuli, including prolonged dehydration in rats105,106 and perfusion of hypertonic saline in sheep,107 no correlation is evident between ADH levels and urine osmolality in the first weeks of life.108 Accordingly, several studies have suggested that reduced urine-concentrating capacity in the newborn may be due to relative resistance of the immature kidney to ADH.109,110 The mechanism for ADH resistance is believed to be caused by local prostaglandin production, which exerts a direct antagonistic effect on cAMP generation in the neonatal period.111 Accordingly, AQP-2 expression in rat collecting duct cells is shown to be lower during early postnatal life and reaches maximal expression at 10 weeks of age, which is consistent with a progressive increase in ADH responsiveness that occurs postnatally.103,112 Interestingly, the failure to demonstrate an increase in urine osmolality in immature rats despite an increase in AQP-2 expression following water deprivation suggests that AQP-2 expression is not a limiting step in the development of urine concentrating ability.103

In addition to water intake and renal concentrating capacity, the rate of renal water excretion in both newborns and adults is determined by the solute load to be excreted. Renal solute load refers to all particles of dietary (predominantly protein and electrolytes) and endogenous origin not somatically incorporated for growth, which require excretion by the kidney.113 The kidney achieves net zero solute balance by excreting solute in excess of what is required for growth. In contrast, in the setting of acute renal failure, positive solute balance is the consequence of failure to excrete renal solutes.

With solute excretion, there is obligatory water loss, and the magnitude of water loss is dependent on the kidney’s concentrating capacity. For preterm and term infants, the ability to excrete water and solute is limited by the maximum concentrating capacity of the immature kidney. The impact of reduced renal concentrating on the ability to excrete renal solute is provided by the following example. A breast milk–fed term neonate receiving a diet of 8 to 16 mOsm/kg/day with a maximal renal concentrating capacity of 600 mOsm/kg would require a minimum urine volume of 0.5 to 1.1 cc/kg/h to excrete that solute load and maintain solute balance. If urine flow were to drop below 0.5 to 1 cc/h without a change in solute load, the result would be a net gain of solute, or positive solute balance. Thus, a urine flow rate of less than 1 cc/kg/h is generally accepted as the definition of acute renal failure in the newborn period, since values below this level are likely to result in progressively positive solute balance. In contrast, a premature infant with a maximal renal concentrating capacity of 400 mOsm/kg would require a minimum urine volume of 0.8 to 1.7 cc/kg/h to excrete the same solute load. Consequently, the generally accepted definition of acute renal failure as urine flow rate less than 1 cc/kg/h may result in underdiagnosis of renal dysfunction in premature infants who have higher obligate urinary water losses.

Sodium Balance in the Newborn Period

Sodium chloride balance is normally maintained by renal sodium reabsorption and excretion over a broad range of intakes. Newborn infants, however, are limited in conserving sodium when challenged by sodium restriction and exhibit a diminished capacity to excrete excess sodium when faced with a sodium load.114 In the first week of life, fractional excretion of sodium, expressed as the percentage of filtered sodium excreted in the urine, is high and inversely proportional to gestational age (eFig. 465.4).115 This natriuretic state provides for the isotonic extracellular volume contraction observed in newborns and is considered physiologic. Consequently, human newborn infants are in a state of negative sodium balance for the first days of life. A reduction in fractional excretion of sodium subsequently occurs by the second and third weeks of life, contributing to a positive sodium balance that is essential for growth.116,117 Factors contributing to the transition from increased to decreased fractional sodium excretion include maturation of sodium transport mechanisms in the postnatal nephron; elevated circulating levels of catecholamines, glucocorticoids, and angiotensin II; and diminishing levels of atrial natriuretic peptide. These factors are discussed individually in the next sections.

Maturation of Sodium Transport Mechanisms

During fetal and postnatal kidney development, there is progressive maturation of each nephron segment involved in sodium transport, which include the proximal convoluted tubule, the descending and ascending limbs of the loop of Henle, and the distal convoluted tubule118,119 (eFig. 465.5). To appreciate the effects of maturation on sodium transport in the neonatal kidney, mechanisms that govern sodium reabsorption in each segment of the mature nephron are briefly reviewed and contrasted with sodium reabsorption in corresponding segments of the immature nephron.

Development of Proximal Tubule Sodium Reabsorption

The mature proximal tubule reabsorbs approximately two thirds of filtered sodium by several different mechanisms.119 Proximal tubule sodium reabsorption occurs predominantly via sodium-dependent organic solute transporters that reclaim filtered glucose, amino acids, or phosphate. Basolateral Na+,K+-ATPase activity provides a gradient for sodium ion (Na+) entry into the proximal tubule epithelial cell by these transport mechanisms. The reabsorption of positively charged sodium ions in this context generates a lumen-negative transepithelial potential difference, which provides a driving force for passive paracellular chloride transport. In the late proximal tubule, sodium chloride (NaCl) transport is coupled to hydrogen ion (H+) secretion by operation of the Na+/H+ exchanger (NHE3).

In the newborn kidney, sodium reabsorption is mitigated by decreased expression levels of all solute transporters, Na+,K+-ATPase, and NHE3.120-123 In addition, passive paracellular reabsorption of sodium chloride is significantly impaired in the newborn kidney because the neonatal proximal tubule is impermeable to chloride.124 Studies of sodium flux in isolated rabbit proximal tubules reveal that sodium transport is one third of adult levels at 2 weeks of postnatal age and increases to adult levels by 6 weeks.125 Consequently, age-related differences in tubular reabsorptive capacity seem to account for higher urinary concentrations of glucose and amino acids in premature and term infants.126,127 Glucocorticoids appear to play an important role in promoting the drop in fractional sodium excretion that occurs after birth by inducing Na+,K+-ATPase and NHE3 expression in the developing proximal tubule.120,128-130 Thyroid hormone may also play a role in tubular maturation because the increase in paracellular chloride permeability observed after birth is prevented in hypothyroid rabbits but is restored following treatment with thyroid hormone.131

Sodium Transport in the Developing Loop of Henle

Sodium chloride reabsorption in the loop of Henle occurs via both active transcellular and passive paracellular pathways. Active transcellular sodium uptake occurs via the luminal Na+-K+-2Cl– cotransporter (NKCC2) and NHE3 in the TAL.132,133 Basolateral Na+,K+-ATPase generates the driving force for sodium chloride uptake by extruding Na+ across the TAL basolateral membrane.134 Na+ is also absorbed via the paracellular pathway due to the lumen-positive voltage caused by recycling of potassium ions (K+) via renal outer medullary potassium (ROMK) channels into the TAL lumen.135

In vitro studies of perfused isolated TAL from newborn animals indicate diminished sodium transport in this segment in the neonate.136 This observation is attributed to low expression levels for NKCC2, NHE3, ROMK, and Na+,K+-ATPase in neonatal kidneys.100,137-140 The spatial pattern of distributions of NKCC2, NHE3, ROMK, and Na+,K+-ATPase become more broadly expanded within the TAL over the first 2 to 3 weeks of postnatal life in rats.140 During this interval, increased transporter expression correlates with increased urine-concentrating capacity over the same interval.140 Administration of dexamethasone to rats immediately after birth was shown to induce sodium transporter expression and increase medullary tonicity,140 suggesting an additional role for circulating levels of glucocorticoids in the perinatal period in development of the urine-concentrating mechanism.

Development of Sodium Transport in the Distal Convoluted Tubule and Cortical Collecting Duct

The distal convoluted tubule and cortical collecting duct are considered sites that provide fine-tuning of sodium reabsorption. Sodium is reabsorbed in the mature distal convoluted tubule predominantly via the thiazide-sensitive sodium chloride cotransporter (NCCT).141 In the cortical collecting duct, sodium is reabsorbed through epithelial sodium channels (ENaC) that reside in principal cells.142 The consequence of sodium transport in these 2 segments generates a negative luminal voltage, which promotes collecting duct cell potassium and H+ secretion via ROMK and H+-ATPase, respectively.142,143

As is the case with all sodium transporters in the developing nephron, NCCT and ENaC expression is low in the neonatal kidney and increases in the postnatal period.139,144 Sodium reabsorptive capacity of the cortical collecting duct increases immediately after birth and reflects increased expression of ENaC as well as Na+,K+-ATPase.145 Endogenous glucocorticoids do not appear to have any effect on maturation of ENaC in the developing kidney.146

Endocrine Regulation of Sodium Homeostasis in the Perinatal Period

The renin-angiotensin system is highly activated in the newborn period.147 High plasma renin activity and aldosterone secretion rates in full-term neonates are thought to promote positive sodium balance following immediate postnatal physiologic natriuresis by increasing sodium reabsorption within the first weeks of life.148 In premature infants, plasma renin levels rise in the first week postdelivery, yet aldosterone levels do not demonstrate a parallel rise as expected.148 It is thought that the failed rise in aldosterone may occur as a result of unresponsiveness of the adrenal gland to angiotensin II or diminished adrenal capacity to synthesize aldosterone. Consequently, mild to moderate salt wasting, elevated serum K+, and hyponatremia may occur in premature infants within the first 2 to 3 weeks of life, reflecting a negative sodium balance during this time interval.149 This clinical scenario must be distinguished from more severe salt wasting, hyponatremia, and hyperkalemia as observed in infants with inherited forms of pseudohypoaldosteronism, which are caused by gene mutations encoding for the mineralocorticoid receptor, MLR,150 or ENaC151 respectively.

Atrial natriuretic peptide (ANP) is produced within cardiac myocytes in response to atrial stretch and activates receptors located within the developing kidney in the glomerulus, distal convoluted tubule, and cortical and medullary segments of the collecting duct as well as in vasa recta bundles and arcuate renal arteries.152,153 ANP induces natriuresis through inhibition of sodium channels via a cyclic guanosine monophosphate (GMP)-dependent signaling mechanism.154 Expanded extracellular volume and increased pulmonary venous return are major stimuli for ANP release in the immediate postnatal period, which is thought to contribute to physiologic natriuresis at that time point.92 ANP levels subsequently fall in response to incipient extracellular volume contraction.155 Studies comparing the physiologic response to ANP administration in newborn and adult rabbits reveal that ANP exerts a diminished natriuretic effect in newborn animals.156 Reduced tissue responsiveness to ANP in the newborn may be due to lower levels of cyclic guanosine monophosphate (cGMP) production as demonstrated in isolated newborn glomeruli exposed to ANP falls during the first week of life.157

Neuroadrenergic Control of Sodium Homeostasis in the Perinatal Period

The role of renal sympathetic nerve activity in sodium reabsorption during the perinatal period is suggested by studies in fetal and newborn sheep which demonstrate that direct renal nerve stimulation decreases sodium excretion.45 Conversely, renal denervation prior to birth increases sodium excretion in the immediate postnatal period; however, the decrease is small and present only for the first 24 hours of life.41 In vitro data suggest that proximal tubules may respond to α1-B-adrenoreceptor activation by inducing NHE3 and Na+,K+-ATPase activities.158-160 Expression of α1-B-adrenoreceptors is greatest in near-term fetuses and in the immediate postnatal period, and it declines later in life,161 suggesting that direct regulation of sodium reabsorption by sympathetic nerve activity becomes attenuated with maturation.

Dopamine is known to induce a natriuretic response in adult animals through a cAMP-dependent mechanism that may involve inhibition of Na+,K+-ATPase or NHE3 activities.162,163 The renal natriuretic response to dopamine is decreased, however, in immature animals.164 In fact, dopamine receptor activation in preterm infants results in sodium reabsorption yet causes sodium excretion in adults.164,165 It is thought that the age-related response to dopamine is independent of dopamine receptor density or binding affinity but dependent on coupling cAMP downstream signaling events with changes in Na+,K+-ATPase or NHE3 activity.162,166

Potassium Balance in the Newborn Infant

Infants require a positive potassium balance for somatic growth.167 During fetal life, K+ is actively transported across the placenta into the fetus, and fetal K+ concentrations are maintained at levels exceeding 5 mEq/L even in the face of maternal K+ deficiency.168,169 Newborns tend to have higher serum K+ values than older children,170 reflecting the need to retain K+ during this period. Plasma K+ levels drop rapidly from 6.4 ± 0.4 mEq/L on the first day of life to 5.2 ± 0.3 mEq/L on day 5 in term infants, and plasma K+ is subsequently regulated within a narrow range thereafter as in adults.171 Thirty to fifty percent of very-low-birth-weight infants, in the absence of K+ intake, will exhibit plasma K+ greater than 6.5 mEq/L in the first 2 days of life, which usually returns to the normal range after 72 hours.172 The postnatal course of plasma K+ levels differs in preterm and term infants. Plasma K+ increases to a maximum level during or after the third week of life in preterm infants.173 Possible explanations for this difference in plasma K+ measurement include immaturity of Na+,K+-ATPase and limited renal capacity to excrete potassium.170

In newborns, renal K+ clearance is low, even when corrected for low GFR.167 Under circumstances of normal K+ intake, the overall tendency of the immature kidney to retain potassium is a physiologically appropriate response essential for growth. However, the limited capacity of the immature kidney to excrete potassium is clinically relevant in conditions of excess dietary K+ intake or increased release of K+ from intracellular stores.170

Maturation of Potassium Transport in the Developing Nephron

Physiologic studies in both infant and adult animals show that 65% to 75% of filtered potassium is passively reabsorbed by the proximal tubule.174 The remainder of K+ reabsorption occurs in the TAL via NKCC2.175 A small amount is reabsorbed in the distal tubule and cortical collecting duct via a H+/K+-ATPase exchanger (eFig. 465.6).176Urinary K+ excretion is achieved predominantly by secretion of K+ in the cortical collecting duct via apical ROMK K+ channels.177,178 Under basal conditions, cortical collecting duct K+ secretion is dependent on high intracellular K+ concentrations, low urinary K+ concentrations, and a lumen-negative electrochemical gradient generated in parallel by Na+ reabsorption and basolateral Na+,K+-ATPase activity, which favor ROMK-mediated K+ movement into the urinary space.170

In neonates, K+ excretion is significantly lower than in adults due, in part, to the low secretory capacity of the neonatal cortical collecting duct. Studies comparing K+ secretion in adult and neonatal isolated cortical collecting duct cultures reveal no significant net K+ secretion in neonatal collecting ducts until after the third week of postnatal life.179 K+ secretion rates in these studies did not approach adult levels until 6 weeks of age.179 The postnatal increase in collecting duct K+ secretory capacity is believed to be due to a developmental increase in the number of ROMK channels.180,181 Molecular analyses of ROMK expression in newborn rats demonstrate increasing ROMK mRNA and protein levels in the second week of postnatal life, which coincides with an increase in K+ secretion over the same time frame.180

Factors Affecting Potassium Transport in the Developing Nephron

Potassium excretion in the mature cortical collecting duct is strongly influenced by an increase in urine flow rate.170 High flow rates result in low tubular K+ concentrations as secreted K+ is rapidly diluted in fast-flowing urine, whereas low tubular flow rates result in higher luminal K+ concentrations, which oppose the electrochemical gradient for K+ secretion. Recent evidence suggests that the effect of tubular flow may be mediated by high-conductance K+ channels, termed maxi-K channels, which facilitate K+ secretion in response to luminal stretch via a Ca2+-activated mechanism.182 Expression of maxi-K channel mRNA and protein are not detected until the fourth week of postnatal life,182 suggesting that the neonatal kidney is incapable of regulating K+ secretion in response to changes in urine flow. These data are consistent with the observation in cultured collecting ducts that increased urine flow does not elicit an increase in K+ secretion until the fifth week of postnatal life.183

In mature kidneys, mineralocorticoid activity plays a significant role in regulating potassium balance by stimulating K+ secretion in the cortical collecting duct.184 Consequently, the diminished response of the immature kidney to aldosterone, as discussed in the section “Endocrine Regulation of Sodium Homeostasis in the Perinatal Period,” may be a limiting factor for mineralocorticoid activity in regulating neonatal potassium homeostasis.

Acid-Base Balance in the Newborn Period

The newborn infant generates acid during somatic growth through protein metabolism and formation of hydroxyapatite during bone mineralization.185 Approximately 2 to 3 mEq of acid in the form of H+ per kilogram body weight per day must be excreted to avoid acidosis.185 Despite the need for healthy newborns to maintain acid-base homeostasis, mechanisms of urinary acidification and bicarbonate generation are still quite immature at birth. Consequently, the newborn infant, and particularly the premature infant, are at risk of acidosis when challenged with an increased acid load.

The newborn infant generates acid during somatic growth through protein metabolism and formation of hydroxyapatite during bone mineralization.185 Approximately 2 to 3 mEq of acid in the form of H+ per kilogram body weight per day must be excreted to avoid acidosis.185 Despite the need for healthy newborns to maintain acid-base homeostasis, mechanisms of urinary acidification and bicarbonate generation are still quite immature at birth. Consequently, the newborn infant, and particularly the premature infant, are at risk of acidosis when challenged with an increased acid load.

Normal plasma bicarbonate concentration in the term newborn is estimated at a mean value of 20 ± 2 mmol/L and may be lower in preterm and low birth weight infants186 (eTable 465.3). In fact, plasma bicarbonate levels have been recorded as low as 14.5 mmol/L in low-birth-weight human infants without negatively affecting mean weight gain over the first 3 weeks of life.186 There is a steady rise in postnatal development of renal acidifying processes, as demonstrated in humans by a progressive increase in net acid excretion by the third week of postnatal life.187 Plasma bicarbonate concentration subsequently increases within the first 3 weeks of life to approximately 22 ± 2 mmol/L and remains stable thereafter. Recognition that low-birth-weight and premature infants may demonstrate physiological low levels of plasma bicarbonate is crucial to avoid misdiagnosis and inappropriate treatment of metabolic acidosis in the newborn period.

Development of Renal Mechanisms of Acid-Base Regulation

Renal acid-base regulation is achieved through reabsorption of filtered bicarbonate and secretion of H+. To achieve high rates of H+ excretion, secreted H+ is buffered by urinary ammonia (NH3), sulfate, and phosphate. Appreciating the effects of tubular maturation on acid-base balance first requires an understanding of mechanisms of bicarbonate reabsorption, H+ secretion, and urinary buffering in the mature proximal tubule, loop of Henle, and cortical collecting duct (eFig. 465.7). These mechanisms are briefly reviewed in the following paragraphs.

In the mature kidney, the proximal tubule contributes to acid-base homeostasis via 2 mechanisms: bicarbonate reabsorption and ammonia generation. The mature proximal tubule is responsible for reabsorbing 80% of filtered bicarbonate through the combined actions of NHE3 and H+-ATPase, which secrete H+ into the tubular lumen, and carbonic anhydrase, which catalyzes the ultimate conversion of secreted H+ and filtered bicarbonate (HCO3) into carbon dioxide (CO2) and water.125,188 Ammoniagenesis in the proximal tubule results in generation of NH3 through the action of glutaminase, which catalyzes glutamine deamination.189 NH3 is subsequently secreted into the proximal tubule lumen where it combines with H+ to generate ammonium (NH4+). Intraluminal H+ buffering by NH3 in the proximal tubule maintains a favorable gradient for H+ secretion in that segment.

The mature TAL reabsorbs approximately 15% of filtered bicarbonate in a mechanism that involves NHE3 and NKCC2.190 In addition, the TAL reclaims NH3 by dissociation of NH4+ and H+.191 NH3 reabsorption in the TAL results in the generation of a medullary concentration gradient for NH3 that promotes NH3 secretion into the collecting duct, where it plays a pivotal role in urinary acidification.192-194 Distal urinary acidification in the collecting duct occurs primarily by secretion of H+ by α-intercalated cells via apical vacuolar H+-ATPase. Intraluminal buffering of H+ by NH3 and filtered sulfate and phosphate maintains a favorable gradient for H+ secretion in the collecting duct.185

Several factors limit the newborn kidney’s capacity to reabsorb bicarbonate, secrete acid, or respond to an acid load (eTable 465.4). Lower NHE3 and Na+,K+-ATPase activities are thought to account for the reduced capacity for bicarbonate reabsorption in the newborn proximal tubule.125 Adrenalectomy prevents the maturational increase in NHE3 at both the protein and mRNA levels, suggesting that glucocorticoids may be responsible for the postnatal maturational increase in NHE3 activity.195 Likewise, reduced activity of carbonic anhydrase expressed on the proximal tubule brush border is believed to cause lower thresholds for bicarbonate reabsorption in the newborn period.196,197 The renal threshold for bicarbonate increases with advancing maturation.198 Small premature infants may excrete some bicarbonate in the urine, whereas full-term infants excrete virtually no bicarbonate at these concentrations.198 Back diffusion of bicarbonate from the bloodstream into the immature tubular lumen is not believed to contribute to lower bicarbonate reabsorption in developing proximal tubules.199

Microperfusion studies of neonatal rabbits reveal a diminished capacity of the newborn collecting duct to secrete acid when compared to corresponding segments in adult controls.200 This may be explained by the finding that the rate of ammonia synthesis is lower in neonates than in adults.201 The observation that glutaminase activity is lower in the newborn kidney renders the neonate less capable of defending against an acid load by increasing the rate of ammonia production.201 In addition, the immature kidney reabsorbs NH3 in the TAL less efficiently due to decreased expression and functional activity of NKCC2.202,203 Consequently, the buffering capacity of NH3 in the collecting duct is lower in the neonatal kidney owing to a shallow medullary concentration gradient for NH3 secretion.

Calcium Homeostasis and Transport in the Developing Kidney

In order to meet the demands for bone growth and mineralization during fetal life, the fetus maintains higher serum calcium levels than maternal levels.204 Higher fetal than maternal calcium levels are achieved by active transport of calcium across the placenta.205 Whereas in adult animals, parathyroid hormone (PTH), 1,25-hydroxyvitamin D (1,25-VitD), and calcitonin play crucial roles in regulating calcium homeostasis, corresponding maternal hormones do not cross the placenta to play a role in fetal calcium homeostasis.204 In fact, high fetal serum calcium levels suppress fetal PTH release.206 Animal data suggest that PTH-related peptide (PTHrP) produced by the fetal parathyroid may be responsible for regulating calcium uptake into the fetus.206

After birth, serum calcium in the newborn becomes dependent on nutritional sources and may be reflected by a relative decline in serum calcium over the first 24 hours of life.207 Accordingly, in response to decreasing serum calcium levels in the newborn period, PTH secretion is stimulated after birth. Term infants typically achieve normal serum calcium levels during the second week of life, although the degree to which the neonatal parathyroid responds to low serum calcium is dependent on gestational age.208 Preterm infants may exhibit transient hypocalcemia during the first week of life, reflecting relative immaturity of the parathyroid to raise serum calcium by releasing PTH.209 Newborn stores of vitamin D are usually adequate unless there is significant maternal dietary inadequacy.204 Levels of 25-hydroxyvitamin D, which is synthesized in the liver and converted to active 1,25-dihydroxyvitamin D in the kidney, correlate with gestational age and are lower in premature infants; however, the premature kidney is shown to be capable of generating active vitamin D through 1-hydroxylation.210

Under normal circumstances, nearly all (98%) of filtered calcium is reabsorbed in the mature nephron.211 Most filtered calcium is reabsorbed by the mature proximal tubule and loop of Henle by paracellular mechanisms.212 The mature distal tubule and connecting tubule reabsorb calcium in response to PTH and 1,25-VitD, which have individually been shown to induce expression of epithelial calcium transporters.213,214 In addition, PTH is known to stimulate a rapid increase in Ca2+ reabsorption via a cAMP-dependent pathway.215

In newborns, the amount of calcium excreted in the urine increases over the first 2 weeks of life.216 It is unclear, though, whether the effect on calcium excretion is regulated or occurs in response to the postnatal increase in GFR.67 The preterm and newborn kidney are capable of responding to exogenous PTH, as revealed by increased production of renal cAMP, which intensifies with advanced postnatal age.217,218 Animal studies have shown that expression of luminal calcium channels TRPV5 and TRPV6 are expressed in fetal mouse kidneys shortly before birth.219 Analysis of their individual expression patterns reveals that TRPV5 and TRPV6 are unlikely to fulfill redundant roles. TRPV6 levels reach maximum expression at 1 week of life in newborn mice and subsequently decrease to 10% of TRPV5 levels. In contrast, TRPV5 expression levels increase and reach a maximum at the third week of life, following which a reduction in TRPV5 expression is detected and remains constant into adulthood. These expression data suggest that the newborn kidney may be acutely sensitive to calcium early in life in order to maintain positive calcium balance during periods of rapid growth. Conversely, the strong tendency of the newborn kidney to reabsorb calcium may heighten the risk for renal parenchymal calcium deposition (termed nephrocalcinosis) with loop diuretic use.

Phosphate Transport in the Developing Kidney

Total body phosphorus increases from approximately 0.16 moles per kilogram in the newborn to 0.36 moles per kilogram in the adult, reflecting a net positive balance of phosphorus during childhood.220 The attainment of a net positive balance is dependent on dietary phosphorus intake, intestinal absorption, and the ability of the kidneys to reclaim filtered inorganic phosphate. In contrast to most other transport processes in the immature kidney, fractional reabsorption of phosphate is greater in the developing or neonatal kidney (approximately 99% reabsorbed) than in the adult kidney (approximately 80% reabsorbed).221,222It is worth noting that enhanced tubular reabsorption of phosphate occurs in immature animals despite that serum phosphate levels are higher in newborn animals than in adults.220

The majority of filtered phosphate is reabsorbed in the mature proximal tubule by type II sodium-dependent phosphate cotransporters (SLC34), of which there are two isoforms: SLC34A1 or NaPi-IIa, and SLC34A3 or NaPi-IIc.223 A third isoform, SLC34A2 or NaPi-IIb, functions as a phosphate transporter in nonrenal cells.223 The NaPi-IIc isoform predominates in the neonatal period, and mutations in the corresponding gene, SLC34A3, have been identified as the cause of autosomal recessive hypophosphatemic rickets.224 As the proximal tubule matures, NaPi-IIa becomes the predominant isoform.225

Several factors appear to influence the relatively higher rates of phosphate reabsorption that are observed in the newborn kidney. Evidence suggests that the capacity for phosphate uptake is higher in newborn proximal tubules than in adults. In vitro studies analyzing phosphate transport in proximal tubule brush border vesicles have shown that the number of NaPi transporters is 4-fold higher in vesicles from newborn guinea pig kidneys than in vesicles from adult kidneys.226 Growth hormone may play a role in upregulating NaPi-II activity in the developing kidney, as revealed by the reduced tubular phosphate transport in mice treated with a growth hormone–releasing factor antagonist227 and by the partial restoration of phosphate transport following growth hormone administration in mice for which the gene encoding growth hormone had been genetically mutated.228 Notwithstanding its high capacity for phosphate reabsorption, the newborn kidney appears to be less able than the adult kidney to adapt to fluctuations in phosphate intake. This conclusion was drawn from studies of phosphate transport in isolated proximal tubule vesicles of newborn and adult guinea pigs fed either a phosphate-supplemented or phosphate-depleted diet.226 This study showed that phosphate uptake was reduced to a lower extent in vesicles originating from proximal tubules of phosphate-supplemented newborn guinea pigs. Conversely, an expected increase in phosphate uptake was not observed in vesicles of phosphate-deprived newborn animals, suggesting that the capacity to adapt to changes in phosphate intake is compromised in the newborn. The mechanism for this lack of adaptation is, however, unclear.

In the adult, PTH increases phosphate excretion by inhibiting NaPi-II activity.229 In the newborn, the renal response to PTH is blunted, resulting in minimal depression of proximal tubular phosphate reabsorption when PTH is present.217 The observed lack of PTH effect on phosphate transport in the newborn kidney may, however, be physiologically advantageous because the consequence of net retention of both calcium and phosphorus in the neonatal setting is conducive to growth.220

Magnesium Transport in the Developing Kidney

Magnesium is an essential cofactor for many biologic process, including protein synthesis, nucleic acid stability, and neuromuscular excitability.230

The kidney plays an important role in magnesium homeostasis by regulating urinary magnesium excretion. The importance of the kidney in magnesium homeostasis is highlighted by the demonstration of clinical hypomagnesemia in humans with mutations in genes encoding for transporters associated with magnesium transport231-238 (see eTable 465.5).

In the mature kidney, 70% to 80% of total serum magnesium is filtered, and less than 5% is excreted under conditions of normal dietary magnesium intake.230 The principal site of magnesium transport in the adult kidney is the TAL, which reabsorbs roughly 70% of filtered magnesium230 (eFig. 465.8). Magnesium reabsorption in this segment occurs by passive paracellular diffusion mediated by a paracellular Ca2+/Mg2+ channel, paracellin-1, which is a member of the claudin family tight junction proteins.239 The driving force for magnesium transport in the TAL is the lumen-positive electrochemical gradient generated by the combined effects of NKCC2 and ROMK.230 Other sites of magnesium transport include the proximal tubule and distal tubule, which reabsorb 15% to 20% and 5% to 10% respectively.230 Active magnesium transport in the distal tubule is mediated by the magnesium channel TRPM6.240

In contrast to the adult kidney, the proximal tubule of the developing kidney reabsorbs most filtered magnesium (50–60%).174 It is suggested that the age-related decrease in proximal tubule magnesium transport is due to changes in paracellular permeability to Mg2+at the level of proximal tubule tight junctions.174,241 Additional support for this hypothesis is provided by demonstrations of altered permeability to other ions in developing proximal tubules (eg, Cl).124 Expression studies analyzing the segment-specific distribution of claudin protein family members in developing and adult rat kidneys have revealed age-dependent changes in claudin expression patterns,242 which may explain segment-specific changes in paracellular permeability that occur with maturation.

In the mature nephron, more than 99% of filtered glucose is reabsorbed in the proximal tubule.243 In the mature nephron, more than 99% of filtered glucose is reabsorbed in the proximal tubule.243 Glycosuria is not uncommon in preterm and full-term neonates,126 reflecting a lower capacity for glucose reabsorption in the developing and immediate postnatal kidney.244 In the mature kidney, 2 high and low affinity Na+-coupled glucose transporters, SGLT1 and SGLT2, respectively, function in reabsorption of filtered glucose in the proximal tubule.245 In the neonate, age-related differences in neonatal renal glucose transport activity correlate with maturational differences in sodium conductance in this period. Consequently, glucose transport in the developing kidney is influenced by factors that affect sodium transport in the postnatal infant, such as surface area expansion of the developing proximal tubule, increasing proximal tubule Na+,K+-ATPase activity, and increased expression of SGLT1 and SGLT2.121,246,247 In addition, animal studies of glucose transport in the developing kidney indicate nearly one third of reabsorbed glucose leaks back into the proximal tubule lumen, possibly due to relative leakiness of this segment in the immature kidney.248,249

The bulk of amino acid transport in the mature kidney occurs in the early proximal tubule (S1) segment.127 Under normal circumstances, this segment demonstrates high capacity for reabsorption of all amino acids.250 Transepithelial uptake of amino acids occurs by active transport mediated by specific Na+/amino acid cotransporters.251 In general, urine amino acid levels are higher in newborns than in mature animals127 (eTable 465.6).252 Consequently, the reduced capacity for amino acid reabsorption renders sick premature infants highly susceptible to amino acid deficiency in the critical care setting.253 The increased urinary excretion of amino acids in newborn animals has been attributed to decreased expression or activity of amino acid transporters, decreased activity of proximal tubule basolateral Na+,K+-ATPase activity, and back leakage due to relative leakiness of the immature proximal tubule.254 The aminoaciduria that occurs in preterm and term neonates is unlikely caused by a nonspecific maturational effect on amino acid transporters because not all filtered amino acids are overexcreted to the same extent during the neonatal period.254 In particular, preterm and term newborns show higher excretion rates for glycine, proline, hydroxyproline, lysine, arginine, ornithine, and taurine,255-259 suggesting that different patterns of maturation exist for specific amino acid transport mechanisms.