Rudolph's Pediatrics, 22nd Ed.

CHAPTER 465. Development of Renal Function

Tino D. Piscione

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.


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 465-1provides 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.6,7Additional 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

Table 465-1. Relationships Between Anatomical Kidney Development and Functional Kidney Development

FIGURE 465-1. Schematic representation of the relationship between nephron formation and gestational age during human fetal renal development. Renal branching morphogenesis, a principal determinant of nephron number (solid line), is complete by midgestation. Renal mass (dashed line) increases exponentially in the latter half of gestation through the additional induction of new nephrons and hypertrophy of existing nephrons. Blue shading represents postnatal period.

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.  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.3 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). 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.



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 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

Factors affecting the drop in renal vascular resistance include changes in intrarenal blood flow distribution during the transition from fetal to postnatal life. Studies of intrarenal blood flow distribution 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.

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

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.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.

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 kallikrein-kinin system generates brady-kinin, a potent local vasodilator, through proteolytic cleavage of high molecular weight kininogen.60 Renal expression of kallikrein rises rapidly in the immediate postnatal period.61,62The 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


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).

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. 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 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.

FIGURE 465-2. Creatinine clearance at 24 to 40 hours after birth in neonates of 27 to 40 weeks’ gestation.

Within the first 48 hours of life, plasma creati-nine 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 creati-nine over time in the neonate suggests a reduction in GFR regardless of gestational age.


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 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). Figure 465-3 illustrates the inverse relationship between gestational age and transdermal water loss,87signifying 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 (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

Table 465-2. Mean Plasma Creatinine Values (SI Units—[µmol/L]) in the Perinatal Period for Different Gestational Ages

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.  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 ).

In addition, several studies have suggested that reduced urine-concentrating capacity in the newborn may be due to relative resistance of the immature kidney to antidiuretic hormone (ADH, or arginine vasopressin).109,110 The mechanism for ADH resistance is believed to be caused by local prostaglandin production, which exerts a direct antagonistic effect on ADH signaling in the neonatal collecting duct.


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. 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

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 ).

Table 465-3. Factors Affecting Water Balance in the Sick and Healthy Neonate

Proximal tubule sodium reabsorption in the mature kidney 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 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.

Active transcellular sodium uptake in the mature loop of Henle occurs via the luminal Na+K+-2Cl cotransporter (NKCC2) and NHE3 in the thick ascending limb (TAL). 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

FIGURE 465-3. The effects of gestational age on transepidermal water loss. Measurements were made from abdominal skin and conducted over the first few days after birth.

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

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

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 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 ubiquitously within the developing kidney. 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 extracellular volume contraction.155

Studies in fetal and newborn sheep demonstrate that direct renal nerve stimulation decreases sodium excretion in the perinatal period. 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-Badrenoreceptors 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.


Infants require a positive potassium balance for somatic growth.167 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

Table 465-4. Total Body Water Composition in Preterm and Term Infants

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 ).176 Urinary 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

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

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.


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 infants.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.

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 NH3through 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 NH3in 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 NH3reabsorption 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.192-194Distal 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

Lower NHE3 and Na+,K+-ATPase activities are thought to account for the reduced capacity for bicarbonate reabsorption in the newborn proximal tubule.125 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

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.


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 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

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 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.67Animal studies have shown that expression of luminal calcium channels TRPV5 and TRPV6 are expressed in fetal mouse kidneys shortly before birth.219 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.

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).221,222

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 NaPiIIc.223The 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

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 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

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

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, the principal site of magnesium transport in the adult kidney is the TAL, which reabsorbs roughly 70% of filtered magnesium230. Magnesium reabsorption in this segment occurs by passive diffusion via a paracellular Ca2+/Mg2+ channel, paracellin-1.239 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 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 permeability to Mg2+.174,241 Additional support for this hypothesis is provided by demonstrations of altered permeability to other ions in developing proximal tubules (eg, Cl).124


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.245Glucose 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

Under normal circumstances, the proximal tubule demonstrates high capacity for reabsorption of all amino acids by specific Na+/amino acid cotransporters.251 In general, urine amino acid levels are higher in newborns than in mature animals.252 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 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 may exist for specific amino acid transport mechanisms.


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 cotrans-porters.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