Renal Disease
Suhas M. Nafday
Craig B. Woda
Jeffrey M. Saland
Joseph T. Flynn
David j. Askenazi
Corinne Benchimol
Luc P. Brion
▪ INTRODUCTION
Clinical neonatal nephrology has changed due to rapid advancements in prenatal sonography, increased survival of extremely-lowbirth-weight (ELBW, <1,000 g) infants with resultant complications, and an explosion of genetic/molecular identification of many renal disorders in recent years; thus, the clinical evaluation of renal function and disease has been dramatically altered.
Congenital anomalies of the kidney and urinary tract (CAKUT) are disorders characterized by variable anatomic defects of the kidney (e.g., renal hypodysplasia, renal agenesis, solitary kidney) and ureter (e.g., ureteropelvic junction obstruction [UPJO], vesicoureteral reflux [VUR]). Several kidney disorders that present during fetal life or in the newborn period are either congenital malformations or part of an inherited disorder. The malformations are usually sporadic, often with a poorly defined pathogenesis. The inherited lesions, in contrast, frequently have clear inheritance patterns such as autosomal dominant or recessive, and in many cases, the locus of the abnormal gene and the associated abnormal protein have been identified. An early diagnosis of these defects allows rapid determination of the best medical and/or surgical treatment, preventing or at least slowing down the evolution toward chronic kidney disease (CKD) and end-stage renal disease (ESRD).
Increasing survival of ELBW infants has created new challenges in the management of fluid and electrolytes, especially related to fluid overload/hypovolemia (more so, in postoperative neonates), hypotension, use of pressors, and acute kidney injury (AKI). The improved survival of ELBW infants has led to a newer version of bronchopulmonary dysplasia (BPD); the therapeutic use of various diuretics for its management has led to an increased incidence of neonatal nephrocalcinosis (NC) over the past decade.
Widespread use of invasive procedures in the neonatal intensive care unit (NICU) including extracorporeal membrane oxygenation (ECMO), placement of vascular catheters, and sophisticated ventilator technology has resulted in a new set of complications, including AKI and renovascular hypertension related to thromboembolic disease.
Thus, the focus of this chapter is to provide readers with up-todate information on embryology and newer molecular aspects of renal development, updates on renal physiologic mechanisms, and an approach to the evaluation of a suspected renal disease, along with an overview of the common renal disorders in term and preterm (<37 weeks of gestational age [GA]) neonates.
▪ DEVELOPMENTAL PHYSIOLOGY
Fetal urine is a key component of amniotic fluid production and helps drive appropriate lung development (1,2). Ultrasound (US) studies of bladder volumes demonstrate that the rate of urine production in a normal fetus is approximately 5 mL/h at 20 weeks of GA and gradually increases to about 40 to 50 mL/h by 40 weeks (1,3). Although the fetal kidney has been largely considered dysfunctional with respect to effective plasma clearance, and overall homeostasis, closer examination of this organ suggests a major role in the growth of the infant, except in very-low-birth-weight (VLBW, <1,500 g) neonates.
Embryology
Kidney development is a complex process involving coordinated interactions between mesenchymal and epithelial cells that lead to highly specialized vascular networks, tubular structures, and interspersed stromal cells. In humans, three pairs of kidneys arise from the intermediate mesoderm; the nonfunctional pronephros at 3 weeks of gestation, followed by the intermediate mesonephros at 4 weeks (which has little function and eventually becomes part of the male epididymis and urinary bladder), and finally the definitive mammalian kidney or metanephros at 5 to 6 weeks. Although the pronephros and mesonephros involute relatively quickly after they form and are thought to have minimal function, absence of these primitive structures leads to renal agenesis.
Within the metanephric kidney, the developmental process initially occurs as the ureteric bud (UB), an offshoot of the wolffian duct, extends and invades into a mass of cells known as the metanephric mesenchyme. Reciprocating inductive signaling between the UB tip and the mesenchymal cells lead to repetitive morphogenic branching of the UB and eventual formation of the ureter, renal pelvis, calyces, and collecting tubules of the mature nephron (4). In contrast, the cells of the metanephric mesenchyme differentiate into renal epithelium, through a process known as mesenchymal-to-epithelial transition, to become the proximal tubule, loop of Henle, and distal convoluted tubule. Thus, nephrogenesis (the formation of new nephrons) and branching morphogenesis occur simultaneously and influence the development of each other. In general, the cells of the metanephric mesenchyme not destined to become tubular epithelium become the interstitial stromal cells and the cells constituting the renal capsule.
Since the UB invades the central aspect of the metanephric mesenchyme, it is important to note that nephrons develop and mature in a centrifugal pattern (2,5,6). Thus, deep juxtamedullary nephrons develop before those located in the nephrogenic zone just under the renal capsule. The full complement of approximately 1 million nephrons per kidney in the human is achieved by 35 to 36 weeks of GA, or at a body weight of about 2,300 g (2). When birth occurs before this age, nephrogenesis continues after birth, but may not reach a full complement, especially in babies with intrauterine growth restriction. Furthermore, evidence suggests that extremely low GA infants and small for GA (SGA) infants may have less number of nephrons than do controls (7) and are at increased risk for CKD and hypertension long term. Once nephrogenesis is complete, the generation of new nephrons is never resumed, even after extensive loss of renal tissue.
Blood vessels arise in a synchronous fashion alongside tubular development. There is strong evidence that blood vessels in the kidney may arise through a combination of metanephric mesenchymal progenitor cells differentiating into endothelial cells (vasculogenesis) as well as infiltration of the metanephric mesenchyme by preformed vessels (angiogenesis) from the surrounding area (8). Vascular progenitor cells within the metanephric mesenchyme express vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2, Flk-1), and VEGF helps direct the movement of these cells toward the developing nephron. This process occurs early in development based on the findings that the first glomerulus is noted by approximately 9 weeks of embryonic life. Ultimately, a coordinated response between renal vessels and nephrogenesis is required to produce a kidney capable of functioning appropriately and maintaining extrauterine life.
Molecular Biology of Renal Development
Over the past 20 years, our understanding of renal development has significantly increased from both a molecular and cellular standpoint through gene manipulation studies and transgenic animal models. These experiments have not only helped identify key genes, transcription factors, signaling molecules, and receptors
involved in normal nephrogenesis but also have provided clues to the pathophysiologic mechanisms underlying many renal and urologic abnormalities. In fact, CAKUT arise from failure of the UB to undergo appropriate branching morphogenesis and represent the largest cause of ESRD in the pediatric population.
involved in normal nephrogenesis but also have provided clues to the pathophysiologic mechanisms underlying many renal and urologic abnormalities. In fact, CAKUT arise from failure of the UB to undergo appropriate branching morphogenesis and represent the largest cause of ESRD in the pediatric population.
Closer examination of the cells located at the UB tip demonstrate high expression of RET (rearranged in transfection) (9), a tyrosine kinase receptor. Glial cell-derived neurotrophic factor (GDNF) is secreted in high amounts by the metanephric mesenchymal cells and is the secretory factor that preferentially binds to RET. Signaling through the RET receptor is important for overall migration and invasion of the UB into the metanephric mesenchyme (10,11,12). In fact, studies in both mice (13) and humans (14) with absent or mutated RET result in renal agenesis, whereas overexpression of RET results in multicystic kidney disease (MCKD) (15). In addition to RET, the UB also expresses bone morphogenic protein (BMP) 4 and 7, members of the transforming growth factor &bgr; (TGF&bgr;) superfamily. The importance of BMP is highlighted by the finding that loss of BMP also results in kidney agenesis (16). Whether BMP may become a viable factor capable of leading to nephron repair in patients with renal disease is still unclear and is actively being explored.
Metanephric mesenchymal cells that are adjacent to the UB tip are referred to as the cap mesenchyme and include the self-renewing nephron progenitor cells, which express key transcription regulators such as Lim1, Eya1, Pax2, Sall1, Meox, Cited1, WT1, and Six2 (17). Studies show that these transcription factors interact with each other in a coordinated and synergistic fashion. Loss of function in one or more of these factors leads to either renal agenesis or renal hypoplasia, while several human syndromes with associated renal dysplasia such as Townes-Brocks, branchiootorenal, and renal coloboma are related to mutations in Sall1, Eya1, and Pax2, respectively. Furthermore, some transcription factors have different temporal effects with regard to overall kidney development. For instance, Kreidberg et al. (18) demonstrated that WT1 functions not only early in nephrogenesis but also at a later phase, promoting podocyte differentiation that is needed for appropriate glomerular function.
The renin-angiotensin-aldosterone system (RAAS) is present during fetal kidney development. All the components of RAAS (renin, angiotensinogen, angiotensin-converting enzyme [ACE], and aldosterone) are first detected in the fetal metanephros early in gestation. Whereas the majority of renin-containing cells are located in the juxtamedullary apparatus of both the newborn and adult, renin message and protein are also present in the arcuate and interlobular arteries in the fetus as early as 17 weeks (19). Angiotensinogen mRNA is detected as early as 8 weeks of gestation in the human kidney (20), while immunoexpression of ACE is noted by 11 weeks in the developing proximal tubular cells (21). Angiotensin receptor type 2 receptors (AT2R) are first detected early in renal development, with the highest expression in the UB tip cells as well as the adjacent mesenchymal cells. Appropriate activation of AT2R by angiotensin II (AII) leads to UB branching and elongation of the collecting duct. At 20 weeks’ gestation, AT2R begin to regress, whereas mRNA of AT1R increases and subsequently persists throughout the remainder of metanephric development.
Disruption of the RAAS system using pharmacologic agents results in complications such as renal medullary hypoplasia, hydronephrosis, renal dysplasia, duplicated renal collecting system, and renal tubular dysgenesis (22). This helps explain fetal anuria and oligohydramnios, leading to respiratory compromise, in a mother taking an ACE inhibitor during pregnancy, a condition termed ACE inhibitor fetopathy.
Studies in fetal rats show that administration of an AT1R antagonist leads to an atrophic papilla, decreased cortical radial artery length, and a decrease in both glomerular size and number (23). Furthermore, studies in neonatal mice show that ACE inhibition leads to urinary concentrating defects secondary to atrophy of the renal papilla as well as reduced medullary micro vessels that prevent appropriate functioning of the countercurrent multiplier system (24).
▪ PHYSIOLOGY
Renal Blood and Plasma Flow
Low rates of fetal and neonatal renal blood flow (RBF) exist in a variety of animal species, whether normalized to body weight, surface area, or kidney weight. RBF is mainly determined by a combination of cardiac output (CO) and more importantly the degree of renal vascular resistance (RVR). RBF in the human fetus, estimated by Doppler ultrasonography, increases from 20 mL/min at 25 weeks of GA to more than 60 mL/min by 40 weeks of GA and reaches adult levels by 2 years of age (25,26). Developmental changes in both CO and glomerular vascular resistance contribute to this postnatal increase in RBF. For instance, the previable fetus receives about 5% of the CO, while the 1-week-old term infant receives about 9% and the adult kidney receives between 20% and 25% of the total CO (27). Given that nephrogenesis is complete well before final levels of RBF are achieved, the maturational increase in RBF cannot be completely explained by increases in renal mass.
Assessment of intrarenal RBF distribution in the fetal kidney shows significant differences compared to the adult kidney, reflecting differences in the relative size, number, and maturity of glomeruli present in the different regions of the kidney during development. While the predominance of blood flow in early fetal life, as expected, is distributed primarily to the medulla and inner cortex, renal maturation is accompanied by a redistribution of blood flow toward the superficial or outer cortex (28,29,30,31) (Fig. 39.1). Thus, at maturity, about 93% of RBF goes to the cortex
(which constitutes about 75% of the renal mass), whereas only 7% is distributed to the renal medulla and perirenal fat.
(which constitutes about 75% of the renal mass), whereas only 7% is distributed to the renal medulla and perirenal fat.
 FIGURE 39.1 Postnatal changes in the intrarenal distribution of blood flow. Relative rates of blood flow per glomerulus in the four cortical zones of the canine kidney. Zone I represents the most superficial region, and zone IV represents the deepest. The total height of the bars in each age group is equal. At birth, the blood flow to the superficial cortex was lowest, with most blood flow perfusing the deep cortex. By 6 weeks of age, this pattern was reversed. Maturation is accompanied by an increase in blood flow to the outer cortex, due primarily to a decrease in renal vascular resistance. From Aperia A, Broberger O, Herin P, et al. Renal hemodynamics in the perinatal period: a study in lambs. Acta Physiol Scand 1977;99:261-269, with permission. |
 FIGURE 39.2 Developmental changes in effective renal plasma flow (ERPF), calculated from the renal clearance of para-aminohippurate (PAH) and corrected for the fraction of PAH extracted by the kidney. The ERPF, used to estimate RBF, increases rapidly between 30 and 40 weeks of GA, reaching adult values by 24 months of postnatal life. From Rubin MI, Bruck E, Rapoport MJ. Maturation of renal function in childhood: clearance studies. J Clin Invest 1949;28:1144. |
The maturational increase in RBF results more from the change in intrarenal distribution and the decrease in RVR (31) than from the rise in CO (32,33,34). The RVR, localized both at the afferent and efferent arterioles, is much higher in the newborn than in the adult (32). Interestingly, the postnatal fall in RVR occurs at a time when the systemic vascular resistance increases about sixfold (32). Data suggest that increases in vasodilatory humoral factors, such as nitric oxide, in combination with simultaneous decrease of the vasoconstrictive RAAS mediate, at least in part, the developmental reduction in RVR. Ultimately, the balance of afferent and efferent arteriolar resistances determines not only the RVR and RBF but also the hydrostatic pressure within the glomerulus and level of glomerular filtration rate (GFR).
Anatomic factors also contribute to the developmental increase and redistribution of RBF. For instance, the complexity of the glomerular capillary network varies early in postnatal life. Inner cortical glomeruli at this age generally have a smaller number of capillaries compared to adults, although they appear similar in overall structure. In addition, few efferent arterioles have vasa recta that descend into the medulla, and thus, most connect directly to the venous system resulting in arteriovenous shunting (33).
Effective renal plasma flow (ERPF) has traditionally been calculated from the renal clearance of the organic acid para-aminohippurate (PAH). PAH predominately enters the renal tubule through secretory mechanisms within the S2 segment of the proximal convoluted tubule (PCT). Renal plasma flow (RPF) increases rapidly between 30 and 40 weeks of GA, reaching adult values by 1 to 2 years of life (26) (Fig. 39.2). PAH clearance averages 150 mL/min/1.73 m2 body surface area (BSA) in full-term infants at 2 weeks of life, increasing to almost 200 mL/min/1.73 m2 by 3 months of age (34). Published values of RPF in premature infants must be interpreted with caution because acid secretory pathways are immature during this time and few nephrons have vasa recta allowing for appropriate delivery of PAH to the basolateral surface of PCT cells.
Renin-Angiotensin-Aldosterone System
The RAAS, pivotally involved in blood pressure (BP) regulation as well as in sodium and water homeostasis, is very active in the fetus and newborn (35,36,37) (Fig. 39.3). Plasma renin activity (PRA) is inversely related to GA in the fetus and newborn, decreasing from 60 ng/mL/h at 30 weeks of gestation to about 10 to 20 ng/mL/h by term (38). Although there is a significant decrease in PRA in utero, studies demonstrate that PRA at term is three to five times higher than are adult levels (39,40,41). Similar to adults, PRA in the fetus increases with volume depletion or hypoxia and decreases with fluid excess or &bgr;-adrenergic inhibition. As expected, the high levels of renin in neonates are associated with elevated circulating levels of AII and aldosterone that generally exceed those measured in the adult (42,43,44). These high levels may reflect either increased rates of overall secretion or simply low metabolic clearance rates relative to body size. The effect of AII on glomerular hemodynamics depends on relative activation of AT1R and AT2R, which mediate, respectively, vasoconstriction and vasodilatation of the efferent arteriole (45).
 FIGURE 39.3 Relationship between the renin-angiotensin and kinin systems. See text for details. |
Prostaglandins
Prostaglandins (PGs), particularly PGE2 and PGI2 (prostacyclin), synthesized by the endothelial cells of both the afferent and efferent arterioles, help buffer against circulating vasoconstrictive agents and thus maintain effective RBF and GFR. Urinary excretion of PGs is high in the fetus (46), presumably reflecting a high rate of renal synthesis. Urinary excretion of PGE2 and prostacyclin metabolites in the premature infant are 5 times that noted at term and 20 times that measured in older children (47).
PG synthesis from arachidonic acid is mediated by the enzyme cyclooxygenase (COX), which is the inhibitory target of various nonsteroidal anti-inflammatory drugs (NSAIDs) (48). Two isoforms of COX have been identified, each representing a different gene product and subject to differential regulation. COX-1 has been proposed to participate in glomerulogenesis (49), whereas COX-2 regulates renal perfusion and glomerular hemodynamics (50). Differences in intrarenal COX-1 and 2 localization between the adult and fetal human kidney may account for the variable renal responses to PG inhibition observed between the two groups (49).
Maternal administration of indomethacin, a nonselective COX inhibitor, increases fetal RVR and reduces fetal RBF, GFR, and urine output, ultimately leading to oligohydramnios (51,52,53). Postnatal administration of a PG synthase inhibitor to preterm infants (54), to close a patent ductus arteriosus (PDA), may also compromise renal function, leading to a reduction in RBF, GFR, and urine volume.
Renal Nerves and the Adrenergic System
The renal vascular bed of the fetal kidney is less reactive to renal nerve stimulation than is that of the newborn and adult kidney (55). In contrast, circulating catecholamine levels, particularly norepinephrine, are very high just before and immediately after birth (56) and fall to adult values within a few days of life. The high plasma levels of catecholamines act directly to increase afferent arteriolar tone and indirectly, via stimulation of renin and AII release, to increase efferent resistance, possibly contributing to the maintenance of the high RVR characteristic of the neonatal kidney (57). The fetal and neonatal kidney demonstrates enhanced sensitivity to catecholamines compared to the adult kidney, related in part to developmental differences in adrenergic receptor density (58).
Dopamine and Dopamine Receptors
Under normal conditions in adults, dopamine has a biphasic response in the renal vasculature. Low concentrations of dopamine, through binding to dopaminergic receptors, lead to marked vasodilation and increased RBF, whereas high concentrations, via their effect on &agr;-adrenergic receptors, result in vasoconstriction. In contrast, fetal and neonatal kidneys have a blunted response to low-dose dopamine (59), which results from a limited generation of the vasodilatory second messenger cyclic adenosine monophosphate (cAMP) (60) and a low density of renal dopamine-1-like receptors (61). In contrast, intrarenal dopamine infusions in both fetal and neonatal animals (62) lead to marked vasoconstriction, given the abundance of &agr;-adrenoceptors present by term (63).
Arginine Vasopressin
Arginine vasopressin (AVP), more commonly known as antidiuretic hormone (ADH), was noted to have vasoconstrictive properties when first discovered. Studies show that the plasma concentration of AVP in neonates increases abruptly after birth and is highest in infants whose mothers labored before vaginal delivery (64). However, under basal conditions, infusion of synthetic AVP does not alter either RBF or RVR in fetal sheep as would be expected (65). Yet, AVP may play a role in certain stress-induced responses (i.e., during hemorrhage), given the marked decrease in RBF and increase in RVR that correlates closely with the rise in plasma AVP during these states (3,66). The differential role of AVP is poorly understood but may be related to variations in the expression of vasopressin type 1 receptors during stress.
Atrial Natriuretic Factor
Atrial natriuretic factor (ANF) release from atrial cardiocytes is stimulated in the fetus by an increase in intracardiac pressure and atrial distention (67,68,69), and levels fall in response to a decrease in central venous pressure, such as during hemorrhage (70). ANF has multiple functions within the mature kidney such as antagonizing renal vasoconstriction, increasing GFR, and inhibiting renin secretion, ultimately promoting tubular sodium excretion (71). However, the natriuretic and diuretic response to systemically infused ANF in the newborn is attenuated compared to adults (72,73,74). While ANF receptors have been identified on near-term fetal glomerular membranes, ANF binding capacity is age dependent, increasing sevenfold between fetal and adult life (75). The blunted response of the immature subject to ANF can additionally reflect an ineffective production of the second messenger cyclic GMP (73).
Glomerular Filtration
The first glomerulus is detected as early as 9 weeks of gestation, and GFR in the human fetus begins immediately thereafter (76). Estimates of GFR correlate well with postmenstrual age (PMA), a relationship that persists whether the fetus remains in utero or is born prematurely (77,78). Specifically, GFR averages approximately 8 to 10 mL/min/1.73 m2 at 28 weeks and increases to 25 mL/min/1.73 m2 by 34 weeks of PMA. After 34 weeks of GA, the GFR often increases by three- to fourfold within 1 week (77,79), coinciding with completion of nephrogenesis (Fig. 39.4). Thus, an infant born prematurely at 28 weeks of GA shows little increase in GFR until the infant is about 6 weeks old, that is, until a PMA of 34 weeks is attained and nephrogenesis has been completed (80). Of note, GFR continues to increase rapidly during the first 4 months of life, followed by a slower rise to adult levels by 2 years of age (25,81,82).
At birth, the more mature glomeruli in the juxtamedullary cortex are nearly as large as are glomeruli in the adult kidney. As such, deep glomeruli have higher filtration rates than do the more recently formed superficial glomeruli, which may not begin filtration for some time. Single nephron GFR (SNGFR) depends on four factors: mean glomerular transcapillary hydraulic pressure difference, plasma oncotic pressure, glomerular plasma flow rate, and glomerular capillary ultrafiltration coefficient, which depends on surface area. Studies suggest that the rise in overall GFR is mainly due to an increase in SNGFR of superficial nephrons through an increase in glomerular surface area and in glomerular hydrostatic pressure related to enhanced perfusion of the renal cortex (28,33,83) (Fig. 39.1).
Autoregulation of Renal Blood Flow and Glomerular Filtration Rate
Autoregulation in the adult kidney allows for maintenance of constant RBF and GFR even as the mean arterial pressure (MAP) and renal perfusion pressure vary widely (typically, 80 to 150 mm Hg). Autoregulation is accomplished primarily by changes in the RVR at the level of the afferent and efferent arterioles. Although MAP (i.e., 20 to 60 mm Hg) in the fetus and neonate is less than the lower limit of autoregulatory range defined for adults, experimental evidence suggests that the fetus and newborn are able to autoregulate RBF appropriately in the setting of their low arterial pressure (84,85,86).
The autoregulatory response to a decrease in MAP is mainly due to a combination of renal afferent arteriole dilation with subsequent constriction of the efferent arteriole. The latter effect is due, at least in part, to enhanced renal sympathetic tone, renin release, AII generation, activation of the AT1R (45,87), and activation of hormones such as AVP and endothelin, which enhances proximal tubular sodium and water reabsorption.
The autoregulatory response to a decrease in MAP is mainly due to a combination of renal afferent arteriole dilation with subsequent constriction of the efferent arteriole. The latter effect is due, at least in part, to enhanced renal sympathetic tone, renin release, AII generation, activation of the AT1R (45,87), and activation of hormones such as AVP and endothelin, which enhances proximal tubular sodium and water reabsorption.
 FIGURE 39.4 Changes in GFR (mL/min), estimated by creatinine clearance, and nephrogenic activity in the kidney cortex (%) are plotted as a function of postconceptional age in the human infant. There is a temporal relationship between the accelerated rate of increase in GFR and completion of nephrogenesis after 34 weeks of gestation. From Arant BS. Neonatal adjustments to extra uterine life. In: Edelman CM Jr, ed. Pediatric kidney disease. Boston, MA: Little, Brown and company, 1992:1021. |
Tubuloglomerular Feedback
Tubuloglomerular feedback serves to maintain a constant rate of filtration so that appropriate water and salt is delivered to distal segments of the nephron. A stimulus (e.g., low tubular flow or low chloride delivery) at the macula densa is transmitted to the afferent arteriole of the nephron leading to changes in SNGFR. For example, low urinary flow in the thick ascending limb of Henle promotes decreased vascular resistance within the afferent arteriole, resulting in improved glomerular blood flow, higher glomerular capillary hydrostatic pressures, and ultimately an improvement in GFR. Although GFR is known to increase with maturation, the mechanisms underlying tubuloglomerular feedback are present early on and unaltered during growth (88,89). Intact RAAS appears to be critical for this signaling pathway (90), and NO may additionally play a modulatory role (91).
Tubular Handling of Electrolytes
The axial and polarized (apical vs. basolateral) distribution of transport proteins along sequential segments of the nephron allows the kidney to reabsorb the bulk of glomerular filtrate proximally and then, in more distal segments, adjust the solute and water content of the urine to maintain homeostasis. Overall, the fully differentiated kidney is generally a reabsorptive organ when it comes to sodium, bicarbonate, phosphate, amino acids, and glucose. Potassium, on the other hand, is both reabsorbed and secreted while hydrogen ions are predominately secreted to help maintain metabolic balance. Thus, the kidney of the full-term, but not necessarily preterm, infant is uniquely suited to meet its developmental stagespecific metabolic demands.
Sodium
Full-term infants are in a state of positive sodium balance, a requisite for appropriate somatic growth. Although the sodium intake per unit of BSA is generally smaller in the newborn than in the adult, the magnitude of this positive balance remains relatively constant within a wide range of sodium intake (92). This positive sodium balance is achieved predominately through enhanced tubular reabsorption of sodium rather than a low GFR (93). Unfortunately, the tendency of the full-term neonatal kidney to retain significant amounts of filtered sodium may become problematic under conditions of salt loading. For instance, full-term newborn infants when given a sodium load in excess of 12 mEq/kg/d experience a rise in serum sodium levels, abnormal increase in weight, and generalized edema (94). The fractional excretion of sodium (FENa) is the ratio of filtered Na that is excreted in the urine, expressed as a percent. FENa in the full-term newborn generally averages about 0.2% (95). Furthermore, after the first few hours of postnatal life, urinary sodium excretion declines rapidly, possibly secondary to contraction of the extracellular fluid (ECF) volume (96).
In contrast, FENa may be as high as 20% during early fetal life, and then decreases progressively during gestation (95,96,97). Premature infants of less than 30 weeks of GA show elevated values of FENa, which may exceed 5% (95,98,99). These infants have urinary sodium losses exceeding dietary sodium intake, even with formula designed for preterm infants or with fortified breast milk, and are at risk for a negative sodium balance (i.e., hyponatremia of prematurity) and loss of body weight. They may require, after the first few postnatal days, at least 2 (and some up to 10) mEq/kg/d of supplemental sodium to maintain a normal serum sodium concentration and remain in positive balance (100). Interestingly, one small randomized trial suggested that sodium supplementation in preterm infants may, in fact, improve neurodevelopment (101).
Sodium is freely filtered at the glomerulus. The initial two-thirds of the proximal tubule of the suckling rat reabsorb approximately 50% of the filtered load of sodium and water (93,102,103), values only slightly less than those reported in the adult (102,104). Studies in several mammalian species demonstrate increases in the reabsorptive capacity of the proximal tubule after birth, consistent with maintenance of glomerulotubular balance during postnatal development (90,105). Premature infants, thus, represent a state of functional imbalance in glomerulotubular feedback whereby the reabsorptive sodium capacity of the proximal tubule lags behind increases in GFR (106,107).
The fractional reabsorption of sodium along the loop of Henle increases by about 20% during postnatal development (102), consistent with functional maturation of this nephron segment. Sodium is absorbed in the thick ascending limb of the loop of Henle (TALH) through the furosemide- and bumetanide-sensitive Na-K-2Cl tritransporter located in the urinary membrane and is extruded from the cell at the basolateral membrane by the Na-K-ATPase pump. In contrast to the maturational increase in sodium reabsorption in the loop of Henle, the fractional reabsorption of sodium along the more distal segments is greater in younger than older animals, thereby explaining the sodium retention and blunted response to sodium loading characteristic of the young animal (93,108).
Clearance studies in preterm infants (100,102,103,104,106,107,109,110,111) suggest that the percent of filtered sodium reabsorbed by the proximal tubule increases by about 5% between 28 and 34 weeks of GA, whereas the percent of distal sodium reabsorption increases by more than 15% during this same period. However, because the proximal tubule reabsorbs a large percentage of the filtered load of sodium, the small percentage increase in fractional reabsorption in this segment contributes to the postnatal increase in renal sodium retention as much as does the larger percentage increase in the distal tubule.
Distal sodium reabsorption occurs in the cortical collecting duct (CCD) by apical sodium entry into principal cells through the amiloride-sensitive epithelial sodium channel (ENaC) and its extrusion at the basolateral membrane by the Na-K-ATPase. In the fully differentiated nephron, the cellular effects of aldosterone induce increases in the density of apical ENaC channels and stimulation of Na-K-ATPase activity (111). The net effect of these actions is enhanced sodium absorption. Although high levels of aldosterone prevail through early postnatal life (45,112), clearance studies in premature infants (45,113) and investigations in neonatal laboratory animals (114) reveal a blunted responsiveness of the immature kidney to aldosterone. The density of aldosterone-binding sites, receptor affinity, and degree of nuclear binding of hormone receptor appear to be similar in immature and mature rats (28), suggesting that the early hyposensitivity to aldosterone represents a postreceptor phenomenon. The resulting relative hypoaldosteronism in the premature infant results in an inability to conserve sodium, manifested clinically by weight loss and hyponatremia. In addition, the sodium wasting, characteristic of the preterm infant, may also be a result of a paucity of ENaC in the urinary membrane of the distal nephron during this time (115).
Urinary sodium excretion during maturation is regulated by the RAAS, renal sympathetic innervation, ANF, dopamine, and glucocorticoids. Direct stimulation of renal nerves in fetal and newborn sheep lead to sodium retention (116), a response qualitatively similar to that observed in adult animals and attributed to norepinephrine acting on &agr;-adrenergic receptors (117). In contrast, studies in newborns indicate a relatively poor natriuretic response to ANF (72,118) as well as dopamine (113,114,119,120,121,122) compared to their adult counterparts. Circulating levels of glucocorticoids, including cortisol and corticosterone, surge in many species during or just
before the period of weaning (122,123). Both endogenous gluco-and mineralocorticoids bind to the mineralocorticoid receptor with equal affinity (124). Although blood glucocorticoid concentrations are approximately 100-fold higher than are aldosterone concentrations, the metabolism of cortisol into inactive derivatives by 11&bgr;-hydroxysteroid dehydrogenase type 2 (11-&bgr;-HSD2) within the CCD protects the mineralocorticoid receptor from glucocorticoids (124). The presence of ENaC, mineralocorticoid receptor, and low levels of 11-&bgr;-HSD2 (in the CCD) suggest that glucocorticoids may act as sodium-retaining steroids during early postnatal life (125).
before the period of weaning (122,123). Both endogenous gluco-and mineralocorticoids bind to the mineralocorticoid receptor with equal affinity (124). Although blood glucocorticoid concentrations are approximately 100-fold higher than are aldosterone concentrations, the metabolism of cortisol into inactive derivatives by 11&bgr;-hydroxysteroid dehydrogenase type 2 (11-&bgr;-HSD2) within the CCD protects the mineralocorticoid receptor from glucocorticoids (124). The presence of ENaC, mineralocorticoid receptor, and low levels of 11-&bgr;-HSD2 (in the CCD) suggest that glucocorticoids may act as sodium-retaining steroids during early postnatal life (125).
Potassium
Potassium is transported actively across the placenta from mother to fetus (126), and thus, fetal potassium is maintained at levels exceeding 5 mEq/L even in the face of maternal potassium deficiency (126,127). Unlike adults, who are in net zero balance, growing infants maintain a state of positive potassium balance (128,129). The relative conservation of potassium early in life is associated with higher plasma potassium values as compared to adults (102,107,129,130). These levels average 5.2 mEq/L from birth to age 4 months, decreasing to 4.2 mEq/L by 3 years of age (130). Under normal circumstances, potassium retention by the newborn kidney is appropriate and a requirement for growth.
Potassium is freely filtered at the glomerulus. Approximately 50% of the filtered potassium is reabsorbed along the proximal tubule in both newborns and adults (102). Up to 40% of the filtered load of potassium reaches the superficial distal tubule of the newborn, in contrast to about 10% in mature animals, providing evidence for functional immaturity of the loop of Henle (102,131). Urinary potassium excretion is derived almost entirely from secretion in distal segments of the nephron, including the CCD. In the adult nephron, potassium secretion occurs by the principal cells of the CCD in association with the electrochemical reabsorption of sodium ions through apical ENaC. The low rates of potassium excretion characteristic of the newborn kidney are due, at least in part, to a low potassium secretory capacity of this segment (132) given reduced delivery of tubular sodium (in full-term infants) in the setting of low dietary Na intake. Furthermore, an increase in tubular fluid flow rate does not stimulate potassium secretion in the neonatal CCD of the rabbit, as it does in the fully differentiated segment, until after weaning (133,134). Baseline and flow-stimulated potassium secretion appear to be limited early in life by a paucity of small-conductance (SK) (135) and calcium-activated maxi-K channels (134), respectively, in the urinary membrane of the CCD. The developmental expression of immunodetectable renal outer medullary potassium (ROMK) channels, the molecular correlate of the SK channel (136,137), and, shortly thereafter, the maxi-K channel immediately precedes the appearance of baseline and flow-stimulated potassium secretion, respectively, in the CCD. In general, the limited potassium secretory capacity of the immature kidney becomes clinically relevant particularly under conditions of potassium excess.
Calcium
A state of positive calcium balance, characteristic of growing individuals, is sustained by the coordinated interaction of bone, intestine, and kidney. Calcium represents the most abundant mineral in the body and plays a diverse role as a major constituent of bone and teeth, as well as in neuromuscular activity and intracellular signal transduction. Urinary excretion of calcium is inversely related to GA and varies directly with both urine flow and sodium excretion (138). High rates of calcium excretion may contribute in part to early neonatal hypocalcemia, which is commonly seen in the first 24 to 48 hours of life (139). The urinary calcium-to-creatinine ratio in full-term infants ranges up to 1.2 mg/mg during the first week of life but may exceed 2 mg/mg in premature neonates (138,140). In children more than 2 years of age, the ratio decreases to approximately 0.2 mg/mg, which persists through adult life (141). The high fractional excretion of calcium in preterm infants may be related to maturational changes in the tubular handling of calcium.
Approximately 50% of filtered calcium is reabsorbed along the superficial proximal tubule in mature rats, yet only 1% of filtered calcium is excreted (102), suggesting that, in the adult, a large portion of filtered calcium is also reabsorbed at a site beyond the proximal tubule or in deep nephrons (102). The fractional reabsorption of calcium in the loop of Henle, like that for sodium, potassium, and chloride, is low in newborn rats, increasing significantly with advancing postnatal age (102,142). Furosemide, through its effect on inhibiting the apical TALH tri-transporter leading to loss of the luminal positive charge, increases urinary calcium excretion resulting in an enhanced risk of promoting NC and nephrolithiasis. Absorption in both the proximal tubule and TALH is predominantly coupled to sodium absorption and is a passive process through paracellular means. Of interest, calcium absorption in the TALH occurs through tight junctions containing paracellin-1, which when mutated leads to familial syndromes such as hypomagnesemic hypercalciuria and NC (143). In contrast, calcium reabsorption within the distal nephron is active, is transcellular, and is regulated independently of sodium (144).
The principal hormones that regulate renal calcium excretion in the adult are parathyroid hormone (PTH), 1,25-dihydroxyvitamin D, and calcitonin (145). Under normal conditions, a reduction in serum calcium results in the release of PTH from the parathyroid glands. PTH directly leads to enhanced calcium concentrations by direct effects on the nephron, and indirectly through the PTH-induced synthesis of the active vitamin D metabolite 1,25-dihydroxyvitamin D, which stimulates intestinal calcium absorption. In mature animals and adults, PTH decreases urinary calcium excretion by stimulating calcium reabsorption across the cortical TALH and distal convoluted tubule (146,147,148,149). Although PTH-responsive adenylate cyclase has been found in preterm rabbits (150) as well as preterm and full-term newborns (151,152), the administration of exogenous PTH has minimal effect on renal calcium or phosphorus handling (153). Thus, it has been suggested that neonatal hypocalcemia may be a result of end-organ unresponsiveness to PTH. Of note, renal production of 1,25-dihydroxyvitamin D increases rapidly after birth, provided that the concentration of the substrate, 25-hydroxyvitamin D, is adequate (154).
Systemic calcium homeostasis is controlled, in large part, by the extracellular G protein-coupled calcium-sensing receptor (CaSR), located on parathyroid and kidney cells in which it senses the extracellular calcium concentration and in turn alters the rate of PTH secretion and renal calcium reabsorption in the TALH and early distal nephron (155,156). There is little expression of CaSR in the fetal kidney (157) but steady-state abundance of CaSR mRNA and protein increase significantly during the first week of life (157).
Phosphate
Inorganic phosphate (Pi) is critical for appropriate growth and development given that it is a major component of bone, muscle, and membrane phospholipids as well as critical for many cellular processes that involve adenosine triphosphate (ATP). Thus, it is imperative that neonates and older infants maintain a higher serum phosphate concentration than do adults. The plasma Pi concentration in infants is 4.5 to 9.3 mg/dL and decreases to 3.0 to 4.5 mg/dL in adulthood (158). This is achieved through enhanced phosphate reabsorption by the kidneys early in life, which progressively declines with advancing age (159,160). The fractional reabsorption of phosphate increases from 85% of the filtered load at 28 weeks of GA to almost 99% at term, decreasing thereafter to approximately 85% between 3 and 20 months of age (161). The high renal reabsorptive capacity for phosphate early in life allows the infant to retain a large portion of phosphate absorbed from the gut and sustain a state of net positive phosphate balance (161).
Ninety percent of plasma Pi is freely filtered at the glomeruli with 10% being protein bound. The movement of Pi across the apical brush border membrane of the PCT is the rate-limiting step in tubular Pi reabsorption. Pi entry in the cells of the PCT is coupled to sodium and is dependent on the electrochemical gradient delivered by the basolateral Na/K ATPase pump (162). While three Na+-Pi cotransporters have been described to date, the expression of the Na+-Pi cotransporter type II (NaPi2) is highly influenced by dietary Pi intake and hormones such as PTH and growth hormone. Studies have also demonstrated that NaPi2 expression is significantly greater in juvenile animals, under normal conditions, and decreases with advancing age (163). Furthermore, the phosphaturic effect of PTH is blunted early in life despite the normal circulating PTH levels in the immediate postnatal period, a response mediated, in large part, by the presence of growth hormone (164) preventing the PTH-induced internalization of apical Na+-Pi cotransporters in the PCT.
It was initially believed that a low GFR in fetal life was responsible for the limited urinary Pi excretion, but studies in experimental animals demonstrated an overall enhanced renal tubular reabsorption of phosphate early in life. The fractional reabsorption of phosphate in the newborn proximal tubule and distal nephron is higher than is that in the adult (165,166). The high intrinsic rate of phosphate reabsorption measured in neonatal proximal tubules has been attributed to an abundance of a growth-related sodium phosphate cotransporter protein in the luminal membrane (167), a high membrane fluidity of the immature nephron that increases the transport activity of the Na+-Pi cotransporter (168), a low intracellular phosphate concentration (169), and the favorable hormonal milieu prevailing in the perinatal period (170,171). Nephron heterogeneity may also explain, in part, the limited urinary phosphate excretion observed in the rapidly growing animal. Because deep nephrons reabsorb more phosphate than do cortical nephrons (171,172), and nephrogenesis begins in the juxtamedullary region, the kidney of the immature animal may contain a relatively greater number of functioning nephrons with a high capacity for phosphate reabsorption.
In contrast, the renal tubule of the preterm infant has limited ability to reabsorb phosphate. The tubular reabsorption of phosphate (at normal serum phosphate levels) is 56% in preterm infants born at 23 to 25 weeks of GA and increases to 85% at 26 to 31 weeks of GA and reaches almost 90% at full term (161). Thus, high phosphaturia in preterm infants may result in a net negative phosphate balance and osteopenia of prematurity if sufficient phosphate intake is not provided. Importantly, in the absence of supplemental phosphate, the serum phosphate level decreases, and once the serum level is below the renal threshold, renal phosphate reabsorption may reach 99% (173).
Magnesium
Ninety-seven percent of the filtered magnesium is reabsorbed by the mature nephron (174), largely a function of the TALH. Magnesium reabsorption is regulated by a number of hormones, including PTH, calcitonin, glucagon, and AVP (175,176). Additionally, dietary magnesium restriction or loading stimulates or inhibits magnesium reabsorption, respectively; this response is mediated by the CaSR in the cortical TALH and distal tubule (177,178). Micropuncture analysis shows that the proximal tubule of the adult animal reabsorbs only about 10% of the filtered magnesium, whereas that of the young developing rat reabsorbs about 60% of the filtered load (102). Thus, postnatal maturation is associated with a decrease in the fractional reabsorption of magnesium in the proximal tubule (102). Overall, the avid retention of magnesium within the PCT by the immature kidney likely contributes to the elevated plasma magnesium levels noted during early postnatal life (179). From a clinical perspective, administration of loop diuretics such as furosemide inhibits magnesium absorption, similar to that seen with calcium, and increases magnesium excretion as a result of the inhibition of the apical tri-transporter and modification of the transepithelial voltage within the TALH (180).
Glucose
Premature infants of less than 34 weeks of gestation have a higher urinary glucose concentration, higher fractional excretion of glucose, and lower maximal reabsorption of glucose than do full-term infants and older children (76). The lower renal threshold for glucose in newborns compared to their adult counterparts is believed to reflect a greater degree of nephron heterogeneity (181).
The neonatal proximal tubule possesses both high- and lowaffinity sodium-coupled glucose transporters that mediate reabsorption of filtered glucose; interestingly, only the low-affinity high-capacity system is present in adults (182,183,184). It is not clear during maturation when the high-affinity system disappears, but its presence early in life may help enable the anatomically immature kidney to reabsorb sugar from the glomerular filtrate.
Organic Acids
Organic acids, including PAH (see discussion of RBF) and endogenously produced uric acid, are eliminated by filtration and proximal tubular secretion. Organic acids are transported from the peritubular circulation across the basolateral surface of the proximal tubule to the tubular fluid. The renal clearance of organic acids is low in the neonate, even when corrected for body size, and increases gradually with age (185). As discussed previously, the limitation in tubular excretion of weak acids may be due, in part, to the preponderance of blood flow to the juxtamedullary region, bypassing tubular secretory sites. Additional variables that may account for the limited clearance of organic acids include the low GFR, limited energy for transport, and restricted expression of organic anion transporter proteins (186).
Amino Acids
The renal reabsorption of many amino acids, including threonine, serine, proline, glycine, and alanine, is lower in newborn animals and humans than in adults, often resulting in aminoaciduria (187,188). This does not appear to be a generalized defect in amino acid reabsorption, because other filtered amino acids (e.g., methionine, isoleucine, leucine, tyrosine) are reabsorbed more completely. Specific transporters for acidic, basic, and neutral amino acids have been identified in the urinary membrane of proximal tubules in newborn kidneys (189,190,191,192). The transient limitation in net transtubular reabsorption of amino acids characteristic of the neonate may arise from intrinsic differences in activity and transport capacity of these discrete transport systems, and/or a lower rate of amino acid efflux out of the cell into the peritubular circulation in the neonate compared to the adult, a mechanism that also would account for the high intracellular concentrations of amino acids observed early in life (189).
Acid-Base
The acid-base status of the fetus is maintained by both placental and maternal mechanisms. The fetal kidney in the second half of pregnancy, however, is able to acidify the urine (193,194). Immediately after birth, the acid-base state of the full-term newborn is characterized by a metabolic acidosis (195) with respiratory compensation generally occurring within 24 hours following birth (196). The normal range for serum bicarbonate is lower for preterm infants (16 to 20 mmol/L) and full-term infants (19 to 21 mmol/L) than for children and adults (22 to 28 mmol/L). The lower levels of buffer base concentration in the blood of infants can be accounted for, in part, by the inability to completely excrete the by-products of growth and metabolism (197).
The concentration of bicarbonate in plasma is determined predominately by the renal bicarbonate threshold, which is lower in preterm and term infants than adults (198,199,200). The low bicarbonate threshold characteristic of the newborn is considered to reflect nephron heterogeneity and/or a low fractional reabsorption of bicarbonate in the immature kidney (128). In the adult nephron, proximal tubular bicarbonate reabsorption is mediated by the presence of an apical sodium-hydrogen exchanger (NHE) and carbonic anhydrase (which facilitates the interconversion of carbonic acid to water and carbon dioxide). Experimental evidence suggests that the low neonatal bicarbonate reabsorption is a product of low activity of carbonic anhydrase as compared to mature kidneys (201,202), even though carbonic anhydrase activity is detected in early fetal kidney development (203,204). Postnatal maturation of the proximal tubular capacity for bicarbonate reabsorption has been proposed to be a result of increases in the activity of both the NHE and carbonic anhydrase within this segment (205,206,207).
The renal response to acid loading increases with advancing gestational and postnatal ages. When compared to adult subjects given a comparable acid load, the infant exhibits a larger fall in blood pH and bicarbonate concentration, a smaller and slower fall in urine pH, and much smaller increase in urinary titratable acid and ammonium excretion (208,209). Premature infants born at 34 to 36 weeks of GA exhibit rates of net acid excretion and ammonium generation that are about 50% lower compared to term infants. Thus, net acid excretion increases to levels observed in term newborns only after 3 to 4 weeks of age (209). In response to acid loading with ammonium chloride, urinary pH values of less than 6 are rarely observed in premature infants until the second month of life (210). In contrast, by the end of the second postnatal week, urinary pH values of 5 or lower are consistently observed in term infants (211,212). The rates of ammonia synthesis and excretion are low in the neonate (213) and, in response to acid loading, do not increase to mature values until 2 months of age (200,211,214). Of note, phosphate loading, administration of cow milk (which is rich in protein and phosphate) instead of breast milk, or high-protein feeding enhances the ability of the newborn to excrete titratable acids and ammonia (212,215).
The final site of urinary acidification is the renal collecting duct. Functional immaturity of this segment and particularly the acid-base transporting intercalated cells therein may further limit the ability of the neonate to effectively eliminate an acid load (216,217). Postnatal differentiation of intercalated cells has been shown to include changes in the morphology and function of these specialized cells with an increase in density along the CCD.
Urinary Concentration and Dilution
The fetal metanephric kidney produces large amounts of hypotonic urine that contribute significantly to the volume and composition of amniotic fluid (94,218,219). Urine osmolality early in life is typically one-fifth that achieved by the adult (65). Yet, the fetal nephron is able to concentrate urine under conditions of stress, such as that induced by maternal water deprivation (220), hemorrhage (213), or infusion of AVP (221,222). After fluid deprivation for 12 to 24 hours, the maximal urine osmolality achieved in premature and full-term newborns is 600 and 800 mOsm/kg, respectively (223,224). The kidney’s maximal urinary concentrating ability (approximately 1,000 to 1,200 mOsm/kg) in both children and adults is generally not attained until at least 6 to 12 months of age (223,225).
Urinary concentration requires a corticomedullary osmotic gradient, the pituitary release of AVP, and the ability of the collecting duct principal cells to increase its water permeability in response to AVP. The limited urinary concentrating ability of the infant appears to be due primarily to an inability to generate a corticomedullary osmotic gradient and diminished responsiveness of the distal nephron to AVP (225,226).
The capacity to concentrate urine has been directly related to elongation of the loops of Henle and their penetration into the medulla (227). The inner medulla and renal papillae are poorly developed in the immature kidney. In the rat, the 1.6-fold increase in length of the renal medulla correlates well with the 1.5-fold increase in urine osmolality observed between 10 and 20 days of age (227). In addition to anatomic maturation of the loops of Henle, urinary concentration requires the generation of a high interstitial solute concentration gradient in the medulla, which is underdeveloped early in life (223,228). Generation of the corticomedullary osmotic gradient necessitates the postnatal maturation of several processes involved in urinary concentration including sodium chloride reabsorption by the TALH, urea sequestration by the principal cells of the inner medullary collecting duct (in the presence of ADH), and functional activation of aldose reductase, an enzyme necessary for generation of intracellular osmolytes, important for maintenance of cell function in the concentrated milieu (229,230). Furthermore, the functionally limited countercurrent multiplier system in the immature kidney prevents the appropriate buildup and maintenance of a medullary gradient needed for effective urinary concentration.
In contrast to urinary concentrating abilities, premature infants less than 35 weeks of GA, studied under conditions of maximal water diuresis, can decrease their urine osmolality to 70 mOsm/kg, whereas infants greater than 35 weeks of GA are able to reduce urine osmolality to 50 mOsm/kg (106). Although the proximal tubular sodium reabsorption is relatively less mature in the preterm infant compared to adults, the high avidity of the distal nephron for sodium reabsorption allows the neonate to generate a free water clearance greater than that in adults (92,231,232). Yet, despite the high capacity for free water clearance, the ability of the neonate to excrete a hypotonic load is limited, presumably as a result of the low GFR.
Antidiuretic Hormone
The limited ability of the immature kidney to concentrate urine is not a result of an inability to synthesize and secrete ADH. In fact, circulating levels of ADH are elevated in preterm and term infants and decrease rapidly in term infants within 24 hours of birth (63,233). Studies in fetal and newborn animals (65,234,235), and in human infants (233,236), indicate a qualitatively appropriate response to osmolar or volume stimuli known to affect ADH release. Furthermore, exogenous administration of ADH or 1-desamino-8-d-AVP (DDAVP) to healthy 1- to 3-week-old newborns leads to a response, albeit of shorter duration and reduced magnitude than that observed at 4 to 6 weeks (237). Cumulative evidence suggests that the blunted sensitivity of the fetal and neonatal kidney to AVP and limited concentrating ability of the neonatal animal is not a result of a paucity of V2 receptors (V2R; receptor to which ADH binds in the collecting duct) (238,239), aquaporin channels involved in water transport across renal tubule epithelia (240), or efficiency of coupling to second messengers (adenylate cyclase and protein kinase A activity) (241,242,243) after the first week of postnatal life but is limited primarily by the poorly developed corticomedullary osmotic gradient.
▪ CLINICAL EVALUATION OF RENAL FUNCTION AND RENAL DISEASES
Early diagnosis of a renal anomaly may help to prevent complications, including those related to the kidney itself (e.g., progressive loss of renal function as a result of systemic hypertension, obstructive or reflux uropathy, or infection) and those related to systemic disorders (shock, hypothermia, respiratory failure, hypoxemia, congenital metabolic disorders), therapy (nephrotoxic dugs), or other organs (e.g., cerebral hemorrhage, seizures or congestive heart failure [CHF] secondary to hypertension, ventricular
arrhythmia secondary to hyperkalemia, urosepsis). In this section, clinical and laboratory features that should raise suspicion of a renal problem are reviewed and an approach to establish the correct diagnosis is presented.
arrhythmia secondary to hyperkalemia, urosepsis). In this section, clinical and laboratory features that should raise suspicion of a renal problem are reviewed and an approach to establish the correct diagnosis is presented.
Incidence of Renal and Urinary Tract Malformations
Use of prenatal US is a good screening tool in detecting congenital malformations of the urinary tract (approximately 80% detection rates). However, accuracy of ultrasonography is operator dependent, and kidney visualization may be limited by high maternal body mass index. The incidence of urinary tract malformations is 1% to 2% by prenatal US screening (244). Unfortunately, many abnormalities are missed even by expert sonographers (245). Prenatally detected renal malformations should result in a careful examination for further anomalies. In about one-third of the cases, renal malformations are within the category of associated malformations, which include multiple non-syndromal malformations, chromosomal aberrations, and nonchromosomal syndromes (246).
Review of Prenatal/Family history
It is imperative to review details of the present pregnancy and pertinent family history along with details of prenatal US while evaluating an infant with renal abnormalities. The risk of renal or urinary tract malformation or renal failure is increased by maternal diabetes and by certain medications or drugs, including ACE inhibitors, angiotensin receptor blockers, nonselective NSAIDs, and selective COX-2 inhibitors. ACE inhibitor fetopathy is characterized by fetal hypotension, anuria-oligohydramnios, growth restriction, pulmonary hypoplasia, renal tubular dysplasia, and hypocalvaria (247). Maternal cocaine abuse and polydrug abuse are associated with higher incidence of genitourinary malformations with odds ratio varying from 5 to 6.1, respectively (248).
Maternal diabetes, especially in poorly controlled cases, is associated with a higher incidence of urogenital malformations (2.6% vs. 1.2% in controls) (249) and neonatal renal vein thrombosis. The risk for renal or urinary tract malformations is higher in an infant of a diabetic mother with a caudal regression syndrome or a femoral hypoplasia-unusual facies syndrome. Fetal alcohol syndrome is associated with unilateral renal agenesis, renal hypoplasia, ureteral duplication, and hydronephrosis (250).
TABLE 39.1 Elements of Prenatal Urologic Ultrasonographic Diagnosis | ||||||||||||||||||||||||||||||||||||||||||||||||
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A high maternal serum or amniotic alpha-fetoprotein (AFP) concentration is associated with several anomalies, including bladder exstrophy, myelodysplasia (which may be associated with urinary tract malformations), and congenital nephrotic syndrome of the Finnish type (CNF). Increased maternal serum AFP concentration is associated with pyelectasis and thick-walled bladder (251).
Oligohydramnios may result from amniotic sac rupture, prolonged leaking, or fetal oligoanuria. The latter can result from bilateral congenital renal disease, bilateral urinary tract obstruction, acquired fetal renal disease secondary to maternal administration of indomethacin or ACE inhibitors (252,253,254), or severe pregnancyinduced hypertension. Among many causes, polyhydramnios may be the first clue to the diagnosis of a nephrogenic defect of urinary concentration, whereas fetal hydrops may be the first sign of congenital nephrotic syndrome.
Positive family history should be sought for hereditary disease, including renal cystic disease, tubular disorders, and nephrotic syndrome. There is a 9% incidence of asymptomatic renal malformations—most often unilateral renal agenesis—in the firstdegree relatives of infants with agenesis or dysgenesis of both kidneys or agenesis of one kidney and dysgenesis of the other (255). The clinician should keep in mind that some autosomal dominant diseases have variable penetrance or time of presentation (e.g., adult-type polycystic kidney disease [PKD]) and that a new mutation may occur. Additionally, a history of prior fetal loss should be carefully reviewed, preferably with an autopsy review.
Prenatal Sonography
Prenatal sonography for diagnosis of CAKUT should include assessment of kidney size, echogenicity, structural malformations; ureters; bladder size, shape, and thickness; ascites; other organs; and amniotic fluid volume. Table 39.1 provides important prenatal findings with possible causes. One study has reported that 25% to 65% of pregnancies with diagnoses of spina bifida, posterior
urethral valves (PUVs), prune belly syndrome, and exstrophy were electively terminated (256). Patients with bilateral hydronephrosis and oligohydramnios may be candidates for fetal intervention aiming at preservation of renal and pulmonary function (257).
urethral valves (PUVs), prune belly syndrome, and exstrophy were electively terminated (256). Patients with bilateral hydronephrosis and oligohydramnios may be candidates for fetal intervention aiming at preservation of renal and pulmonary function (257).
Physical Examination
Special attention should be paid to a detailed physical examination that includes focusing on the presence of dysmorphic features/anomalies, evaluating volume status in a newborn with suspected renal disease, measuring BP accurately, and undertaking a careful abdominal/systemic examination.
Congenital Anomalies
Any dysmorphic feature should alert the provider to underlying renal abnormalities, especially the presence of vertebral, cardiac, limb, or anorectal anomalies suggesting a possible VACTERL syndrome, aniridia, hemihypertrophy, abnormalities of external genitalia, or limb deformities. The most typical sequence related to kidney disease is the oligohydramnios sequence, that is, Potter syndrome, which may result from prolonged leakage of amniotic fluid or from intrauterine oligoanuria. Fetal deformation caused by severe oligohydramnios includes Potter facies, which is characterized by a redundant, wrinkled skin, flat nose, low-set ears, bilateral skin folds arising at the inner canthus, receding chin, and malposition of the hands and feet (258). Lung hypoplasia results from fetal compression as a result of the oligohydramnios (259) and, in some cases, massive abdominal distention. Readers are referred to Online Mendelian Inheritance in Man (OMIM) Web site (http://www.omim.org) for major signs of multiple congenital anomalies associated with CAKUT.
Upper urinary tract anomalies may be associated with several isolated anomalies (e.g., abnormal vertebrae—agenesis, ectopic, horseshoe kidney, duplication, and anorectal malformations— agenesis, duplication, VUR, hypospadias, UPJ obstruction, neurogenic bladder). The presence of specific index signs should raise the suspicion of a known multiple congenital anomaly. The association of the presence of isolated single umbilical artery (SUA) in infants with occult renal malformations has been controversial. In a large series of isolated SUA, there was no excess of significant renal malformations among infants with isolated SUA. Thus, postnatal renal imaging of such infants, especially in an era of now routine prenatal fetal sonography, is not routinely warranted (257,260,261).
Preauricular pits (sinuses) are common congenital abnormalities; usually they are asymptomatic. They can be sporadic or inherited. They may be bilateral, increasing the likelihood of being inherited, in 25% to 50% of cases. Preauricular sinuses are features of other conditions or syndromes in 3% to 10% of cases, primarily in association with deafness and branchio-oto-renal (BOR) syndrome. When other congenital anomalies coexist with these sinuses, or if there is an association of a syndrome or family history of hearing or renal impairment, auditory testing and renal US should be considered (262). In infants with isolated preauricular pits or tags, probably it is not necessary to investigate for a hearing or genitourinary abnormality (262).
Several limb anomalies are part of syndromes or sequences associated with renal or urinary tract malformations, such as skeletal dysplasia, caudal regression syndrome, radial aplasia, femoral hypoplasia, rocker bottom feet, compression deformation, polydactyly, syndactyly, and hemihypertrophy.
Measurement of Blood Pressure
Some neonates have their BP measured directly through an indwelling umbilical artery (UA) catheter; this technique provides the most accurate method of measuring BP, except for minor artifacts from air bubbles or blood clots in the tubing (263). The most commonly used indirect method of BP measurement is the oscillometric technique, which directly measures MAP based on the oscillations of the arterial wall; systolic and diastolic BP are then back-calculated from the MAP using manufacturer-specific algorithms. These devices are usually sufficiently accurate for routine clinical use, although the readings obtained by oscillometric devices may differ between 1 to 5 mm Hg compared to directly measured BP (264). Shock may also lead to inaccurate oscillometric measurements (265). Despite these issues, oscillometric devices clearly are useful for measuring BP in infants without indwelling arterial catheters (especially those who require frequently repeated BP measurement) and in infants who have been discharged from the nursery.
Selection of a proper-sized cuff is crucial for correct indirect BP measurement. As discussed in the Fourth Report of the National High Blood Pressure Education Program (266), the length of the cuff bladder should be 80% to 100% of the arm circumference and the width of the cuff should be one-third the length of the upper arm as measured between the olecranon and acromion. If BP is measured in the calf, it is important to use a wide enough cuff; cuffs designed for use in the upper arm may be too narrow, resulting in a falsely high BP reading. Calf BPs are generally the same as upper arm BPs in neonates, and this similarity has been shown to persist for as long as the first 6 months of life. This has implications for the diagnosis of coarctation of the aorta in neonates (267,268,269).
Many studies have examined the pattern of normal BP in normal and premature infants (270,271,272). Zubrow et al. (273) examined BPs obtained in over 600 infants of varying birth weights (BWs) and GAs admitted to 14 NICUs. They found that BP at birth is closely correlated with GA and BW (Figs. 39.5 and 39.6).
There is a predictable increase in BP over the first 5 days of life that is independent of these factors. Thereafter, BP continues to rise gradually, with the most important determining factor in the Zubrow study being postmenstrual (postconceptual) age (Fig. 39.7). A more recent study of stable NICU infants showed a
similar pattern, with BPs in each GA category of premature infants increasing at a faster rate over the first week of life with subsequent slowing (274). In these infants, they determined that the rate of rise was more rapid in preterm than full-term infants. Dionne et al. (275) have recently summarized available BP data on preterm neonates and have published a table of BP values that is helpful in categorizing an infant’s BP as normal or elevated (Table 39.2).
similar pattern, with BPs in each GA category of premature infants increasing at a faster rate over the first week of life with subsequent slowing (274). In these infants, they determined that the rate of rise was more rapid in preterm than full-term infants. Dionne et al. (275) have recently summarized available BP data on preterm neonates and have published a table of BP values that is helpful in categorizing an infant’s BP as normal or elevated (Table 39.2).
 FIGURE 39.5 Blood pressure by gestational age. Linear regression between gestational age and mean systolic (A) and diastolic (B) BP, along with the upper and lower 95% confidence limits, which approximate mean ± 2 standard deviations. Reprinted from Zubrow AB, Hulman S, Kushner H, et al. Determinants of blood pressure in infants admitted to neonatal intensive care units: a prospective multicenter study. J Perinatol 1995;15:470-479, with permission. |
 FIGURE 39.6 Blood pressure by birth weight. Linear regression between BW and mean systolic (A) and diastolic (B) BP, along with the upper and lower 95% confidence limits, which approximate mean ± 2 standard deviations. Reprinted from Zubrow AB, Hulman S, Kushner H, et al. Determinants of blood pressure in infants admitted to neonatal intensive care units: a prospective multicenter study. J Perinatol 1995;15:470-479, with permission. |
BP increases when an infant is awake, in the knee-chest position, with crying, with pain, and during physical examination and procedures or during feeding (267,276,277,278). Because of these factors, it is important to follow a standard approach for BP measurement in neonates; the protocol described by Nwankwo et al. (279) is appropriate. Measurements in NICU graduates should only be obtained when the infant is asleep or calm (280).
Examination by Systems
Physical examination may show evidence for rash, respiratory failure, insufficient preload, shock, CHF, liver failure, bleeding diathesis, or encephalopathy. Daily body weight should be compared to the normal evolution of postnatal weight (281). Signs of dehydration include weight loss, sunken fontanelle, and signs of hypovolemia. In newborn infants, generalized edema usually starts around the eyes, at the perineum, and on the lateral sides of the trunk. Edema may be a sign of fluid overload, AKI, or nephrotic syndrome, among other causes. Tachyarrhythmia, premature ventricular contractions, or abnormal QRS complexes on cardiac monitoring may be the first sign of hyperkalemia, which may be as a result of, or related to, renal immaturity or AKI. A small chest suggests hypoplastic lungs, which can be associated with renal and urinary tract malformations. Seizures or coma may be as a result of hypertension or complications of renal failure. Motor and sensory dysfunction of the lower limbs suggests an occult spinal dysraphism.
 FIGURE 39.7 Blood pressure by postmenstrual age. Linear regression between postconceptual age and mean systolic (A) and diastolic (B) BP, along with the upper and lower 95% confidence limits, which approximate mean ± 2 standard deviations. Reprinted from Zubrow AB, Hulman S, Kushner H, et al. Determinants of blood pressure in infants admitted to neonatal intensive care units: a prospective multicenter study. J Perinatol 1995;15:470-479, with permission. |
Abdominal examination may show distention, hepatosplenomegaly, peritonitis, pneumoperitoneum, or ascites. In a stable neonate, deep bimanual palpation should be done to assess the presence of a normal kidney in each flank. The examination is easiest soon after birth, before the bowel is filled with gas; later on, it is facilitated by relaxation of the abdominal wall musculature obtained, for instance, by eliciting the sucking reflex. Several characteristics of the kidneys should be evaluated, including location (normally in the flank; an ectopic kidney may be located in the pelvis), size (the normal size for a 3.3 ± 0.5 [mean ± SD] kg infant is 4.2 to 4.3 ± 0.5 cm) (282,283), and long axis (normally cephalocaudal). A horseshoe kidney may be suspected if the lower pole is closer to the midline than the upper pole. The consistency of a normal kidney is firm, in contrast to a cystic or a hydronephrotic kidney, which may be depressible. The surface normally is smooth, but large cysts can be palpated in multicystic or autosomal dominant polycystic kidneys.
Two-thirds of abdominal masses are genitourinary in origin and may be as a result of a polycystic/multicystic kidney, renal vein thrombosis, congenital or acquired hydronephrosis (e.g., as a result of a fungus ball or papillary necrosis), or a renal tumor (281,282). A suprapubic mass suggests bladder distention, which may result from lower urinary tract obstruction (suggested by dribbling), an occult spinal cord lesion (suggested by sphincter dysfunction), or deep sedation. In some patients, one or both kidneys cannot be palpated. This may be as a result of a less than optimal examination (e.g., absence of patient relaxation, bowel distention), unilateral
renal agenesis, renal malposition (in which case the kidney may be felt at another place in the abdomen), or renal hypoplasia or aplasia. Some abnormalities of the abdominal wall, such as bladder exstrophy, cloacal exstrophy, and prune belly syndrome, are associated with renal anomalies.
renal agenesis, renal malposition (in which case the kidney may be felt at another place in the abdomen), or renal hypoplasia or aplasia. Some abnormalities of the abdominal wall, such as bladder exstrophy, cloacal exstrophy, and prune belly syndrome, are associated with renal anomalies.
TABLE 39.2 Neonatal and Infant Blood Pressure Normative Data after 2 Weeks Chronologic Age Based on Postmenstrual Age (Gestational Age + Chronologic Age) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Anorectal anomalies or ambiguous genitalia, including severe hypospadias (284), should raise the suspicion of associated renal or urologic malformations. Percussion of the abdomen may disclose ascites or a large bladder. In the absence of hydrops fetalis, neonatal ascites commonly is as a result of the rupture of an obstructed urinary tract (285).
Urine Evaluation
Time of the First Postnatal Voiding
With early feeding, 97% of all infants void within 24 hours after birth (including in the delivery room) (286). Urine produced in utero normally is dilute, with an average osmolality less than 200 mOsm/kg. Higher osmolality in utero may result from obstructive urinary tract disease, poor tubular reabsorption of sodium, administration of oxytocin or indomethacin to the mother, or intrauterine asphyxia. Urine produced after birth usually is isotonic or hypertonic, probably as a result of increased release of oxytocin and ADH.
Urine Output
In full-term infants, urine output after the first day of life increases progressively, in parallel with daily intake. In low BW (LBW, <2,500 g) and VLBW infants, three phases occur in the early postnatal period: an oliguric phase, during which the urine output is always lower than the intake; a polyuric phase starting between 24 and 72 hours of age, during which the output exceeds the intake; and an adaptive phase, during which the kidney adjusts to the rate of fluid intake (287,288). A diuretic phase is observed in most infants, regardless of respiratory status or environment. The diuretic phase is associated with a high excretion of sodium and chloride, and, in much smaller amounts, potassium and bicarbonate (289).
Urine output may be normal in patients with AKI, because some infants may present with nonoliguric renal failure.
Characteristics of Urination
The neonate should be observed for dribbling or persistence of a large bladder after urination, suggesting either PUV or neurogenic bladder. Urination through an abnormal location suggests hypospadias, epispadias, ambiguous genitalia, or both. Additional discussion can be found in Chapter 40.
Urinalysis
The examination of a freshly voided urine specimen provides valuable information about the condition of the kidneys. Urine collection may be made by attaching an adhesive plastic bag to the perineum, by expressing urine from gel-free diapers, or by bladder catheterization. Urine culture should be obtained by suprapubic bladder aspiration or by bladder catheterization. Urinalysis assesses the presence of protein, glucose, blood, pH and performs microscopic analysis for leukocyturia and hematuria, crystals, and casts and measurement of specific gravity and osmolality. Massive glycosuria may occur when glycemia is greater than 150 mg/dL, whereas mild glycosuria is common in VLBW infants even when glycemia is normal. A yellow-brown to green color may represent conjugated bilirubin. Presence of leukocyte esterase and nitrite may raise suspicion of urinary tract infection (UTI).
Assessment of Renal Function
Measurement of Glomerular Filtration Rate
Inulin clearance is the gold standard marker for assessing GFR in children and adults because it is freely filtered and not secreted or reabsorbed. Other markers include polyfructosan, radionuclides such as 99mtechnetium-diethylenetriaminepentaacetic acid (DTPA), and cystatin C (CysC) (290). GFR may be expressed in mL/min, mL/min/1.73 m2 of BSA, mL/min/kg of body weight, or mL/min/kg of lean body mass; which of these units is most appropriate for infants is controversial.
In the clinical setting, GFR often is estimated by creatinine clearance or by comparing serum creatinine (Scr) concentration to normal values for GA and postnatal age (Figs. 39.8 and 39.9). When neonatal GFR is calculated from Scr, initial values reflect a combination of maternal Scr and neonatal tubular reabsorption from leaky, immature tubules. In full-term infants, Scr decreases exponentially
after birth (291), whereas in VLBW infants, it increases in the first 36 to 96 hours of life and then gradually decreases. In the most immature infants, the increase in Scr is higher and the decrease is more gradual, probably as a result of a slower progression of glomerular function and a greater backflow across the immature tubular and vascular structures (292,293) (Figs. 39.8 and 39.9). Thus, the initial rise in Scr in VLBW infants is probably a result of maturational changes in GFR and tubular creatinine leak and is not necessarily a sign of AKI (294). GFR may be adversely affected by nephrotoxic drugs (e.g., COX inhibitors), septicemia, and the use of diuretics (295). Vieux et al. (296) have published reference values for GFR in very preterm infants (Fig. 39.10).
after birth (291), whereas in VLBW infants, it increases in the first 36 to 96 hours of life and then gradually decreases. In the most immature infants, the increase in Scr is higher and the decrease is more gradual, probably as a result of a slower progression of glomerular function and a greater backflow across the immature tubular and vascular structures (292,293) (Figs. 39.8 and 39.9). Thus, the initial rise in Scr in VLBW infants is probably a result of maturational changes in GFR and tubular creatinine leak and is not necessarily a sign of AKI (294). GFR may be adversely affected by nephrotoxic drugs (e.g., COX inhibitors), septicemia, and the use of diuretics (295). Vieux et al. (296) have published reference values for GFR in very preterm infants (Fig. 39.10).
 FIGURE 39.8 Postnatal evolution of Scr (mmol/L) in preterm infants. Values are given as mean and standard error. From Gallini F, Maggio L, Romagnoli C, et al. Progression of renal function in preterm neonates with gestational age < or = 32 weeks. Pediatr Nephrol 2000;15:119-124. |
If measured reliably, Scr is correlated with the half-life of medications eliminated by glomerular filtration (297,298,299). A reasonably accurate estimation of GFR can be made by using an empirically derived formula (291), which has been applied to normal preterm and term infants (300).
 FIGURE 39.9 Postnatal evolution of creatinine clearance (mL/min/1.73 m2) in preterm infants. Values are given as mean and standard error. From Gallini F, Maggio L, Romagnoli C, et al. Progression of renal function in preterm neonates with gestational age < or = 32 weeks. Pediatr Nephrol 2000;15:119-124. |
Preterm infants: Estimated GFR (mL/min/1.73 m2) = 0.33 × length (cm)/Scr (mg/dL)
Term infants: Estimated GFR (mL/min/1.73 m2) = 0.45 × length (cm)/Scr (mg/dL)
Alternatively, simple mathematical formulae may enable the practitioners to calculate quickly the reference GFR median value for a determined GA (in completed weeks) (296).
Day 7: GFR = -63.57 + 2.85 × GA
Day 14: GFR = -60.73 + 2.85 × GA
Day 21: GFR = -58.97 + 2.85 × GA
Day 28: GFR = -55.93 + 2.85 × GA
Blood Urea Nitrogen
A high value of blood urea nitrogen (BUN) can result from catabolism, dehydration, high protein load (e.g., oral, intravenous, gastrointestinal bleeding), or renal failure. A low value of BUN
can result from ECF expansion or decreased production of urea. The latter may be observed in association with anabolism, low protein intake, urea cycle disorder, liver failure, or liver immaturity (301).
can result from ECF expansion or decreased production of urea. The latter may be observed in association with anabolism, low protein intake, urea cycle disorder, liver failure, or liver immaturity (301).
 FIGURE 39.10 Reference values of GFR (mL/min/1.73 m2) in very premature infants during the first month of life. From Vieux R, Hascoet JM, Merdariu D, et al. Glomerular filtration rate reference values in very preterm infants. Pediatrics 2010;125: e1186-1192. |
New Biomarkers for Acute Kidney Injury
Over the last few years, several novel serum and urinary biomarkers have been under intense scrutiny for their role as noninvasive indicators of early AKI (302). Numerous biomarkers have been tested in critically ill populations. Some of the most promising urine biomarkers are CysC (303,304), neutrophil gelatinase-associated lipocalin (NGAL) (305,306), interleukin-18 (IL-18) (304,307), and kidney injury molecule-1 (KIM-1). Several studies in neonates suggest that these biomarkers can predict a rise in Scr (307,308,309,310,311). More data are needed before these biomarkers can be incorporated into clinical care. Importantly, premature infants have higher levels of urine biomarkers at baseline than do term infants; thus, evaluation of these novel biomarkers needs to be adjusted for GA (312).
Serum CysC has all of the theoretical properties needed to be an ideal marker of renal function. It can be used to determine baseline renal function on day 1 and is increasingly being used to determine renal function in sick neonates. In the majority of studies, the day 1 CysC level ranged between 1 and 2 mg/L, which gradually declines in the first year of life. CysC levels do not differ between male and female infants but depend on GA and PMA. A recent study with 246 patients showed GA- and PMA-dependent changes in CysC; therefore, consideration of these parameters is warranted when assessing CysC levels in neonates (313). CysC levels can be increased in cases of sepsis, AKI, and CAKUT (303).
Plasma Renin Activity
The most common indication for the measurement of PRA is the evaluation of hypertension. Normal levels of PRA are higher in the newborn infant than in older children or adults. See “Developmental Physiology” section and section on “Hypertension.”
Urinary Acidification
Immaturity of renal tubular acidification results in a significantly lower value of serum bicarbonate concentration in VLBW infants than in full-term infants. In parallel, the serum base excess is often between -5 and -10 mEq/L in VLBW infants, compared with 0 to -5 mEq/L in full-term infants, and the anion gap is normally 15 to 22 mEq/L in premature infants, compared to 12 ± 2 mEq/L (<15 mEq/L) in full-term infants. In newborn infants, metabolic acidosis with high anion gap may result from lactic acidosis (asphyxia, hypoxia, shock, congenital heart disease, sepsis, or local tissue damage), an inborn error in metabolism (see Chapter 38), or renal failure. Metabolic acidosis with normal anion gap may result from renal tubular acidosis (RTA), gastrointestinal loss of bicarbonate, or cysteine chloride (in parenteral nutrition). Measurement of urine pH and of urine-to-blood carbon dioxide tension gradient is indicated to rule out distal renal tubular acidosis (dRTA) (314) (see “Tubular Function”).
Urine Electrolytes and Osmolality
The measurement of urinary and blood osmolality, urea, creatinine, and electrolytes is indicated for the differential diagnosis of polyuria and hyponatremia and for the early diagnosis of AKI.
Genetic, Biochemical, and Molecular Diagnostics
Recent technologic advances in chromosomal analysis and “fluorescent in situ hybridization” (FISH), metabolic and molecular testing, and newborn screening now make it possible to diagnose many patients who have genetic disorders in the newborn period. Such accurate and early diagnosis can lead to improved medical care and prognosis for many of these infants (see Chapters 10, 12, 35, and 38). Biochemical diagnosis is possible either by measuring enzyme activity or a chemical in a biologic fluid (e.g., high AFP concentration in maternal serum or amniotic fluid suggesting a diagnosis of CNF in a high-risk family) or in cultured cells obtained from chorionic villi, amniotic cells, or fibroblasts (e.g., for diagnosing cystinosis).
There are a number of methods used in genetic analysis (see Chapter 35). In many disorders, the gene has been mapped to
a specific chromosomal locus and is genetically linked to DNA markers. Genetic diagnosis is then possible on amniotic fluid, chorionic villous, or blood samples, if one or more specific alleles are informative, that is, characteristic for the disease in a given family or in a given population (e.g., in CNF, see later in this chapter). If the gene responsible for a particular disease has been cloned and sequenced, the specific mutation in an affected individual or family can be determined by polymerase chain reaction (PCR), followed by sequence analysis or another method. Molecular diagnosis may be complicated by the fact that a similar phenotype may result from mutations of one of two or more genes, for example, autosomal dominant PKD (ADPKD) (chromosomes 16, 4, and 2) and nephrogenic diabetes insipidus (NDI). Researchers have recently reported sequencing a fetal genome from cell-free fetal DNA in a pregnant mother’s blood heralding the possibility of performing whole genome sequencing as early as the first trimester of pregnancy (315). Readers are referred to excellent reviews for detailed information on genomic diagnosis of kidney diseases (316,317,318).
a specific chromosomal locus and is genetically linked to DNA markers. Genetic diagnosis is then possible on amniotic fluid, chorionic villous, or blood samples, if one or more specific alleles are informative, that is, characteristic for the disease in a given family or in a given population (e.g., in CNF, see later in this chapter). If the gene responsible for a particular disease has been cloned and sequenced, the specific mutation in an affected individual or family can be determined by polymerase chain reaction (PCR), followed by sequence analysis or another method. Molecular diagnosis may be complicated by the fact that a similar phenotype may result from mutations of one of two or more genes, for example, autosomal dominant PKD (ADPKD) (chromosomes 16, 4, and 2) and nephrogenic diabetes insipidus (NDI). Researchers have recently reported sequencing a fetal genome from cell-free fetal DNA in a pregnant mother’s blood heralding the possibility of performing whole genome sequencing as early as the first trimester of pregnancy (315). Readers are referred to excellent reviews for detailed information on genomic diagnosis of kidney diseases (316,317,318).
Imaging of the Kidney and the Urinary Tract
Ultrasonography and Doppler Flow Analysis
US is performed to screen for CAKUT or as one of the first steps in the workup of AKI, hypertension, UTI, or hematuria (319). Indications for the performance of neonatal US are shown in Table 39.3. It has been reported that children with congenital hypothyroidism have an increased prevalence of CAKUT. Thus, it may be helpful to evaluate them for the presence of congenital renal and urologic anomalies with renal US. Further studies of common genes involved in thyroid and kidney development may be warranted (320).
US is a sensitive and reliable method for the detection of renal calcifications, including urolithiasis and NC. The bright foci are almost always located in the medulla, rarely in the pyelocalyceal system (321,322). NC can present as white dots or white flecks and diminishes gradually over a period of months to years. NC does not influence kidney length in the first 2 years of life. In contrast to medullary NC, cortical NC is rare in neonates. Cortical NC develops within a few weeks of acute renal cortical necrosis and may be evident radiographically as a rim of cortical calcification (322). Diffuse cortical NC has been reported in a 2-month-old infant who had primary hyperoxaluria (PH) (323).
Recently, high-resolution images obtained with high-frequency linear array transducers have allowed excellent characterization of renal parenchymal architecture and pathologic conditions. In neonates, the US appearances are distinctive, because the renal cortex has echogenicity equal to or greater than that of the liver and spleen, whereas in older children, the cortex is hypoechoic relative to other organs (324). The differential diagnosis of US anomalies is presented in Table 39.4.
Blood flow through renal vessels can be assessed by Doppler US, which is indicated for the evaluation of hematuria, hypertension, and AKI, especially in a patient with a history of UA catheterization. Pulsed Doppler flow analysis, that is, duplex scanning, allows the measurement of blood flow velocity, which gives an assessment of RBF, and calculation of the ratio of enddiastolic minimum velocity to systolic peak velocity (i.e., diastolic-to-systolic ratio), thereby helping in the assessment of RVR (325).
Voiding Cystourethrogram
VUR and bladder obstruction should be ruled out in patients with hydronephrosis, renal dysplasia, trabeculated bladder, bladder distention, or myelomeningocele. Lateral views of the male urethra are mandatory for the diagnosis of PUV (326). In a neonate with symptomatic UTI, US may be done initially to assess the presence of obstructive uropathy and signs of renal involvement; recent studies suggest that US may be omitted if a third trimester prenatal US has excluded CAKUT (327,328). If no dilatation is seen and there is a good response to treatment, voiding cystourethrogram (VCUG) can be delayed. If US demonstrate an abnormal bladder, VCUG should be undertaken as soon as possible.
TABLE 39.3 Indications for Ultrasonography to Rule Out Renal-Urinary Tract Malformations and/or Acquired Renal Disease in Newborn Infants | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Renal Radionuclide Scan
Mercaptoacetyltriglycine (MAG-3) has become the isotope of choice in neonates and infants. It has a high protein binding and thus remains in the blood pool rather than being distributed in the extravascular space, as with 99mTc-DTPA. The renal extraction of MAG-3 is virtually double that of DTPA (326,329). In contrast, 99mTc-dimercaptosuccinic acid (DMSA) binds to the PCTs and is only minimally excreted into the urine; it is preferred for the analysis of renal morphology and differential function. Typical indications for radionuclide studies include renovascular hypertension, lack of visualization of a kidney by US, preoperative evaluation of the severity of urinary tract obstruction, and evaluation of differential renal function. However, due to immaturity of renal function in newborn infants, many pediatric nephrologists and urologists will wait until the infant is at least 1 month postterm before ordering such studies in order to obtain an interpretable result.
TABLE 39.4 Renal Ultrasonographic Patterns in Newborn Infants | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Computed Tomography and Magnetic Resonance Imaging
Computed tomography (CT) and magnetic resonance imaging (MRI) are indicated in the diagnosis of renal tumors, renal abscess, and nephrolithiasis. MRI T2-weighted images (which emphasize the difference in transverse relaxation times between different tissues) are independent of renal function, and provide images in which water is bright, and with excellent contrast between normal and abnormal tissues (329). MRI offers many advantages: The contrast medium, gadolinium chelate, is not nephrotoxic, no ionizing radiation is used, and high-resolution three-dimensional images can be obtained (329). Lack of nephrotoxicity makes MRI the ideal modality to follow renal transplants (330). However, caution should be exercised in undertaking gadolinium-enhanced MRI in patients with AKI and in infants with CKD, since nephrogenic systemic fibrosis with gadolinium has been reported (331,332). Additionally, MRI appears to be more sensitive than US in detecting a tethered cord in a patient with bladder distention and lack of VUR or urethral stenosis on VCUG. Gadolinium-enhanced magnetic resonance (MR) angiography using a fast three-dimensional gradient echo sequence allows a good depiction of the major vessels.
Renal Pathology
Renal biopsy is indicated in nephrotic syndrome and may be indicated in PKD, hematuria, or persistent severe renal failure of unclear origin. Major contraindications to renal biopsy include bleeding diathesis, anticoagulant therapy, moderate or severe hypertension, solitary kidney, and intrarenal tumor (333). The technique involves visualization of the kidney using US, radioisotope, or radiopaque contrast. The most common complication is macroscopic hematuria, which occurs in 5% to 7% of biopsies.
▪ ACUTE KIDNEY INJURY
Introduction
The term AKI has replaced what was previously known as acute renal failure, primary to highlight that this condition should be recognized early during the course of “injury” as opposed to waiting until the organ has failed. AKI occurs whenever there is a sudden deterioration in the ability of the kidneys to maintain proper homeostasis. This can be associated with an acute decrease in GFR (functional change) or anatomical change (i.e., acute tubular damage). AKI can be manifested as accumulation of uremic toxins, electrolyte abnormalities, or inability to maintain adequate fluid balance. Because the placenta fulfills the role of the kidney in utero, congenital malformations associated with limitation of renal function will not lead to renal dysfunction until delivery.
Pathophysiology and Differential Diagnosis of AKI in Neonates
With advancements in the field of critical care medicine and other fields of pediatrics, the etiology of AKI has changed in large tertiary centers, whereby less than 10% of those with AKI (334) and those who receive continuous renal support (335) have a primary renal diagnosis. Similarly, most neonates who develop AKI are born with normal kidney function, and the cause of AKI is inherent to the interventions, other organ failures, presence of sepsis/shock, or nephrotoxic medications. Primary renal diseases (such as congenital nephrotic syndrome or acute glomerulonephritis) are rare in newborns. However, many infants with renal failure in the neonatal ICU have congenital diagnosis (Table 39.5).
AKI is commonly multifactorial. Classically, the underlying cause of rising Scr/drop in urine output has been divided into prerenal azotemia, renal injury, and postrenal obstruction. As newer diagnostic techniques become available at the bedside, we will soon be able to also differentiate infants with AKI as having functional change (i.e., rise in Scr), structural (markers of tubular injury) damage, or both.
Prerenal Azotemia
Prerenal azotemia (sometimes referred to “prerenal failure”) occurs in response to decreased RBF. Causes of prerenal azotemia are listed in Table 39.6. Renal hemodynamic changes associated with autoregulation of GFR decrease water and sodium losses, so as to maintain systemic volume expansion and BP.
In patients with prerenal azotemia and intact tubular function, tubular reabsorption of sodium and urea increases. This is reflected
by low urine sodium concentrations (FENa < 1%), low urine urea concentration (FEUrea < 35%), and increased blood urea:creatinine ratio. These renal indices should be interpreted with caution when baseline tubular function is affected by prematurity, salt-losing state, or CKD. In one study of children with AKI, FEUrea was found to be a more useful index (336). However, another study in neonates suggests that FEUrea does not help differentiate prerenal insult from acute tubular necrosis.
by low urine sodium concentrations (FENa < 1%), low urine urea concentration (FEUrea < 35%), and increased blood urea:creatinine ratio. These renal indices should be interpreted with caution when baseline tubular function is affected by prematurity, salt-losing state, or CKD. In one study of children with AKI, FEUrea was found to be a more useful index (336). However, another study in neonates suggests that FEUrea does not help differentiate prerenal insult from acute tubular necrosis.
TABLE 39.5 Etiology of Congenital Acute Kidney Injury | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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This period of renal hypoperfusion, referred to as “renal angina,” is critical to recognize and treat to prevent cellular damage (337). Correction of the underlying cause of hypoperfusion restores GFR unless renal hypoperfusion is severe enough to cause renal tubular and endothelial damage, that is, intrinsic AKI.
Intrinsic Acute Kidney Injury
Ischemic Acute Kidney Injury
Prerenal azotemia and ischemic AKI are a continuum of physiologic responses. Prolonged or severe hypoperfusion causes injury to renal parenchymal cells, particularly to tubular epithelium of the terminal medullary portion of the proximal tubule (S3 segment) and of the medullary portion of the TALH. In contrast to prerenal azotemia, renal function abnormalities in intrinsic AKI are not immediately reversible. The severity of intrinsic AKI ranges from mild tubular dysfunction to acute tubular necrosis, renal infarction, and corticomedullary necrosis with irreversible renal damage. Prerenal azotemia and intrinsic acute tubular necrosis can be differentiated using several methods (Table 39.7).
The course of ischemic AKI may be subdivided into the early, initiation, extension, maintenance, and recovery phases (338
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