In the past 25 years, the field of clinical neonatal nephrology has expanded significantly in concert with major advances and changes in the care and survival of neonates, particularly premature neonates. The widespread use of invasive vascular catheters, for example, has resulted in a new set of complications, including acute kidney injury (AKI) and renovascular hypertension related to thromboembolic disease. The improved survival of infants with extremely low birth weight and bronchopulmonary dysplasia has led to the relatively new complication of neonatal nephrocalcinosis. The increased use of prenatal ultrasonography has created new paradigms for the prenatal management of urinary tract anomalies (see Chapter 12). Kidney and urinary tract development is a complex process involving interactions between genes involved in the formation and maturation of the glomeruli, tubules, renal blood vessels, extracellular matrix, and uroepithelium. This carefully coordinated process involves the regulated activation and inactivation of hundreds of genes that encode transcription factors, growth factors and receptors, structural proteins, adhesion molecules, and other regulatory proteins.49 Since the mid-1990s, the rapidly expanding field of molecular genetics has provided important new insights into the mechanisms involved in renal and urinary tract development. This section highlights some of the important pathways involved in these processes and provides examples of human kidney diseases resulting from abnormalities in normal development. The process of kidney embryogenesis involves the formation of three different kidneys in succession: the pronephros, mesonephros, and metanephros. The formation of these structures during intrauterine development is illustrated in Figure 101-1. The pronephros, a vestigial structure of 7 to 10 solid or tubular cell groups called nephrotomes, develops in the cervical region and disappears by the end of the fourth week of gestation. As the pronephros regresses, the mesonephros appears and is characterized by excretory tubules that form an S-shaped loop, with a glomerulus and Bowman capsule at the proximal end. At the distal portion, the tubule enters the collecting duct (also referred to as the mesonephric or Wolffian, duct), which does not drain into the coelomic cavity. During the second month of gestation, the urogenital ridge, which is the forerunner of the gonads, develops. By the end of the second month of gestation, most portions of the mesonephros disappear. However, a few caudal tubules remain in close proximity to the testis and ovaries, developing into the vas deferens in males and remaining as remnant tissue in females. The formation of the metanephric, or definitive, kidney begins at 5 weeks of gestation, when a portion of the Wolffian duct swells to form the ureteric bud. The ureteric bud, composed of epithelium, then invades the nearby metanephric mesenchyme. This epithelial-mesenchymal signaling is initiated through interactions of the glial cell-derived neurotrophic factor (GDNF) expressed by the metanephric mesenchyme with its receptor, Ret, located on the tip of the ureteric bud. The ureteric bud then undergoes a series of divisions (called “branching morphogenesis”) that form the collecting ducts of the kidney as well as the major and minor caliceal system of the renal pelvis. At the tip of the branches the mesenchymal cells of the metanephric blastema are induced by the advancing ureteric bud to differentiate into the epithelial cells that eventually become the glomeruli and renal tubules. Foci of the metanephric blastema become condensed adjacent to the branching ureteric bud to form “comma”-shaped bodies that then elongate to form S-shaped bodies (Figure 101-2). The lower portion of the S-shaped body becomes associated with a tuft of capillaries to form the glomerulus, because the upper portion forms the tubular elements of the nephron. The metanephric kidney ascends from the pelvic to the thoracolumbar region. This process is thought to occur as the result of a decrease in body curvature and body growth of the lumbar and sacral regions. In the pelvis, the metanephric kidney receives its blood supply from a pelvic branch of the aorta. During ascent, the metanephric kidney receives its blood supply from arterial branches at higher levels of the aorta. Although the pelvic vessels usually degenerate, the persistence of these early embryonic vessels leads to supernumerary renal arteries. The metanephric kidney becomes functional during the second half of pregnancy. Nephrogenesis, which is the formation of new nephron units, is complete at 34 weeks of gestation, when each kidney contains its definitive complement of approximately 800,000 to 1.2 million nephrons.3 Although the GDNF/Ret tyrosine kinase signaling pathway is essential for normal renal development, studies in animal models have highlighted the important role of multiple other proteins and signaling mechanisms in nephrogenesis. As illustrated in Table 101-1, examples in mouse models include growth factors such as fibroblast growth factor (FGF), adhesion molecules such as integrin alpha 8, the transcription factor WT-1, and the canonical Wnt/beta catenin signaling pathway. Alterations in the actions of one or more of these proteins/pathways can result in renal/urogenital anomalies such as renal dysplasia, polycystic kidneys, and glomerulosclerosis. TABLE 101-1 Examples of Mouse Models of Developmental Kidney Diseases From the Kidney Development Database at http://golgi.ana.ed.ac.uk/kidhome.html. Accessed November 13, 2013; and the OMIM Database at http://www.ncbi.nlm.nih.gov/omim. Accessed November 13, 2013. Specific mutations have now been identified in several congenital and inherited monogenic kidney diseases, which have provided important clues to the pathogenesis of disease (Table 101-2). For example, patients with congenital nephrotic syndrome of the Finnish type have mutations in the gene encoding nephrin, an important component of the glomerular basement membrane. Bartter syndrome, a disorder that may present in the newborn period with hypokalemia, metabolic alkalosis, and severe dehydration, is caused by mutations in the ion transport proteins responsible for sodium and potassium handling in the loop of Henle. A variety of congenital abnormalities of the kidney and urinary tract have been found to be associated with mutations in developmentally expressed genes, including those of the renin-angiotensin system.72,81 TABLE 101-2 Examples of Inherited Renal Disorders with a Known Genetic Basis that Present in Infancy From the OMIM Database at http://www.ncbi.nlm.nih.gov/omim. Accessed November 13, 2013; and references 72 and 81. For some of these disorders, the pathogenesis may be evident from the nature of the abnormal protein product, such as impaired renal water handling in patients with nephrogenic diabetes insipidus who harbor mutations in genes encoding aquaporin 2 or the vasopressin V2 receptor, the key proteins that regulate water handling in the collecting tubule.63 However, there are several disorders, such as polycystic kidney disease, for which the causative genes have been identified but the precise mechanisms by which the mutated gene and its aberrant protein product actually cause disease have not been fully delineated. The bladder and urethra are formed during the second and third months of gestation, which is illustrated in Figure 101-3. During the fourth to seventh week of development, the cloaca, which is located at the proximal end of the allantois and is the precursor to the urinary bladder and urethra, is divided by the urorectal septum into the primitive urogenital sinus (anterior portion) and the anorectal canal (posterior portion). The primitive urogenital sinus develops into the bladder (upper portion), prostatic and membranous urethra (pelvic portion) in males, and the penile urethra (males) or urethra and vestibule (females). As the cloaca develops, the caudal portion of the mesonephric ducts is absorbed into the bladder wall. Similarly, the caudal portions of the ureters, which originate from the mesonephric ducts, enter the bladder. During these processes, the ureteral orifices move cranially and the mesonephric ducts move closer together to enter the prostatic urethra, forming the trigone of the bladder. At the end of the third month of gestation, the epithelial proliferation of the prostatic urethra forms outbuddings that constitute the prostate gland in males. In females, the cranial portion of the urethra forms buds that develop into the urethral and paraurethral glands.81 During intrauterine life, the kidneys play only a minor role in regulating fetal salt and water balance because this function is maintained primarily by the placenta. The most important functions of the prenatal kidneys are the formation and excretion of urine to maintain an adequate amount of amniotic fluid. After birth, there is a progressive maturation in renal function, which appears to parallel the needs of the neonate for growth and development (Table 101-3). TABLE 101-3 Normal Values for Renal Function *Based on enzymatic or Jaffe creatinine measurements †Based on IMDS-traceable creatinine measurements The glomerular filtration rate (GFR) in the fetal kidney increases steadily with advancing gestational age. By 32 to 34 weeks’ gestation, a GFR of 14 mL/min per 1.73 m2 is achieved, which further increases to 21 mL/min per 1.73 m2 at term. The GFR continues to increase postnatally, achieving adult values of approximately 120 mL/min per 1.73 m2 by the age of 2 years. The achievement of adult GFR may be delayed in preterm infants, especially those with very low birth weights and those with nephrocalcinosis.77 The progressive increase in GFR during the initial weeks of postnatal life primarily results from an increase in glomerular perfusion pressure. Subsequent increases in GFR during the first 2 years of life are caused primarily by increases in RBF and the maturation of superficial cortical nephrons, which lead to an increase in the glomerular capillary surface area. Newborn infants have a limited capacity to concentrate their urine, with maximal urinary osmolality of 800 mOsm/kg in a term infant compared to that of a 2-year-old, which approximates adult values of 1400 mOsm/kg (see Table 101-3). In contrast, the term newborn infant has full ability to maximally dilute its urine in response to a water load, achieving adult values of 50 mOsm/kg. Preterm infants are unable to fully dilute their urine, but can achieve urine osmolalities of 70 mOsm/kg. However, the response of premature infants to an acute water load may be limited because of their low GFR and the decreased activity of sodium transporters in the diluting segment of the nephron. The excessive administration of water may place the newborn infant at a high risk for dilutional hyponatremia and hypervolemia. Urinary diluting and concentrating capacity in term and preterm infants is discussed in more detail in Chapter 44. The antenatal history should be reviewed thoroughly, with particular attention devoted to medications, toxins, and unusual environmental exposures during the pregnancy. Classic fetal RAS (renin-angiotensin syndrome)-blockade syndrome, previously known as angiotensin converting enzyme (ACE) fetopathy, is characterized by renal failure, limb deformities, hypotension, pulmonary hypoplasia, and hypocalvaria, and may occur following exposure to ACE inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs), particularly in the second and third trimesters.19 Structural and functional alterations of the newborn kidney have also been described in infants with antenatal exposure to nonsteroidal anti-inflammatory drugs, selective COX-2 inhibitors, mycophenolate mofetil, certain antiepileptic medications and chemotherapeutic agents, such as doxorubicin and cyclophosphamide.66 A review of the family medical history is important, including any prior fetal or neonatal deaths. Certain of the congenital abnormalities of the kidney and urinary tract disorders (renal hypoplasia/dysplasia, multicystic dysplastic kidney, and vesicoureteral reflux), as described previously, may have familial clustering. In other disorders, including polycystic kidney disease and congenital nephrotic syndrome, a clear genetic basis has been established. The results of prenatal ultrasonography should be carefully reviewed, with particular attention devoted to kidney size, echogenicity, structural malformations, amniotic fluid volume, and bladder size and shape (Box 101-1). Although the bladder may be identified and its volume discerned at 15 weeks of gestation, the kidneys are not visualized until after the 16th to 17th week of gestation in most fetuses. The presence of small or enlarged kidneys, renal cysts, hydronephrosis, bladder enlargement, or oligohydramnios suggests significant renal or urologic pathology. The evaluation of blood pressure and volume status is critical in the newborn with suspected renal disease. Hypertension may be present in infants with polycystic kidney disease, acute kidney injury (AKI), renovascular or aortic thrombosis, or obstructive uropathy. Hypotension may be present in infants with volume depletion, hemorrhage, or sepsis, any of which may lead to AKI. Edema may occur in infants with AKI, hydrops fetalis, or congenital nephrotic syndrome. Ascites may be present in infants with urinary tract obstruction, congenital nephrotic syndrome, or volume overload. Special attention should be paid to the abdominal examination. In the neonate, the lower pole of each kidney is easily palpable because of the neonate’s reduced abdominal muscle tone. The presence of an abdominal mass in a newborn should be assumed to involve the urinary tract until proved otherwise because two thirds of neonatal abdominal masses are genitourinary in origin.22 The most common renal cause of an abdominal mass is hydronephrosis, followed by a multicystic dysplastic kidney. Less common renal causes of an abdominal mass include polycystic kidney disease, renal vein thrombosis, ectopic or fused kidneys, and renal tumors. The abdomen should be examined for the absence of or laxity in the abdominal muscles, which may suggest Eagle-Barrett (“prune-belly”) syndrome. Distention of the newborn bladder may suggest lower urinary tract obstruction or an occult spinal cord lesion. A number of anomalies should alert the physician to the possibility of underlying renal defects, anomalies such as abnormal external ears, aniridia, microcephaly, meningomyelocele, pectus excavatum, hemihypertrophy, persistent urachus, bladder or cloacal exstrophy, an abnormality of the external genitalia, cryptorchidism, an imperforate anus, and limb deformities. Although screening renal ultrasonography of infants with a single umbilical artery had previously been recommended, in the era of routine prenatal ultrasonography, the prevalence of clinically significant abnormalities is low, and this practice is no longer recommended.29 A constellation of physical findings designated the oligohydramnios (Potter) sequence may be seen in infants with bilateral renal dysplasia, antenatal urinary tract obstruction, or disorders such as autosomal recessive polycystic kidney disease and other forms of severe neonatal kidney disease (Figure 101-4). The marked reduction of fetal kidney function results in oligohydramnios or anhydramnios, which causes fetal deformation by compression of the uterine wall. The characteristic facial features include wide-set eyes, depressed nasal bridge, beaked nose, receding chin, and posteriorly rotated, low-set ears. Other associated anomalies include a small, compressed chest wall, arthrogryposis, hip dislocation, and clubfoot. Such patients often have respiratory failure caused by pulmonary hypoplasia; complications include spontaneous pneumothorax and/or pneumomediastinum resulting from their requirement for high ventilator pressures. Although 98% of term infants void during the first 30 hours of life,23 a delay in urination for up to 48 hours should not be a cause for immediate concern in the absence of a palpable bladder, abdominal mass, or other signs or symptoms of renal disease. A failure to void for longer than 48 hours may suggest impairment of renal function and should prompt further investigation. The serum creatinine level is the simplest and most commonly used indicator of neonatal kidney function. The serum creatinine concentration immediately after birth reflects the maternal creatinine concentration, neonatal muscle mass, and GFR at the time of delivery. In term infants, the serum creatinine level gradually decreases from a range of 0.6 to 1 mg/dL (depending on the mother’s serum creatinine) at birth to a mean value of 0.4 mg/dL within the first 2 weeks of life (see Table 101-3).14 However, in preterm infants, the plasma creatinine level does not fall steadily from birth but instead rises in the first 48 hours before beginning to fall to equilibrium levels.48 Failure of the serum creatinine level to fall or a persistent increase in serum creatinine suggests impairment of renal function. Estimation of GFR is difficult in neonates because formulas used in children have not been validated in infants less than 1 year of age. A diagnostic voiding cystourethrography (VCUG) should be considered an important part of the radiologic examination in infants with significant hydronephrosis, renal dysplasia or anomaly, or documented urinary tract infection. This study is the procedure of choice to evaluate the urethra and bladder and ascertain the presence or absence of vesicoureteral reflux. Voiding cystourethrography involves the instillation of a radiopaque contrast agent into the bladder by urinary catheterization. Films of the urethra during voiding and of the bladder and ureters toward the end of voiding are essential. Other radiologic tests may occasionally be used for diagnostic purposes in the neonate (see Chapter 40). Radioisotopic renal scanning is of value in locating anomalous kidneys, determining kidney size, and identifying obstruction or renal scarring. Radioisotopic scans also provide information about the relative blood flow to each kidney and the contribution of each kidney to overall renal function, but may be difficult to interpret in the first few weeks of life because of the relatively low GFR in newborns. Abdominal computed tomography is useful in the diagnosis of renal tumors, renal abscesses, and nephrolithiasis. Acute kidney injury is an increasingly common condition in the NICU, ranging from mild dysfunction to complete anuric kidney failure. AKI is characterized by deterioration in kidney function over hours to days, leading to an inability of the kidneys to excrete nitrogenous waste products and maintain fluid and electrolyte homeostasis. Although standard definitions have been published for AKI in children and adults, there remains no consensus definition for neonatal AKI, although a serum creatinine greater than 1.5 mg/dL has been used in many published studies. Difficulty in establishing a reliable definition of AKI is because of the variability in serum Cr in neonates of different gestational ages, overall very low GFR of even term neonates, and change in serum Cr from that reflective of maternal Cr after birth. Advances in the field of urinary biomarkers such as neutrophil gelatinase-associated lipocalin may ultimately be helpful in both the earlier detection and the definition of acute kidney injury in neonates.51,53 Data on the incidence of AKI in the hospitalized neonatal population are variable, mainly because of the different criteria used to define the condition, with rates ranging from 8% to 24%.5 Risk factors for development of neonatal AKI include very low birth weight (<1500 g), low 5-minute Apgar score, maternal drug administration (NSAIDs and antibiotics), intubation at birth, respiratory distress syndrome, patent ductus arteriosus, phototherapy, and neonatal medication administration (NSAIDs, antibiotics, diuretics).20,26 Signs of AKI may include oliguria, systemic hypertension, cardiac arrhythmia, evidence of fluid overload or dehydration, decreased activity, seizure, vomiting, and anorexia. Laboratory evidence may include elevated serum creatinine and blood urea nitrogen, hyperkalemia, metabolic acidosis, hypocalcemia, hyperphosphatemia, and a prolonged half-life for medications excreted by the kidney (e.g., aminoglycosides, vancomycin, theophylline). The causes of neonatal AKI are multiple and can be divided into prerenal, renal, and postrenal categories (Box 101-2). Prerenal azotemia is the most common type of AKI in the neonate and may account for up to 85% of all cases. Prerenal azotemia is characterized by inadequate renal perfusion, which if promptly treated, is followed by improvements in renal function and urine output. The most common causes of prerenal azotemia are dehydration, hemorrhage, septic shock, necrotizing enterocolitis, patent ductus arteriosus, and congestive heart failure. The administration of medications that reduce renal blood flow, such as indomethacin or ibuprofen, ACE inhibitors, and phenylephrine eye drops can result in prerenal azotemia. In utero exposure to nonselective nonsteroidal anti-inflammatory drugs, COX2 inhibitors, angiotensin-converting enzyme inhibitors, and angiotensin receptor antagonists can also induce neonatal AKI.15 The most common cause of intrinsic AKI in neonates is ATN. The causes of ATN include perinatal asphyxia, sepsis, cardiac surgery, a prolonged prerenal state, and nephrotoxic drug administration. The pathophysiology of ATN is complex and appears to involve interrelationships among renal tubular cellular injury, hypoxia, and altered glomerular filtration and hemodynamics.59 Other causes of intrinsic AKI in the newborn include renal dysplasia, autosomal recessive polycystic kidney disease, and renal arterial or venous thrombosis. Transient AKI of the newborn is a poorly understood, rapidly reversible syndrome characterized by oliguric AKI and hyperechoic renal medullary pyramids on ultrasound.46 This syndrome has been reported in otherwise healthy term infants with sluggish feeding and is thought to be related to the deposition of Tamm-Horsfall protein and/or uric acid in the renal tubular collecting system. A careful history should focus on prenatal ultrasound abnormalities, perinatal asphyxia, the pre- or postnatal administration of potentially nephrotoxic drugs, and a family history of renal disease. The physical examination should focus on signs of volume depletion or volume overload, the abdomen, genitalia, and a search for other congenital anomalies or signs of the oligohydramnios (Potter) sequence. Levels of electrolytes, blood urea nitrogen, creatinine (Cr), calcium, phosphorus, albumin, and uric acid should be monitored at least daily or more frequently if significant metabolic abnormalities are present. Urine should be sent for urinalysis, urine culture, and urine sodium and creatinine determination. The fractional excretion of sodium (FENa), as well as other diagnostic indexes, may be useful in differentiating prerenal from intrinsic AKI (Table 101-4). TABLE 101-4 Diagnostic Indexes in Acute Kidney Injury
The Kidney and Urinary Tract of the Neonate
Kidney and Urinary Tract Development
Development of the Kidney
Mutant Gene/Protein
Mutant Mouse Phenotype
Abnormal Kidney/Urinary Tract/Process
AGTR2/angiotensin type II receptor
Varied urinary tract abnormalities
Altered vascular tone/renal blood flow
GDNF/glial-derived growth factor
Renal agenesis
Ureteric bud absent
HNF1B/hepatocyte nuclear factor 1-beta
Polycystic kidneys
Collecting tubule hyperplasia
Inv/inversin
Cystic kidneys
Altered left-right polarity
ITGA8/integrin, α8
Renal dysplasia
Abnormal ureteric bud induction and impaired collecting tubule branching
LMX1B/Lim homeobox transcription
Massive proteinuria/glomerular
Altered glomerular basement membrane architecture
PDGFB/platelet-derived growth factor-beta
Hemorrhage and capillary leak
Abnormal glomeruli; impaired angiogenesis
PKHD1/fibrocystin
Polycystic kidneys
Collecting tubule hyperplasia
WT1/Wilms tumor suppressor gene protein
Renal agenesis; glomerulosclerosis
Absence/loss of metanephric mesenchyme
Disease
Mutated Gene/Protein
Kidney Disease
Protein Function
Autosomal recessive polycystic kidney disease
PKHD1/fibrocystin
Polycystic kidneys
Receptor-like properties; unknown function
Bartter syndrome, neonatal/infantile
CCKb/kidney chloride channel B
ROMK/inwardly rectifying potassium channel
Hypokalemic metabolic alkalosis, recurrent dehydration
Sodium, potassium and/or chloride transport in the loop of Henle
Branchio-oto-renal syndrome
EYA1/eyes absent 1, Drosophila homologue
Renal dysplasia
Gene transcription factor regulator
Congenital nephrotic syndrome (Finnish type)
NPHS1/nephrin
Nephrotic syndrome
Glomerular filtration barrier component
Denys-Drash Syndrome
WT1/Wilms tumor suppressor gene
Hypertension, renal failure, Wilms tumor
Transcription factor
Distal renal tubular acidosis with sensorineural deafness
ATP6N1B/H+-ATPase
Metabolic acidosis
Hydrogen ion transporter
Eagle-Barrett (“prune belly”) syndrome
CHRM3/acetylcholine receptor
ACTA2/alpha-smooth muscle actin2
Megacystis, absent or decreased abdominal musculature, renal dysplasia, cryptorchidism
Bladder detrusor muscle formation and/or function
Fanconi-Bickel syndrome
GLUT2/solute carrier family 2 protein
Fanconi syndrome (global proximal tubular dysfunction)
Facilitative glucose transporter
Infantile nephronophthisis
INV/nephrocystin 2
Polyuria, small kidneys, renal failure
Left-right asymmetry determinant
Infantile nephropathic cystinosis
CTNS/cystinosin
Cystinosis, renal failure
Cystine transporter
Nail-patella syndrome
LMX1B/Lim homeodomain protein
Proteinuria, nephrotic syndrome
Type IV collagen regulator production
Nephrogenic diabetes insipidus (NDI)
AVPR2/ADH receptor
AQP2/Aquaporin 2 water channel
X-linked NDI
Autosomal NDI
Water absorption in the collecting tubule
Renal coloboma syndrome
PAX2/PAX2 protein
Hypoplastic kidneys, renal failure
WT1 regulator
Simpson-Golabi-Behmel
GPC3/glypican 3
Nephromegaly, renal dysplasia
Cell division and growth control
Development of the Bladder and Urethra
Physiology of the Developing Kidney
AGE
GFR (mL/min/1.73 m2)
RBF (mL/min/1.73 m2)
Maximum Urine Osm (mOsm/kg)
Serum Creatinine (mg/dL)
Fena (%)
Newborn
Premature (30-34 weeks)
14 ± 3
40 ± 6
480
0.6-1.3*
2-6
Term
21 ± 4
88 ± 4
800
0.6-1*
<1
1-2 weeks
50 ± 10
220 ± 40
900
0.27-0.5*
<1
6 months-1 year
77 ± 14
352 ± 73
1200
0.18-0.29*
<1
1-3 years
96 ± 22
540 ± 118
1400
0.24-0.43†
<1
Adult
118 ± 18
620 ± 92
1400
0.6-1.3†
<1
Glomerular Filtration
Concentration and Dilution of Urine
Evaluation of the Neonate with Renal Disease
History
Physical Examination
Laboratory Evaluation
Urinalysis
Assessment of Renal Function
Radiologic Evaluation
Clinical Problems
Hematuria
Acute Kidney Injury
Prerenal Azotemia
Intrinsic (Renal) Acute Kidney Injury
Evaluation
Test
Prerenal AKI
Intrinsic AKI
BUN/Cr ratio (mg/mg)
>30
<20
FENa (%)
≤2.5
≥3.0
Urinary Na (mEq/L)
≤20
≥50
Urinary Osm (mOsm/kg)
≥350
≤300
Urinary specific gravity
>1.012
<1.014
Ultrasonography
Normal
May be abnormal
Response to volume challenge
U/O >2 mL/kg/h
No increase in urinary output
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The Kidney and Urinary Tract of the Neonate
