Advances in neonatology, perinatology, and molecular genetics have defined new disease processes and raised new questions in the field of nephrology. For example, the advent of prenatal ultrasonography has created questions about the prenatal management of urinary tract anomalies. The use of invasive vascular catheters has led to a new set of complications, including renal artery and aortic thrombosis associated with umbilical artery catheterization. The administration of loop diuretics and steroids to infants with bronchopulmonary dysplasia has led to neonatal nephrocalcinosis. Simultaneously, genetic similarities among children whose conditions were formerly considered phenotypically distinct are redefining congenital anomalies of the kidneys and urinary tract.
This chapter reviews the anatomic and functional development of the kidney, outlines the recommended approach to evaluation of the neonate with suspected renal disease, and comments on the more common nephrologic and urologic problems seen in preterm and term neonates.
The definitive mammalian kidney, the metanephros, starts developing at 5 weeks’ gestation and begins to produce urine by 10 to 12 weeks’ gestation. Development of the metanephros occurs through a series of interactions between the metanephric blastema and the ureteric bud. The ureteric bud progressively branches and grows, eventually forming the ureter, renal pelvis, and intrarenal collecting system.
At the same time, mesenchymal cells of the metanephric blastema are induced by the advancing ureteric bud to differentiate into epithelial cells that eventually become the glomeruli and renal tubules. Foci of metanephric blastema cells interact with the surrounding extracellular matrix and condense adjacent to the branching ureteric bud to form comma-shaped bodies, which then elongate to form S-shaped tubular structures ( Fig. 16-1 ). The lower portion of the S -shaped structure becomes associated with a tuft of capillaries and forms the glomerulus; the upper portion forms the tubular elements of the nephron.
The complex process of kidney development appears to be under the control of growth factors, a series of key regulatory genes, and renal innvervation. A number of genes that control DNA transcription are crucial in the control of cellular events in renal development. For example, mutation of the transcription factor gene PAX 2 , which is normally expressed in developing renal tissue, is associated with a syndrome characterized by vesicoureteral reflux, hypoplastic kidneys, reduced calyces, and optic nerve colobomas. Mutations in another transcriptional factor gene, WT-1 , results in renal agenesis, which suggests that this gene product may be crucial for outgrowth of the ureteric bud.
During intrauterine life, the kidneys play a minor role in regulating fetal salt and water balance, because this function is maintained primarily by the placenta. The primary function of the kidneys prenatally is to produce large amounts of hypotonic or isotonic urine to provide adequate amniotic fluid. After birth, a progressive maturation in renal function begins that appears to parallel the neonate’s metabolic needs for growth and development. In general, maturation of most renal functions is complete by 2 years of age ( Table 16-1 ).
|Age||Glomerular Filtration Rate (mL/min/1.73 m 2 )||Renal Blood Flow (mL/min/1.73 m 2 )||Maximal Urine Osmolality (mOsm/kg)||Serum Creatinine (mg/dL)||Fractional Excretion of Sodium (%)|
|32-34 wk gestation||14 ± 3||40 ± 6||480||1.3||2-5|
|Full Term||21 ± 4||88 ± 4||800||1.1||<1|
|1-2 wk||50 ± 10||220 ± 40||900||0.4||<1|
|6 mo–1 yr||77 ± 14||352 ± 73||1200||0.2||<1|
|1-3 yr||96 ± 22||540 ± 118||1400||0.4||<1|
|Adult||118 ± 18||620 ± 92||1400||0.8-1.5||<1|
Renal Blood Flow
Both absolute renal blood flow and the percentage of cardiac output directed to the kidneys increases steadily with advancing gestational age (see Table 16-1 ). Renal blood flow in the human fetus and term infant are estimated to be as low as 4% and 6% of the cardiac output, respectively. The relatively low renal blood flow of the neonate is related to high renal vascular resistance caused by increased levels of renin, angiotensin, aldosterone, endothelin, and catecholamines. Postnatally, there is a sharp increase in renal blood flow, which reaches 8% to 10% of cardiac output at 1 week of life and achieves adult values of 20% to 25% of cardiac output at 2 years of age. This dramatic increase in renal blood flow is related to decreasing renal vascular resistance and increasing cardiac output and perfusion pressure.
In addition to the increase in overall renal blood flow, there is a marked change in distribution of blood flow within the neonatal kidney in the postnatal period. Because of a preferential decrease in vascular resistance in the outer cortex, there is a pronounced increase in superficial renal cortical blood flow.
Glomerular Filtration Rate
Glomerular filtration rate (GFR) in the fetal kidney increases with gestational age. By 32 to 34 weeks, a GFR of 14 mL/min/1.73 m 2 is achieved, and the rate further increases to 21 mL/min/1.73 m 2 at term (see Table 16-1 ). The GFR continues to increase postnatally, achieving adult values of 118 mL/min/1.73 m 2 by age 2 years. In preterm infants born before 34 weeks’ gestation, the GFR remains stable until the conceptual age (gestational age plus postnatal age) exceeds 34 weeks, at which time the GFR begins to increase. Although adult values for GFR are attained by 2 years of life in term infants, achievement of adult GFR is delayed in preterm infants, especially in very low-birth-weight infants and infants with nephrocalcinosis.
Several factors are responsible for the postnatal increase in GFR. The increase in GFR during the initial weeks of postnatal life is primarily due to an increase in glomerular perfusion pressure. Subsequent increases in GFR during the first 2 years of life are primarily due to increases in renal blood flow and maturation of superficial cortical nephrons, which lead to an increase in glomerular filtration surface area.
During the first week of postnatal life, an infant’s GFR passes through three distinct phases to maintain fluid and electrolyte homeostasis. The initial 24 hours of life (prediuretic phase) is characterized by a transitory increase in GFR at 2 to 4 hours of life followed by a return to low baseline GFR and minimal urine output regardless of salt and water intake. This phase may extend up to 36 hours of life in the preterm infant, with delay in onset of the transitory increase in GFR. During the second and third days of life (diuretic phase), the GFR increases rapidly, and the infant experiences diuresis and natriuresis regardless of salt and water intake. By the fourth to fifth day of life (postdiuretic phase), the GFR decreases slightly, then continues to increase slowly with maturation, with salt and water excretion varying according to intake.
Importantly, the duration and timing of these phases differ among infants, so that individualization of fluid and electrolyte therapy is required. If insensible fluid losses are overestimated during the prediuretic phase, excess fluid intake may result in dilutional hyponatremia. On the other hand, a deficiency in fluid intake during this phase may lead to volume contraction and hypernatremia. During the diuretic phase, hypernatremia may develop as a result of excessive urinary fluid losses.
The change in distribution of intracellular fluid (ICF) and extracellular fluid (ECF) in the fetus and newborn infant is summarized in Table 16-2 . In the healthy term infant, ECF volume decreases and ICF volume increases in the first few days of life. In the preterm infant, total body water decreases, primarily as a result of ECF losses in the first week of life, a process that is delayed in infants with respiratory distress syndrome. The change in ICF during the first week of life is variable and may be dependent on total energy intake and corresponding change in body weight during this period. For example, in preterm infants with more than a 10% loss in body weight during the first week of life, there is a decrease in ECF without an increase in ICF.
|% Body Weight|
|Age||Extracellular Fluid||Intracellular Fluid||Total Body Fluid|
Capillary filtration between the intravascular and interstitial fluid compartments is higher in the neonatal period than it is later in life, which leads to a relatively large interstitial fluid compartment. This phenomenon may be due to a number of factors, including increased hydrostatic pressure, decreased intravascular osmotic pressure, and increased levels of atrial natriuretic factor, vasopressin, and cortisol. The relatively large interstitial fluid compartment enables the neonate to better tolerate hemorrhage because the large volumes of interstitial fluid can shift into the intravascular space, but it may also lead to reduced ability to excrete a free water load.
Renal sodium losses are inversely proportional to gestational age, and the fractional excretion of sodium (FE Na ) may be as high as 5% to 6% in infants born at 28 weeks’ gestation ( Fig. 16-2 ). As a result, preterm infants younger than 35 weeks’ gestation may display negative sodium balance and hyponatremia during the initial 2 to 3 weeks of life due to high renal sodium losses and inefficient intestinal sodium absorption. Up to 4 to 5 mEq/kg/day of sodium may be necessary in preterm infants to offset high renal sodium losses during the first few weeks of life.
Healthy term neonates have basal sodium handling similar to that of adults, as demonstrated by an FE Na of less than 1.0%, although a transient increase in FE Na occurs during the second and third days of life (diuretic phase). Urinary sodium losses may be increased in certain conditions, including renal dysplasia, hypoxia, respiratory distress, hyperbilirubinemia, acute tubular necrosis (ATN), polycythemia, increased fluid and salt intake, and the use of theophylline or diuretics. Pharmacologic agents such as dopamine, labetalol, propranolol, captopril, and enalaprilat that influence adrenergic neural pathways in the kidney and the renin-angiotensin axis may also increase urinary sodium losses in the neonate.
The mechanisms responsible for increased urinary sodium losses in the preterm infant are multifactorial. Glomerulotubular imbalance, which occurs when GFR exceeds the reabsorptive capacity of the renal tubules, occurs because of the preponderance of glomeruli compared with tubular structures, renal tubular immaturity, large extracellular volume, and reduced oxygen availability. Decreased renal nerve activity may also contribute; studies in fetal and newborn sheep demonstrate an inverse relationship between renal nerve stimulation and urine sodium excretion. Finally, fetal and postnatal kidneys exhibit diminished responsiveness to aldosterone compared with adult kidneys, which results in the attenuation of sodium reabsorption.
Urinary Concentration and Dilution
As noted in Table 16-1 , renal concentrating capacity is low at birth and progressively increases following delivery from 800 mOsm/kg H 2 O in the first 2 weeks of life to adult values of 1400 mOsm/kg H 2 O between 1 and 3 years of age. This improvement in ability to excrete a concentrated urine is due to increased urea generation, improved end-organ responsiveness to vasopressin, and anatomic maturation of the renal medulla and its vasculature.
The ability of the neonatal kidney to excrete a water load is somewhat limited in comparison with that of the adult kidney. For example, term and premature newborns can dilute their urine to an osmolality of 50 mOsm/kg and 70 mOsm/kg, respectively, whereas adults can dilute their urine to 30 mOsm. This inability to maximally dilute the urine is due to reduced GFR as well as to decreased activity of transporters in the early distal tubule (diluting segment), which are most prominent in the preterm infant.
The range of normal serum bicarbonate levels is lower than that of adults, and infants maintain a mild metabolic acidosis ( Fig. 16-3 ). This limitation in acid-base homeostasis seen in neonates, particularly preterm infants, is related to immaturity of both proximal and distal tubular function.
The proximal tubular bicarbonate threshold, defined as the steady-state serum bicarbonate level above which significant amounts of bicarbonate appear in the urine, is much lower in neonates than in adults, which leads to incomplete bicarbonate reabsorption. The cause of the low proximal tubular bicarbonate threshold is unknown. Studies in the fetal lamb have demonstrated that renal tubular reabsorption of bicarbonate is inversely proportional to ECF volume. Therefore, expanded ECF compartment characteristic of the preterm and term infant may be related to the low renal bicarbonate threshold and low plasma bicarbonate concentration. Limited distal tubular excretion of titratable acid and incomplete development of tubular ammonia production also contribute to the relative metabolic acidosis of the newborn.
Newborn infants may display two forms of acidosis. In the first 24 hours of life, an early type of combined respiratory and metabolic acidosis may develop as a result of stress during birth and disturbances in cardiopulmonary adaptation. Late metabolic acidosis, on the other hand, may develop during the first week of life and is most pronounced in the second and third weeks of life. This type of acidosis is due to an imbalance between net acid input, primarily from dietary protein intake and bone mineralization, and renal capacity for net acid excretion. Late metabolic acidosis may result in poor weight gain or skeletal growth. Late metabolic acidosis usually resolves spontaneously by the end of the first month of life as a result of the rapid postnatal increase in the renal capacity for net acid excretion.
An important consequence of chronic metabolic acidosis in the newborn is enhanced urinary calcium losses, negative calcium balance, and bone demineralization, which may contribute to the phenomenon of osteopenia of prematurity. The mechanism for this process is multifactorial. Acidosis causes release of calcium from bones directly and via parathyroid hormone secretion. Acidosis also inhibits intestinal calcium absorption and impairs 1α-hydroxylation of 25-hydroxyvitamin D. Finally, acidosis increases urinary flow rate and urinary calcium excretion. Therefore, persistent metabolic acidosis should be corrected with sodium bicarbonate, with a goal of achieving a serum bicarbonate level of 17 to 18 mEq/L.
Calcium and Phosphorus Balance
Within 24 to 48 hours after birth, the serum calcium concentration decreases, a phenomenon that is most pronounced in preterm infants. Although the exact mechanism of neonatal hypocalcemia is unknown, it appears to be due to suppressed parathyroid hormone secretion and elevated plasma phosphate concentration. In most neonates, the ionized calcium level remains above a physiologically acceptable concentration and the infant experiences no clinical symptoms. Symptomatic hypocalcemia may occur, however, in neonates stressed by illness or in the presence of aggressive fluid administration, diuresis, and sodium supplementation, all of which increase urinary calcium losses.
The normal serum phosphorus level in the newborn ranges from 4.5 to 9.5 mg/dL, whereas adult values are 3.0 to 4.5 mg/dL. The higher serum phosphorus level in the newborn is due to enhanced dietary phosphorus intake, particularly in infants fed cow’s milk formulas; lower GFR; and higher tubular reabsorption of phosphorus. Tubular reabsorption of phosphorus is lower, however, in preterm infants and increases progressively during gestation as a result of maturation of renal tubular function. The phosphorus losses seen in premature infants cause relative phosphorus deficiency, which may result in inadequate bone mineralization. For premature infants, therefore, greater attention must be given to nutritional supplies of phosphorus and calcium in enteral and parenteral formulations.
The evaluation of an infant with suspected renal disease must be comprehensive and begins with a careful history taking and thorough physical examination. Selected laboratory studies may be useful in determining the cause and severity of renal dysfunction. Limited radiologic evaluation may be useful in clarifying renal anatomy and detecting complications of vascular catheters.
Results of prenatal ultrasonography should be carefully reviewed with particular attention to kidney size, echogenicity, malformations, amniotic fluid volume, and bladder size and shape. The presence of unilateral or bilateral small or enlarged kidneys, renal cysts, hydronephrosis, bladder enlargement, or oligohydramnios may suggest significant renal or urologic abnormalities.
The causes of congenital renal disease are multifactorial but may include exposure to teratogens. The antenatal history should be reviewed, with particular attention given to medications, toxins, or unusual exposures during the pregnancy. Congenital renal anomalies have been described in infants with antenatal exposure to angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, nonsteroidal antiinflammatory drugs, gentamicin, corticosteroids, calcineurin inhibitors, and cocaine.
Review of the family medical history should include information on any prior fetal or neonatal deaths. Although there is no hereditary cause for most congenital renal anomalies, there is a clear genetic basis for certain diseases such as polycystic kidney disease and nephronophthisis.
Evaluation of blood pressure and volume status is critical in the newborn with suspected renal disease. Hypertension may be present in infants with autosomal recessive polycystic kidney disease, acute renal failure, or renovascular or aortic thrombosis. Hypotension, on the other hand, in addition to cardiovascular disorders, may suggest volume depletion, hemorrhage, or sepsis, all of which may lead to acute renal failure. Edema may be seen in acute renal failure, in hydrops fetalis, or with massive urinary protein losses associated with congenital nephrotic syndrome. Ascites may be seen in acute renal failure with volume overload, congenital nephrotic syndrome, or urinary tract obstruction with rupture.
Special attention should be paid to the abdominal examination. In the neonate, the lower pole of both kidneys should be easily palpable because of the neonate’s reduced abdominal muscle tone. An abdominal mass present in a newborn should be assumed to involve the urinary tract until proven otherwise, because the majority of neonatal abdominal masses are genitourinary in origin. The most common renal cause of an abdominal mass is hydronephrosis, followed by multicystic dysplastic kidney. Less common causes of an abdominal mass are polycystic kidney disease, renal vein thrombosis, ectopic or fused kidneys, renal hematoma or abscess, and renal tumors. The newborn bladder should be able to be percussed just above the symphysis pubis and, if it is enlarged, lower urinary tract obstruction should be suspected. A palpable prostate in a male newborn is always abnormal and suggests posterior urethral valves. The abdomen should be examined for absence or laxity of the abdominal muscles, which may suggest Eagle-Barrett (prune-belly) syndrome.
A number of anomalies should alert the physician to the possibility of underlying renal defects, including abnormal ears, aniridia, microcephaly, meningomyelocele, pectus excavatum, hemihypertrophy, persistent urachus, bladder or cloacal exstrophy, abnormality of the external genitalia, cryptorchidism, imperforate anus, and limb deformities. A single umbilical artery should raise suspicion of renal disease. In one study, 7% of otherwise normal infants with a single umbilical artery were found to have significant persistent renal anomalies. The utility of screening all infants with a single umbilical artery, however, remains controversial.
The question of whether to perform further investigation in well infants with an isolated single umbilical artery is both controversial and clinically relevant, with the incidence of single umbilical artery approximating 0.3% of newborns. Some reviews recommend that all infants with a single umbilical artery undergo routine screening with ultrasonography with or without micturating cystourethrography. Deshpande et al looked at 137 consecutively examined infants born with a single umbilical artery in a 6-year period. Of those infants, 122 with an isolated single umbilical artery underwent renal ultrasonography and only 2 infants (1.6%; 95% confidence interval: 0.20 to 5.5) had clinically significant renal anomalies. The authors of that study concluded that postnatal renal ultrasonography was not routinely warranted in infants with an isolated single umbilical artery.
A constellation of physical findings called the Potter sequence may be seen in infants with bilateral renal agenesis. Lack of fetal renal function results in severe oligohydramnios, which causes fetal deformation by uterine wall compression. 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 and arthrogryposis. The condition is uniformly fatal. “Potter-like” features may be noted in infants with in utero urinary tract obstruction or chronic amniotic fluid leakage. In this group of infants, pulmonary and renal function are generally not as severely impaired and the prognosis is less grim. In infants with significant renal defects, pneumothorax or pneumomediastinum are common clinical associations related to varying degrees of pulmonary hypoplasia.
Twenty-five percent of male infants and 7% of female infants void at the time of delivery. Although 98% of full-term infants void in the first 30 hours of life, 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. Failure to void for longer than 48 hours should prompt further investigation, including kidney and bladder ultrasonography to rule out urinary tract anomalies.
Evaluation of the urine is a vital part of the examination of any neonate suspected of having a urinary tract abnormality. Collection of an adequate, uncontaminated specimen is difficult in the neonate. A specimen collected by cleaning the perineum and applying a sterile adhesive plastic bag enables analysis of urinary protein or electrolytes. Tests for heme and cultures may give erroneous results. For cultures, bladder catheterization produces a reliable specimen but may be technically difficult in preterm infants. Suprapubic bladder aspiration has been considered the collection method of choice in infants without intraabdominal abnormalities or bleeding disorders, although anecdotal evidence suggests that few clinicians opt for that approach.
Analysis of the urine should include inspection, measurement of specific gravity, urinary dipstick testing, and microscopic analysis. The urine of newborns is usually clear and nearly colorless. Cloudiness may be caused by either urinary tract infection or the presence of crystals. A yellow-brown to deep olive-green color may indicate increasing amounts of conjugated bilirubin. Porphyrins, certain drugs such as phenytoin, bacteria, and urate crystals may stain the diaper pink and be confused with bleeding. Brown urine suggests bleeding from the upper urinary tract, hemoglobinuria, or myoglobinuria.
Urinary specific gravity may be measured using a clinical refractometer or a urinary dipstick. The specific gravity of neonatal urine is usually very low (<1.004) but may be factitiously elevated by high-molecular-weight solutes such as contrast agents, glucose or other reducing substances, or large amounts of protein. Gouyon and Houchan showed that dipstick estimation of urinary specific gravity was an unreliable test of urinary concentrating ability in the neonate and suggested that urinary osmolarity is a more reliable measure of the kidney’s concentrating and diluting ability.
Urine dipstick evaluation can detect the presence of heme-containing compounds (red blood cells, myoglobin, and hemoglobin), protein, and glucose. White blood cell products such as leukocyte esterase and nitrite may also be detected by urine dipstick and should raise suspicion of urinary tract infection, which should prompt the clinician to order a urine culture. Microscopic urinalysis should be performed if the urinary dipstick result is abnormal and is useful in detecting the presence of red blood cells, casts, white blood cells, bacteria, and crystals.
Clinical evaluation of neonatal renal function begins with measurement of serum creatinine level. As discussed previously, normal values for serum creatinine vary with gestational age and postnatal age (see Table 16-1 ). The serum creatinine level is relatively high at birth, with normal values up to 1.1 mg/dL in term babies and 1.3 mg/dL in preterm infants, but decreases to a mean value of 0.4 mg/dL within the first 2 weeks of life. In general, each doubling of the serum creatinine level represents a 50% reduction in GFR; for example, an increase in creatinine concentration from 0.4 mg/dL to 0.8 mg/dL reflects a 50% reduction in GFR. The Schwartz formula, which estimates GFR using serum creatinine level and body length, has been applied to normal preterm and term infants. Recently, the methodology for measuring serum creatinine has changed from the Jaffe method to one involving the plasma disappearance of iohexol. This has led to a revision of the Schwartz formula for children aged 1 to 16 years. The new formula, which has not yet been studied in term or preterm infants, is as follows:
Renal ultrasonography is the initial procedure of choice in infants with suspected renal disease. Renal ultrasonography offers a noninvasive anatomic evaluation of the urinary tract without the use of contrast agents or radiation exposure. Renal ultrasonography can demonstrate kidney size and morphology, presence of nephrocalcinosis or nephrolithiasis, complications of infection (renal abscess, perinephric abscess), obstruction (hydronephrosis, hydroureter), and bladder morphology.
Voiding cystourethrography is the procedure of choice to evaluate the urethra and bladder and to ascertain the presence or absence of vesicoureteral reflux. This study involves urinary catheterization and instillation of radiopaque dye into the infant’s bladder. A voiding cystourethrogram should be considered in all infants with urinary tract obstruction, renal dysplasia or anomaly, or documented urinary tract infection.
Other radiologic tests may occasionally be used for diagnostic purposes in the neonate. A technetium 99m ( 99 mTc) MAG-3 (mercaptoacetyltriglycine) or 99 mTc DTPA (diethylene triamine pentaacetic acid) diuretic renal scan may be helpful in confirming urinary tract obstruction in an infant with hydronephrosis or hydroureter on ultrasonography. A renal scan using 99 mTc DMSA (dimercaptosuccinic acid) or 99 mTc glucoheptonate may help to identify renal scarring related to prior pyelonephritis or umbilical artery catheter–related embolic phenomenon. Computerized tomography may be helpful in evaluating suspected renal abscess, mass, or nephrolithiasis.
Hematuria and Proteinuria
At 16 hours of age, a 4300-g 41-week infant born to a mother with gestational diabetes develops macroscopic hematuria. Physical examination reveals a listless, pale infant with a large left flank mass. Urinalysis demonstrates hematuria (4+) with more than 250 red blood cells/mm. Laboratory findings include a hematocrit of 36%, a platelet count of 75,000/mm 3 , and a serum creatinine concentration of 1.0 mg/dL. Renal ultrasonography shows an enlarged left kidney with impaired venous flow by Doppler study, consistent with renal vein thrombosis.
The infant is treated conservatively with hydration and careful observation of fluid balance and renal function. Within 48 hours, the macroscopic hematuria resolves and renal function remains stable. Serial ultrasound examinations reveal gradual resolution of the thrombosis over the next 7 days, with improvement in renal venous blood flow. At 6 months of age, the infant’s serum creatinine concentration is 0.4 mg/dL and renal ultrasound findings are normal.
Hematuria may be suspected by urinary dipstick testing (microscopic) or visual examination (macroscopic or gross). Confirmation of hematuria requires microscopic examination showing at least 5 red blood cells per high-power field. A positive urinary dipstick result with negative findings on microscopic examination for red blood cells suggests myoglobinuria or hemoglobinuria. Myoglobinuria may be seen in infants with inherited metabolic myopathies, infectious myositis, and rhabdomyolysis related to prolonged seizure activity, corticosteroid use, or direct muscle trauma. Hemoglobinuria may be present in erythroblastosis fetalis and other forms of hemolytic disease.
The most frequent cause of hematuria in the neonate is ATN following birth asphyxia, exposure to nephrotoxic drugs, or sepsis. Another important cause of hematuria is renal vein thrombosis, which must be considered in infants of diabetic mothers and in infants with cyanotic congenital heart disease, polycythemia, or marked dehydration. Other causes of hematuria are urinary tract infection, blood dyscrasias, bladder hemangioma, renal tumor, nephrolithiasis, congenital urinary tract malformations, and cortical necrosis. Glomerulonephritis, which represents a common cause of hematuria in childhood and adolescence, is extremely uncommon in the neonatal population.
Proteinuria is defined as a urinary dipstick reading of 1+ (30 mg/dL) or higher with a specific gravity of 1.015 or less, or a reading of 2+ (100 mg/dL) or higher with a specific gravity of more than 1.015. False-positive dipstick readings for protein may result from very concentrated urine, alkaline urine, infection, and detergents. Average quantitative protein excretion declines with increasing gestational age, from 182 mg/m 2 per 24 hours in premature infants to 145 mg/m 2 per 24 hours in full-term infants to 108 mg/m 2 per 24 hours in infants 2 to 12 months of age.
Common causes of neonatal proteinuria include ATN, fever, dehydration, cardiac failure, high-dose penicillin therapy, and contrast agent administration. Persistent massive proteinuria and edema in a neonate should prompt consideration of congenital nephrotic syndrome, an autosomal recessive disorder characterized by proteinuria, failure to thrive, large placenta, and chronic renal dysfunction.
Acute Kidney Injury
A 2300-g female infant is delivered after a 36-week uncomplicated pregnancy. Fetal decelerations were noted before delivery, and a tight nuchal cord is present. Apgar scores are 1 at 1 minute and 4 at 5 minutes. The infant is resuscitated using intubation, compressions, and epinephrine. Arterial blood gas analysis shows a pH of 7.10, P co 2 of 54 mm Hg, and P o 2 of 93 mm Hg. Initial laboratory work reveals normal electrolyte levels and a serum creatinine concentration of 0.9 mg/dL.
Over the next 3 days, the infant becomes oliguric, and laboratory results are as follows: Na, 127 mmol/L; K, 6.5 mmol/L; Cl, 106 mmol/L; HCO 3 , 15 mmol/L; blood urea nitrogen, 18 mg/dL; and creatinine, 2.0 mg/dL. Urinalysis shows hematuria (2+) and proteinuria (1+). Renal ultrasonography shows hyperechoic parenchyma without evidence of renal dysplasia or obstruction. Peritoneal dialysis is initiated for supportive treatment of presumed ATN. After 10 days, dialysis is discontinued as the infant’s renal function recovers. The infant is discharged home at 21 days of age with a serum creatinine concentration of 1.0 mg/dL. Follow-up laboratory work 6 weeks later shows the serum creatinine level to be 0.5 mg/dL.
Acute kidney injury (AKI) is characterized by a sudden impairment in renal function that leads to an inability of the kidneys to excrete nitrogenous wastes. Both the clinical care of infants and studies of AKI are complicated by the difficulty of defining the condition. A consensus definition of AKI based on biomarkers is a serum creatinine level of more than 1.5 mg/dL. Creatinine, however, is a metabolic product of muscle. Normal levels reflect maternal levels initially and fall as the infant’s production and excretion find their own steady state. Clinically, oliguric AKI is characterized by a urine flow rate of less than 0.5 to 1 mL/kg/hr, whereas in nonoliguric AKI, urine flow rate is maintained at a higher level. This measure of renal function is unreliable when diuretics have been administered. A prospective study of 229 infants found the incidence of AKI to be 18% among very low-birth-weight infants. The causes of neonatal AKI are multiple and can be divided into prerenal, renal, and postrenal categories ( Box 16-1 ).
Acute kidney injury (AKI) is a common clinical problem in neonatal intensive care units and is usually associated with a contributing condition such as hypovolemia, hypotension, or hypoxia, often due to sepsis, asphyxia, and heart failure. Attention has been focused on biomarkers for AKI that might enable early recognition and prompt interventions to limit renal injury. The level of neutrophil gelatinase–associated lipocalin (NGAL), and specifically urinary NGAL (UNGAL), predicts renal failure sooner than serum creatinine level, and the immunoassay can be done as quickly as creatinine determination.
Neonatologists tend to focus on the lung, brain, and gastrointestinal tract, giving little attention to the kidney. This needs to change. In the first prospective epidemiologic study addressing AKI in preterm infants with a birth weight of less than 1500 g, 18% of 229 infants manifested AKI when a creatinine-based definition was used. However, because the investigators did not measure serum creatinine concentration in every infant every day, this number may be an underestimate. Furthermore, AKI is a serious condition, and there is an independent association between AKI and mortality when analyzed both by gestational age and by birth weight. Most infants who developed AKI were extremely premature and developed AKI within the first week of life. Sicker babies whose condition was depressed at birth and who required mechanical ventilation and blood pressure support in addition to umbilical artery catheterization were most likely to manifest AKI. The next steps are to identify early and reliable markers of AKI, intervene appropriately, and improve outcomes. These infants all need long-term follow-up to monitor their renal function and watch for the onset of hypertension.