Kidney problems in the neonate may be the result of specific inherited, developmental abnormalities or the result of acquired events either in the prenatal or in the postnatal period. For this reason, evaluation includes a detailed review of the history (family history, gestational history, and the neonatal events) as well as a review of the presenting clinical features and relevant laboratory/radiologic findings. An understanding of the developmental processes and the differences in renal physiology in the neonatal period compared to that at later ages is necessary for evaluation.
I. RENAL EMBRYOGENESIS AND FUNCTIONAL DEVELOPMENT
A. Embryogenesis
The development of the human kidney is a self-regulating process in which kidney function directs multiple interdependent cellular processes of the developing nephrons and tubules. Nephrogenesis requires a fine balance of numerous factors that can be disturbed by various genetic and/or epigenetic prenatal events including nutritional deficiencies, toxic insults, hypertension, pharmacology, prematurity, and low birth weight resulting in low nephron number at birth.
The mature human kidney is the final product of three embryonic organs: the pronephros, the mesonephros, and the metanephros. The transient pronephros, the first structure containing rudimentary tubules, disappears at the end of the fourth week of gestation. Despite its transient nature, the pronephros is required for normal kidney development. The mesonephros follows and develops concomitantly and contains well-developed
nephrons comprising vascularized glomeruli connected to proximal and distal tubules draining into a mesonephric duct. Ultimately, the mesonephros fuses with the cloaca, contributes to the formation of the urinary bladder and in the male, the genital system. The metanephros is the final developmental stage and can be identified around the fifth or sixth week of gestation. The metanephros has two components: the ureteric bud (UB) and the metanephric mesenchyme. The UB is the origin of the metanephros, originating from the Wolffian mesonephric duct.
The UB is a branching epithelial tube of programmed intermediate mesenchymal cells whose inductive signals stimulate development of epithelial precursors. It induces mesenchymal cells to migrate closer to each other in preparation for their conversion into epithelial cells. With each division of the UB, a new layer of nephrons is induced from stem cells; as development proceeds, the metanephros is located at progressively higher levels, reaching the lumbar position by 8 weeks of gestation.
The developmental history of the nephron and collecting system differ: Whereas the nephron arises from mesenchymal cells undergoing mesenchymal-epithelial transitions, the tubules form from reiterated UB branching.
The beginning of the UB from the Wolffian duct begins at the 28th day of gestation, branching in a highly reproducible manner with a nephron induced at each of its tips. These branches eventually form the collecting system (ducts, renal pelvis, ureter, and bladder trigone). Multiple gene regulatory networks have been reported to act either as inducers (e.g., c-Ret, GDNF, ETv4, ETv5, SOX8, SOX9, Wnt11, Angiotensin II, PAX2, AT2R) or inhibitors (e.g., FoxC1, FoxC2, BMP4, Slit2). The GDNF/c-Ret/Wnt1 pathway, for example, is considered a major positive regulator of UB development, playing multiple crucial roles in cell movements and growth. In its absence, kidneys display severe branching abnormalities, lack of UB leading to renal hypoplasia, renal agenesis, abnormal ureter-bladder connections, etc.
Most nephrons in human kidneys are endowed by 36 weeks of gestation; nephron number varies from 300,000 to 1,800,000 (average 900,000) nephrons per kidney. Nephrons cannot regenerate; therefore, nephron endowment has profound implications for future chronic kidney disease (CKD) development. Four stages of nephron development have been defined: stage I, where the renal vesicle appears; stage II, transformation of renal vesicle to a comma-shaped body; stage III, capillary loop stage; and stage IV, maturing nephron stage including proximal tubules, the loop of Henle, distal tubules, and development of the juxtaglomerular complex and part of the afferent arterioles. During this stage, the renal interstitium differentiates into the various components of cortex, medulla, etc. Disruption of any part of this sequence leads to reduced nephron numbers. Once the nephron number has been determined, postnatal factors (such as acute kidney injury or chronic illness) can only further decrease the nephron population.
Gene-targeting experiments have greatly improved our understanding of kidney and urinary tract morphogenesis, but our understanding is incomplete with respect to the complete contribution of genetic expression regulating the ups and downs of UB and epithelial cell interactions, as well as the metanephric mesenchyme and in stromal cells during renal development. This complex picture demonstrates that mutations or altered
epigenetic modulation of genes expressed during nephrogenesis compromises ureteric elongation and branching and therefore the process of mesenchymal-epithelial transition. The consequence of even subtle changes in the reciprocal and complex interactions between these cell types has severe consequences on the ultimate development of the human kidney.
B. Functional Development At birth, the kidneys replace the placenta as the major homeostatic organs, maintaining fluid and electrolyte balance and removing harmful waste products. This transition occurs with increases in renal blood flow (RBF), glomerular filtration rate (GFR), and tubular functions. Because of this postnatal transition, the level of renal function relates more closely to the postnatal age than to the gestational age at birth.
1. RBF remains low during fetal development, accounting for only 2% to 3% of cardiac output. At birth, RBF rapidly increases to 15% to 18% of cardiac output because of (i) a decrease in renal vascular resistance, which is proportionally greater in the kidney compared to other organs, (ii) an increase in systemic blood pressure, and (iii) increase in inner to outer cortical blood flow.
2. Glomerular filtration begins soon after the first nephrons are formed and GFR increases in parallel with body and kidney growth (˜1 mL/minute/kg of body weight). Once all the glomeruli are formed by 34 weeks’ gestation, the GFR continues to increase until birth because of decreases in renal vascular resistance. GFR is less well autoregulated in the neonate than in older children. It is controlled by maintenance of glomerular capillary pressure by the greater vasoconstrictive effect of angiotensin II at the efferent than afferent arteriole where the effect is attenuated by concurrent prostaglandin-induced vasodilatation.
GFR at birth is lower in the most premature infants and rises after birth dependent on the degree of prematurity. In term babies, GFR rises quickly, doubling by 2 weeks of age and reaching adult levels by 1 year of age. Similar values are reached by premature infants, although over a longer time interval (see
Table 28.5).
3. Tubular function
a. Sodium (Na+) handling. The ability of the kidneys to reabsorb Na
+ is developed by 24 weeks’ gestation, although tubular resorption of Na
+ is low until after 34 weeks’ gestation. This is important when evaluating a preterm infant for prerenal azotemia because they will be unable to reabsorb sodium maximally and thus will have elevated fractional excretion of sodium (FENa; see
Table 28.1). Very premature infants cannot conserve Na
+ even when Na
+ balance is negative. Hence, premature infants below 34 weeks’ gestation often develop hyponatremia when receiving formula or breast milk even in the absence of kidney injury or damage. Na
+ supplementation is warranted. After 34 weeks’ gestation, Na
+ reabsorption becomes more efficient so that 99% of filtered Na
+ can be reabsorbed, resulting in an FENa of <1% if challenged with renal hypoperfusion (prerenal state). Full-term neonates can retain Na
+ when in negative Na
+ balance but, like premature infants, are also limited in their ability to excrete a Na
+ load because of their low GFR.
b. Water handling. The newborn infant has a limited ability to concentrate urine due to limited urea concentration within the renal interstitium (because of low protein intake and anabolic growth). The resulting decreased osmolality of the interstitium leads to a decreased concentrating ability and thus a diminished capacity to reabsorb water by the neonatal kidney. The maximal urine concentration (osmolality) is only 500 mOsm/L in premature infants and 800 mOsm/L in term infants. Although this is of little consequence in infants receiving appropriate amounts of water with hypotonic feeding, it can become clinically relevant in infants receiving higher osmotic loads. In contrast, both premature and full-term infants can dilute their urine normally with a minimal urine osmolality of 35 to 50 mOsm/L. Their low GFR, however, limits their ability to handle water loads.
c. Potassium (K+) handling. The limited ability of premature infants to excrete large K+ loads is related to decreased distal tubular K+ secretion, a result of decreased aldosterone sensitivity, low Na+-K+-ATPase activity, and their low GFR. Premature infants often have slightly higher serum K+ levels than older infants and children. If there is a question of renal potassium handling and possible abnormal hyperkalemia, potassium should be accurately measured using a central blood draw (as opposed to a heel stick).
d. Acid and bicarbonate handling are limited by a low serum bicarbonate threshold in the proximal tubule (14 to 16 mEq/L in premature infants, 18 to 21 mEq/L in full-term infants) which improves as maturation of Na
+-K
+-ATPase and Na
+-H transporter occurs. Essentially, premature infants are born with a mild proximal RTA that improves with maturation. In addition to proximal tubular handling of bicarbonate, the production of ammonia in the distal tubule and proximal tubular glutamine synthesis are decreased. The lower rate of phosphate excretion
limits the generation of titratable acid, further limiting infants ability to eliminate an acid load. Very low birth weight infants can develop mild metabolic acidosis during the second to fourth week after birth that may require administration of additional sodium bicarbonate.
e. Calcium and phosphorous handling in the neonate is characterized by a pattern of increased phosphate retention associated with growth. Serum phosphorus levels are higher in newborns than in older children and adults. The intake and filtered load of phosphate, parathyroid hormone (PTH), and growth factors modulate renal phosphate transport. The higher phosphate level and higher rate of phosphate reabsorption are not explained by the low GFR or to tubular unresponsiveness to extrarenal factors (PTH, vitamin D). More likely, there is a developmental mechanism that favors renal conservation of phosphate in part due to growth hormone effects, as well as a growth-related Na+ -dependent phosphate transporter, so that a positive phosphate balance for growth is maintained. Tubular reabsorption of phosphate (TRP) is also altered by gestational age, increasing from 85% at 28 weeks to 93% at 34 weeks and 98% by 40 weeks.
Calcium levels in the fetus and cord blood are higher than those in the neonate. Calcium levels fall in the first 24 hours, but low levels of PTH persist. This relative hypoparathyroidism in the first few days after birth may be the result of this physiologic response to hypercalcemia in the normal fetus. Although total plasma Ca+ values <8 mg/dL in premature infants are common, they are usually asymptomatic because the ionized calcium level is usually normal. Factors that favor this normal ionized Ca+ fraction include lower serum albumin and the relative metabolic acidosis in the neonate.
Urinary calcium excretion is lower in premature infants and correlates with gestational age. At term, urinary calcium excretion rises and persists until approximately 96 months of age. The urine calcium excretion in premature infants varies directly with Na+ intake, urinary Na+ excretion, and inversely with plasma Ca2+. Neonatal stress and therapies such as aggressive fluid use or furosemide administration increase Ca2+ excretion, aggravating the tendency to hypocalcemia or nephrocalcinosis.
4. Fetal urine contribution to amniotic fluid volume is minimal in the first half of gestation (10 mL/hour) but increases significantly to an average of 50 mL/hour and is a necessary contribution to pulmonary development. Oligohydramnios or polyhydramnios may reflect dysfunction of the developing kidney and warrants a more thorough evaluation of the fetal kidneys.
II. CLINICAL ASSESSMENT OF KIDNEY FUNCTION. Assessment of kidney function is based on the patient’s history, physical examination, and appropriate laboratory and radiologic tests.
A. History
1. Prenatal history includes any maternal illness, drug use, or exposure to known and potential teratogens.
a. Maternal use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, or indomethacin decreases glomerular
capillary pressure and GFR and has been associated with neonatal kidney failure.
b. Oligohydramnios may indicate a decrease in fetal urine production. It may be associated with kidney agenesis, dysplasia, polycystic kidney disease, or severe obstruction of the urinary tract system. It most often is a sign of poor fetal perfusion due to placental insufficiency as seen in preeclampsia or maternal vascular disease (see
Chapters 2 and
4).
Conversely, polyhydramnios is seen in pregnancies complicated by maternal diabetes (see
Chapter 2) and in fetal anomalies such as esophageal atresia (see
Chapter 64) or anencephaly (see
Chapter 57). It also may be a result of renal tubular dysfunction with inability to fully concentrate urine.
c. Elevated serum/amniotic fluid alpha-fetoprotein and enlarged placenta are associated with congenital nephrotic syndrome.
2. Family history. The risk of renal disease is increased if there is a family history of urinary tract anomalies, polycystic kidney disease, consanguinity, or inherited renal tubular disorders. Familial diseases (congenital nephrotic syndrome, autosomal recessive polycystic disease of kidney [ARPKD], hydronephrosis, or dysplasia) may be recognized in utero or remain asymptomatic until later life.
3. Delivery history. Fetal distress, perinatal asphyxia, sepsis, and volume loss may lead to ischemic or anoxic injury. Although often multiorgan, the neonatal kidneys are at particular risk for ischemic injury due to their low GFR and relative hypoxia at baseline.
4. Micturition. Seventeen percent of newborns void in the delivery room, approximately 90% void by 24 hours, and 99% void by 48 hours. The rate of urine formation ranges from 0.5 to 5.0 mL/kg/hour at all gestational ages. The most common cause of delayed or decreased urine production is improper recording of initial void or inadequate perfusion of the kidneys. Delay in micturition may also be due to intrinsic kidney abnormalities or obstruction of the urinary tract.
B. Physical examination. Careful examination will detect abdominal masses in 0.8% of neonates. Most of these masses are either renal in origin or related to the genitourinary (GU) system. It is important to consider in the differential diagnosis whether the mass is unilateral or bilateral (
Table 28.2). Edema may be present in infants with congenital nephrotic syndrome (due to low oncotic pressure) or from fluid overload if input exceeds output. Tubular defects and use of diuretics can cause salt and water losses which can lead to dehydration.
Many congenital syndromes may affect the kidneys; thus, a thorough evaluation is necessary in those presenting with congenital renal anomalies. Findings associated with congenital kidney anomalies include low-set ears, ambiguous genitalia, anal atresia, abdominal wall defect, vertebral anomalies, aniridia, meningomyelocele, tethered cord, pneumothorax, pulmonary hypoplasia, hemihypertrophy, persistent urachus, hypospadias, and cryptorchidism among others (
Table 28.3). Spontaneous pneumothorax may occur in those who have pulmonary hypoplasia associated with renal abnormalities.
C. Laboratory evaluation. Kidney function tests must be interpreted in relation to gestational and postnatal age (see
Tables 28.4 and
28.5).
1. Urinalysis reflects the developmental stages of renal physiology.
a. Specific gravity. Full-term infants have a limited concentrating ability with a maximum specific gravity of 1.021 to 1.025.
b. Protein excretion varies with gestational age. Urinary protein excretion is higher in premature infants and decreases progressively with postnatal age (see
Table 28.4). In normal full-term infants, protein excretion is minimal after the second week of life.
c. Glycosuria is commonly present in premature infants of <34 weeks’ gestation. The tubular resorption of glucose is <93% in infants born before 34 weeks’ gestation compared with 99% in infants born after 34 weeks’ gestation. Glucose excretion rates are highest in infants born before 28 weeks’ gestation.
d. Hematuria is abnormal and rare in the term newborn. It is more frequent in the premature infants and may indicate intrinsic kidney damage or result from a bleeding or clotting abnormality (see section III.G).
e. The urinary sediment examination will usually demonstrate multiple epithelial cells (thought to be urethral mucosal cells) for the first 24 to 48 hours. In infants with asphyxia, an increase in epithelial cells and transient microscopic hematuria with leukocytes is common. Further investigation is necessary if these sediment findings persist. Hyaline and fine granular casts are common in dehydration or hypotension. Uric acid crystals are common in dehydration states and concentrated urine
samples. They may be seen as pink or reddish brown diaper staining (particularly with the newer absorptive diapers).
2. Method of collection
a. Suprapubic aspiration is the most reliable method to obtain an uncontaminated sample collection for urine culture. Ultrasound guidance will improve chance of success.
b. Bladder catheterization is used if an infant has failed to pass urine by 36 to 48 hours and is not apparently hypovolemic (see section III.B), if precise determination of urine volume is needed, or to optimize urine drainage if functional or anatomic obstruction is suspected.
c. Bag collections are adequate for most studies such as determinations of specific gravity, pH, electrolytes, protein, glucose, and sediment but should never be used for urine culture. Bagged samples are not appropriate when urinary tract infection (UTI) is suspected. Bladder catheterization can cause trauma of the urethral mucosa; therefore, bag collection is the preferred method if hematuria is suspected.
d. Diaper urine specimens are reliable for estimation of pH and qualitative determination of the presence of glucose, protein, and blood.
3. Evaluation of renal function
a. Serum creatinine at birth reflects maternal kidney function. In healthy term infants, serum creatinine levels fall from 0.8 mg/dL at birth to 0.5 mg/dL at 5 to 7 days and reach a stable level of 0.3 to 0.4 mg/dL by 9 days. Premature infants’ serum creatinine may rise transiently for the first few days and then will reduce slowly over weeks to months depending on the level of prematurity. The rate of decrease in serum creatinine in the first few weeks is slower in younger gestational age infants with lower GFR (
Table 28.5).
b. Blood urea nitrogen (BUN) is another potential indicator of kidney function. However, BUN can be elevated as a result of increased production of urea nitrogen in hypercatabolic states or increased protein intake, sequestered blood, tissue breakdown, or from hemoconcentration.
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