Embryology
Three paired renal systems develop from the nephrogenic ridge of the mesoderm.
The first two systems, the pronephros and the mesonephros, have limited function in the human being and are transient. The mesonephric tubules and duct form the efferent ductules of the epididymis, the vas deferens, the ejaculatory ducts, and the seminal vesicles in men. In women, they result in the vestigial epoophoron and the paroophoron.
The metanephros is the third and final excretory system and appears in the fifth week of gestation. The metanephros is made up of two different cell types. These differentiate into the pelvicalyceal system, which is well delineated by the 13th or 14th week, and the nephrons, which continue to form up to the 34th week of gestation to a final complement of 1 million nephrons per kidney. Urine is produced by the 12th week.
Parallel development of the lower urinary tract occurs with opening of the mesonephric duct to the allantois and cloaca at 5 weeks gestation. Shortly thereafter, at 6 weeks, the urorectal fold forms as a septum dividing the gastrointestinal (GI) tract (posterior compartment) from the anterior genitourinary (GU) compartment—the urogenital sinus. At 7 weeks, separate vesicoureteral openings form and the allantois degenerates to a cord that becomes the urachus and the upper bladder, although the trigone develops from the Wolffian duct remnant. Müllerian system development produces a ureterovaginal cord, which in women becomes the vaginal vestibule, vagina, and uterine cervix. In men, müllerian system regression leads to the prostatic urethra.
Disruption of normal renal development may lead to renal malformations, such as renal agenesis, renal hypoplasia, renal ectopy, renal dysplasia, and cystic disease.
Functional development. At birth, the kidney replaces the placenta as the major homeostatic organ, maintaining fluid and electrolyte balance and removing harmful waste products. This transition occurs with changes in renal blood flow (RBF),
glomerular filtration rate (GFR), and tubular functions. The level of renal function relates more closely to the postnatal age than to the gestational age at birth.
RBF remains low in the fetus, 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) an increase in inner to outer cortical blood flow.
Glomerular filtration begins soon after the first nephrons are formed and GFR increases in parallel with body and kidney growth (approximately 1 mL/min/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. It is controlled by maintenance of glomerular capillary pressure by the greater vasoconstrictive effect of angiotensin II at the efferent then afferent arteriole where the effect is attenuated by concurrent prostaglandin-induced vasodilatation.
GFR at birth is lower in the most premature and after birth rises 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 and similar values are eventually reached by premature infants (Table 28.5).
Tubular function
Sodium (Na+) handling. The ability to reabsorb Na+ is developed by 24 weeks’ gestation. However, tubular resorption of Na+ is low until 34 weeks gestation. This is important when evaluating the infant for prerenal azotemia, as 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 receiving formula or breast milk without Na+ supplementation can develop hyponatremia. 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. 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.
Table 28.1 Commonly Used Equations and Formulas
CrCl (mL/min/1.73 m2) = K × Length (cm)/PCr
CrCl (mL/min/1.73 m2) = UCr × Uvol × 1.73/PCr × BSA
FeNa = 100 × (UNa + × PCr)/(PNa × UCr)
TRP = 100 × (1 — ((UP × PCr)/(PP × UCr)))
Calculated Posm ≥2 × plasma [Na+] + [glucose]/18 + BUN/2.8
Plasma anion gap = [Na+] — [Cl−] — [HCO3–]
BSA = body surface area; CrCl = creatinine clearance; FeNa = fractional excretion of sodium; PCr = plasma creatinine; Posm = plasma osmolarity; PNa = plasma sodium; TRP = tubular reabsorption of phosphorus; UCr = urinary creatinine; Uvol = urinary volume per minute.
Water handling. The newborn infant has a limited ability to concentrate urine due to limited urea concentration within the interstitium because of low protein intake and anabolic growth. The resulting decreased osmolality of the interstitium leads to a decreased capacity to reabsorb water and concentrating ability of the neonatal kidney. The maximal urine osmolality is 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 high osmotic loads. In contrast, both premature and full-term infants can dilute their urine with a minimal urine osmolality of 25 to 35 mOsm/L. Their low GFR, however, limits their ability to handle water loads.
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+ adenosine triphosphatase (ATPase) activity, and low GFR.
Acid and bicarbonate handling are limited by a low serum bicarbonate threshold in the proximal tubule (14—16 mEq/L in premature infants, 18—21 mEq/L in full-term infants), which improves as maturation of Na+ —K+ ATPase and Na+-H transporter occurs. In addition, 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 their 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.
Calcium and phosphorous handling in the neonate is characterized by a pattern of increased phosphate retention associated with growth. The intake and filtered load of phosphate, parathyroid hormone (PTH), and growth factors modulate phosphate transport. The higher phosphate level and higher rate of phosphate reabsorption are not explained by a low GFR or 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 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, 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.
Fetal urine contribution to amniotic fluid volume is minimal (10 mL/hour) in the first half of gestation 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.
History
Prenatal history includes any maternal illness, drug use, or exposure to known and potential teratogens.
Maternal use of ACE-inhibitors, angiotensin receptor blockers, or indomethacin decreases glomerular capillary pressure and GFR and has been associated with neonatal renal failure.
Oligohydramnios may indicate a decrease in fetal urine production. It may be associated with renal agenesis, renal 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 or premature rupture of membranes (see Chaps. 2 and 4).
Polyhydramnios is seen in pregnancies complicated by maternal diabetes (see Chap. 2) and in fetal anomalies such as esophageal atresia (see Chap. 62) or anencephaly (see Chap. 57). It also may be a result of renal tubular dysfunction with inability to fully concentrate urine.
Elevated serum/amniotic fluid α-fetoprotein and enlarged placenta are associated with congenital nephrotic syndrome.
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 kidney disease [ARPKD], hydronephrosis, dysplasia) may be recognized in utero or remain asymptomatic until later life.
Delivery history. Fetal distress, perinatal asphyxia, sepsis, and volume loss may lead to ischemic or anoxic injury.
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 inadequate perfusion of the kidneys; however, delay in micturition may be due to intrinsic renal abnormalities or obstruction of the urinary tract.
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 GU system. It is important to consider in the differential diagnosis whether the mass is unilateral or bilateral (see 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.
Table 28.2 Abdominal Masses in the Neonate (see Chap. 62)
Type of mass
Total percentage
Renal
55
Hydronephrosis
Multicystic dysplastic kidney
Polycystic kidney disease
Mesoblastic nephroma
Renal ectopia
Renal vein thrombosis
Nephroblastomatosis
Wilms tumor
Genital
15
Hydrometrocolpos
Ovarian cyst
Gastrointestinal
20
Source: From Pinto E, Guignard JP. Renal masses in the neonate. Biol Neonate 1995;68(3):175-184.
Many congenital syndromes may affect the kidneys; thus, a thorough evaluation is necessary in those presenting with congenital renal anomalies. Findings associated with congenital renal 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 (see Table 28.3). Spontaneous pneumothorax may occur in those who have pulmonary hypoplasia associated with renal abnormalities.
Laboratory evaluation. Renal function tests must be interpreted in relation to gestational and postnatal age (see Tables 28.4 and 28.5).
Urinalysis reflects the developmental stages of renal physiology.
Specific gravity. Full-term infants have a limited concentrating ability with a maximum specific gravity of 1.021 to 1.025.
Table 28.3 Congenital Syndromes with Renal Components (see Chap. 10)
Dysmorphic disorders, sequences, and associations
General features
Renal abnormalities
Oligohydramnios sequence (Potter syndrome)
Altered facies, pulmonary hypoplasia, abnormal limb and head position
Renal agenesis, severe bilateral obstruction, severe bilateral dysplasia, autosomal recessive polycystic kidney disease
VATER and VACTERL syndrome
Vertebral anomalies, anal atresia, tracheoesophageal fistula, radial dysplasia, cardiac and limb defects
Renal agenesis, renal dysplasia, renal ectopia
MURCS association and Rokitansky sequence
Failure of parameso-nephric ducts, vaginal and uterus hypoplasia/atresia, cervicothoracic somite dysplasia
Renal hypoplasia/agenesis, renal ectopia, double ureters
Prune belly
Hypoplasia of abdominal muscle, cryptorchidism
Megaureters, hydronephrosis, dysplastic kidneys, atonic bladder
Spina bifida
Meningomyelocele
Neurogenic bladder, vesicoureteral reflux, hydronephrosis, double ureter, horseshoe kidney
Caudal dysplasia sequence (caudal regression syndrome)
Sacral (and lumbar) hypoplasia, disruption of the distal spinal cord
Neurogenic bladder, vesicoureteral reflux, hydronephrosis, renal agenesis
Anal atresia (high imperforate anus)
Rectovaginal, rectovesical, or recto-urethral fistula tethered to the spinal cord
Renal agenesis, renal dysplasia
Hemihypertrophy
Hemihypertrophy
Wilms tumor, hypospadias
Aniridia
Aniridia, cryptorchidism
Wilms tumor
Drash syndrome
Ambiguous genitalia
Mesangial sclerosis, Wilms tumor
Small deformed or low-set ears
Renal agenesis/dysplasia
Autosomal recessive
Cerebrohepatorenal syndrome (Zellweger syndrome)
Hepatomegaly, glaucoma, brain anomalies, chondrodystrophy
Cortical renal cysts
Jeune syndrome (asphyxiating thoracic dystrophy)
Small thoracic cage, short ribs, abnormal costochondral junctions, pulmonary hypoplasia
Cystic tubular dysplasia, glomerulosclerosis, hydronephrosis, horseshoe kidneys
Meckel-Gruber syndrome (dysencephalia splanchnocystica)
Encephalocele, microcephaly, polydactyly, cryptorchidism, cardiac anomalies, liver disease
Polycystic/dysplastic kidneys
Johanson-Blizzard syndrome
Hypoplastic alae nasi, hypothyroidism, deafness, imperforate anus, cryptorchidism
Hydronephrosis, caliectasis
Schinzel-Giedion syndrome
Short limbs, abnormal facies, bone abnormalities, hypospadias
Hydronephrosis, megaureter
Short rib-polydactyly syndrome
Short horizontal ribs, pulmonary hypoplasia, polysyndactyly, bone and cardiac defects, ambiguous genitalia
Glomerular and tubular cysts
Bardet-Biedl syndrome
Obesity, retinal pigmentation, polydactyly
Interstitial nephritis
Autosomal dominant
Tuberous sclerosis
Fibrous-angiomatous lesions, hypopigmented macules, intracranial calcifications, seizures, bone lesions
Polycystic kidneys, renal angiomyolipoma
Melnick-Fraser syndrome (branchio-oto-renal [BOR] syndrome)
Preauricular pits, branchial clefts, deafness
Renal dysplasia, duplicated ureters
Nail-patella syndrome (hereditary osteo-onychodysplasia)
Hypoplastic nails, hypoplastic or absent patella, other bone anomalies
Proteinuria, nephrotic syndrome
Townes syndrome
Thumb, auricular and anal anomalies
Various renal abnormalities
X-Linked
Oculocerebrorenal syndrome (Lowe syndrome)
Cataracts, rickets, mental retardation
Fanconi syndrome
Oral-facial-digital (OFD) syndrome type I
Oral clefts, hypoplastic alae nasi, digital asymmetry (X-linked, lethal in men)
Renal microcysts
Trisomy 21 (Down syndrome)
Abnormal facies, brachycephaly, congenital heart disease
Cystic dysplastic kidney and other renal abnormalities
X0 syndrome (Turner syndrome)
Small stature, congenital heart disease, amenorrhea
Horseshoe kidney, duplications and malrotations of the urinary collecting system
Trisomy 13 (Patau syndrome)
Abnormal facies, cleft lip and palate, congenital heart disease
Cystic dysplastic kidneys and other renal anomalies
Trisomy 18 (Edwards syndrome)
Abnormal facies, abnormal ears, overlapping digits, congenital heart disease
Cystic dysplastic kidneys, horseshoe kidney, or duplication
XXY, XXX syndrome (Triploidy syndrome)
Abnormal facies, cardiac defects, hypospadias and cryptorchidism in men, syndactyly
Various renal abnormalities
Partial trisomy 10q
Abnormal facies, microcephaly, limb and cardiac abnormalities
Various renal abnormalities
Protein excretion varies with gestational age. Urinary protein excretion is higher in premature infants and decreases progressively with postnatal age. In normal full-term infants, protein excretion is minimal after the second week of life.
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.
Hematuria is abnormal and may indicate intrinsic renal damage or result from a bleeding or clotting abnormality (see III.G.).
The 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, there is 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).
Method of collection
Suprapubic aspiration is the most reliable method to obtain an uncontaminated sample collection for urine culture. Ultrasound guidance will improve chance of success.
Bladder catheterization is used if an infant has failed to pass urine by 36 to 48 hours and is not hypovolemic (see III.B.), if precise determination of urine volume is needed, or to optimize urine drainage if functional or anatomic obstruction is suspected.
Bag collections are adequate for most studies such as determinations of specific gravity, pH, electrolytes, protein, glucose, and sediment but not urine culture. It is the preferred method for detecting red blood cells in the urine.
Table 28.4 Normal Urinary and Renal Values in Term and Preterm Infants
Preterm infants <34 wk
Term infants at birth
Term infants 2 wk
Term infants 8 wk
GFR (mL/min/1.73m2)
13-58
15-60
63-80
Bicarbonate threshold (mEq/L)
14-18
21
21.5
TRP (%)
>85%
>95%
Protein excretion (mg/m2/24 h) (mean ± 1 SD)
60 ±96
31 ±44
Maximal concentration ability (mOsmol/L)
500
800
900
1,200
Maximal diluting ability (mOsmol/L)
25-30
25-30
25-30
25-30
Specific gravity
1.002-1.015
1.002-1.020
1.002-1.025
1.002-1.030
Dipstick
pH
5.0-8.0
4.5-8.0
4.5-8.0
4.5-8.0
Proteins
Neg to + +
Neg to +
Neg
Neg
Glucose
Neg to + +
Neg
Neg
Neg
Blood
Neg
Neg
Neg
Neg
Leukocytes
Neg
Neg
Neg
Neg
Neg = negative.
Diaper urine specimens are reliable for estimation of pH and qualitative determination of the presence of glucose, protein, and blood.
Evaluation of renal function
