Kidney and Urinary Tract Disorders

Key Points

When a fetal urinary tract anomaly is identified, careful ultrasound examination is required to exclude coexistent anomalies.
In the presence of a coexistent anomaly, the risk for aneuploidy and single-gene disorders as an underlying aetiology should be considered and investigated.
Sonographic features associated with long-term poor renal function include hyperechogenic kidneys, renal cyst formation, oligohydramnios and the inability of the bladder to refill after drainage.
In cases of severe bilateral renal disease and associated severe oligohydramnios in the midtrimester, lethal pulmonary hypoplasia is probable and termination of pregnancy may be considered.
In ongoing pregnancies, multidisciplinary perinatal management should be planned with involvement of paediatric nephrologists and surgeons. Careful postdelivery assessment of the baby should be performed.
In selected cases of severe lower urinary tract obstruction, prenatal procedures (shunting or cystoscopy) appear to improve the short-term outcome and possibly also the long-term outcome.

Embryology

The development of the urinary tract starts from the third week of the embryonic period. Whereas the kidneys and ureters develop out of the intermediate mesoderm, the bladder and urethra arise from the urogenital sinus. Initially, the urogenital ridge is derived from the intermediate mesoderm on both sides of the primitive aorta. The intermediate mesoderm gives rise to a nephrogenic cord, which forms the pronephros, mesonephros and metanephros. The pronephros is a primitive excretion system which involutes almost completely by the fourth week. The mesonephros is composed of well-developed nephrons with vascularised glomeruli, draining into the mesonephric duct. It subsequently involutes except for the most caudal part, which turns into the male gonads and the vas deferens: the Wolffian duct. The permanent kidney develops from the caudally migrating mesonephric duct, now called the metanephric duct, from which a ureteric bud emerges ( Fig. 33.1 ). This ureteric bud outgrowth is a critical element in the development of the kidney. Signals from the ureteric bud interact with the adjacent metanephric mesenchyme. In response, these mesenchymal cells differentiate into the different cell types of the glomerulus and the proximal tubule, the loop of Henle and the distal tubule. Consequently, mesenchymal cells excrete molecular signals that induce the ureteric bud to branch and interact with new mesenchymal zones to form a new set of glomeruli. This branching of the ureteric bud is essential in the development of the number of glomeruli or nephrons. The ureter, the pyelocalyceal system and the most distal element of the nephron, the ductus colligens, are all derived from the ureteric bud.

• Fig. 33.1, Embryonic development of the fetal kidney and urinary tract. A, Development of the metanephros at the end of the fifth week. B, The ureteric bud emerges from the caudally migrating mesonephric duct and interacts with the surrounding metanephrogenic blastema. C–E, Branching of the ureter and development of the ureter, renal pelvis, calices and collecting tubules.

The lower urinary tract forms from the urogenital sinus which is an ectodermal derivative, segregated from the cloaca by the ingrowth of the urorectal septum ( Fig. 33.2 ). The urogenital sinus develops into bladder and proximal urethra and reaches out for the caudal tail of the metanephric tube, which then connect as the vas deferens.

• Fig. 33.2, Division of the cloaca into the urogenital (UG) sinus and the rectum by ingrowth of the urorectal septum. The UG sinus develops into bladder and proximal urethra.

At birth, each kidney contains about 1,000,000 functional units, called nephrons. The branching process is completed by 22 weeks’ gestation, but the induction of the mesenchyme by the epithelial ureteric structures is not completed before 34 to 36 weeks, accounting for the progressive maturation of fetal renal function. The functional maturation continues further because of an increase in size of the existing nephrons.

The metanephros is formed in the sacral region at the level of S1 but in an adult the kidney lies at the upper lumbar level (T12–L3). The ascent of the kidneys occurs between the 6th and 9th gestational weeks, probably as a result of differential growth of the sacral and lumbar regions, which lead to an unfolding of the lower pole of the embryonic body ( Fig. 33.3 ). The transitory vessels supporting the kidney during its ascent normally disappear. During their ascent, the kidneys turn 90 degrees towards the vertebral cords.

Fetal urine production begins by 10 to 11 weeks’ gestation. As clearing waste products out of blood is done by the placenta, the main function of the kidneys in the prenatal period is the production of amniotic fluid. The biochemistry of fetal urine is not well documented until 16 weeks. Later in gestation, analysis of fetal urine suggests that the various functions of the kidney do not develop at the same time. Whereas glomerular protein resorption and tubular reabsorption of glucose and phosphate are already mature at 20 weeks, the tubular reabsorption of sodium and β-2-microglobulin and the tubular secretion of calcium is more progressive during the second half of pregnancy.

The estimated rate of urine production increases exponentially with gestation from 5 mL/h at 20 weeks to 50 mL/h at 40 weeks.

Normal Sonographic Development of the Fetal Kidneys and Urinary Tract

From about 10 to 12 weeks of pregnancy, the fetal kidneys and adrenal glands can be visualised at both sites of the lumbar spine. The kidneys should be seen by ultrasound at 13 weeks, and they are usually easy to identify because of their relatively hyperechoic appearance in the first trimester. The visualisation of the renal arteries by colour Doppler can facilitate their identification ( Fig. 33.4A ). The sonographic corticomedullary differentiation starts at 15 weeks and becomes clearer with advancing gestational age ( Fig. 33.5 ). Kidney echogenicity becomes less than that of the liver and spleen from 17 weeks on.

• Fig. 33.4, Ultrasound appearance of the kidneys and fetal bladder in the first ( A ) and second ( B ) trimesters of pregnancy. Normal female and male external genitalia at 20 weeks of pregnancy ( C ).

• Fig. 33.5, The normal corticomedullary differentiation throughout pregnancy. With advancing gestational age, the differentiation between the renal cortex and medulla becomes clearer. The medulla becomes hypoechogenic because of the appearance of the medullary pyramids (arrows) .

The fetal bladder should always be visualised by 13 weeks (or crown–rump length >67 mm), and megacystis can be identified by ultrasound as early as 10 to 14 weeks at which time bladder length should not exceed 7 mm (see Fig. 33.4A ). Identification of the bladder later on in pregnancy is easy because of its location in the pelvis, between the umbilical arteries ( Fig. 33.4B ). Fetal urine production starts at 10 to 11 weeks of pregnancy and increases significantly beyond 16 weeks. At 20 weeks, about 90% of amniotic fluid consists of fetal urine.

Ultrasound examination of the normal urinary tract consists of the assessment of the presence, location and size of both kidneys and the evaluation of their structure and echogenicity. In addition, the presence, size and shape of the fetal bladder are examined, as well as development of the external genitalia ( Fig. 33.4C ) and the amount of amniotic fluid. The amount of amniotic fluid may be estimated subjectively or more objectively by measuring the deepest pocket or the amniotic fluid index.

Classification and Pathology of Fetal Renal and Urinary Tract Anomalies

The embryonic development of the urogenital system in humans is a complex process; consequently, renal anomalies are common and constitute about 20% of all congenital anomalies.

Malformations of the urogenital system can be classified into:

1.
Urinary tract anomalies
2.
Renal malformations
3.
Bladder malformations
4.
Genital malformations

Urinary Tract Anomalies

Urinary Tract Dilation

Dilation of the urinary tract is a common finding occurring in 1% to 2% of pregnancies. Whereas pyelectasis is defined as a dilation of the renal pelvis, hydronephrosis consists of a dilation of both the renal pelvis and the calyces. The severity of urinary tract dilation can be assessed by different grading systems: descriptive (mild, moderate or severe hydronephrosis), quantitative (value of the anteroposterior diameter of the renal pelvis (APRPD)) and semiquantitative (e.g., grading system of the Society of Fetal Urology).

Measuring the APRPD is the generally accepted method. The APRPD is measured in a cross-sectional plane through both kidneys at the level of the hilus ( Fig. 33.6 ) . A consensus on the ideal threshold value to diagnose urinary tract dilation is lacking, but the most accepted cutoff values are 4 mm in the second trimester and 7 mm in the third.

• Fig. 33.6, Measurement of the anteroposterior diameter of the renal pelvis.

The semiquantitative grading system, as proposed by the Society of Fetal Urology (SFU), classifies antenatal hydronephrosis in 5 grades, taking into account the evaluation of the renal pelvic dilation, the presence of minor or major calyceal dilation and the evaluation of parenchymal thickness ( Table 33.1 ). Recently, Nguyen and coworkers proposed the Urinary Tract Dilatation (UTD) Classification System which is a consensus consolidation of a number of previous studies including the SFU system. This grading system is based on the APRPD, calyceal dilation, parenchymal thickness and appearance, dilation of the ureter and assessment of the bladder and provides a description of urinary tract dilation that can be applied both prenatally and postnatally as well as a standardised approach for perinatal evaluation ( Table 33.2 and Fig. 33.7 ).

TABLE 33.1

Hydronephrosis Grading System of the Society of Fetal Urology (SFU)

Adapted from Nguyen HT, Herndon CD, Cooper C, et al. The Society of Fetal Urology consensus statement on the evaluation and management of antenatal hydronephrosis. J Pediatr Urol 6 :212–231, 2010.

Hydronephrosis Grade	Pattern of Renal Sinus Splitting
0	No splitting
1	Urine in pelvis barely splits sinus
2	Urine fills intrarenal pelvis Urine fills extrarenal pelvis; major calyces dilated
3	SFU grade 2+ minor calyces uniformly dilated and parenchyma preserved
4	SFU grade 3 with parenchymal thinning

SFU, Society of Fetal Urology.

TABLE 33.2

Ultrasonography Parameters Included in the Urinary Tract Dilatation (UTD) Classification System and Normal Values

Adapted from Nguyen HT, Benson CB, Stein DR, et al. Multidisciplinary consensus on the classification of prenatal and postnatal urinary tract dilation (UTD classification system). J Pediatr Urol 10 (6):982–998, 2014.

US Findings	16–27 wk	>28 wk	Postnatal (>48 hr)
APRPD ^a	<4 mm	<7 mm	<10 mm
Calyceal dilation ^b Central Peripheral	No No	No No	No No
Parenchymal thickness ^c	Normal	Normal	Normal
Parenchymal appearance ^d	Normal	Normal	Normal
Ureter(s) ^e	Normal	Normal	Normal
Bladder ^f	Normal	Normal	Normal
Unexplained oligohydramnios	No	No	No

a Antero-posterior renal pelvic diameter (AP RPD) (mm): measured on transverse image at the maximal diameter of infrarenal pelvis.

b Calyceal dilation: yes or no.

c Parenchymal thickness: normal or abnormal (subjective assessment).

d Parenchymal appearance: normal/abnormal (evaluate echogenicity, corticomedullary differentiation and for cortical cysts).

e Ureter: normal or abnormal (dilation = abnormal; however, transient visualisation is considered normal postnatally).

f Bladder: normal or abnormal (evaluate wall thickness, presence of ureterocele, dilated posterior urethra).

• Fig. 33.7, Risk stratification based on UTD Classification System by Nguyen and coworkers. 8 AP, anterio-posterior; GU, genitourinary; RPD, renal pelvic diameter; UTD, urinary tract dilatation.

The underlying aetiology of fetal urinary tract dilation is diverse and may result either from overdistension secondary to a distal obstructive lesion or from retrograde urine flow as a consequence of reflux. It can occasionally be difficult to distinguish between these two broad pathologies and significant overlap exists. Transient or physiologic dilation is the most common aetiology, accounting for 50% to 70% of mostly mild urinary tract dilations. With increasing dilation or progression to hydronephrosis, the likelihood of a significant uropathy on postnatal evaluation increases.

Fetal obstructive uropathies are usually classified by ultrasound according to the level of the dilation ( Table 33.3 ). For high- and midlevel obstruction, the lesions can be either uni- or bilateral. This is important from a prognostic point of view because postnatal renal function is likely to be normal in unilateral cases with preserved amniotic fluid volume.

TABLE 33.3

Level of Dilation, Sonographic Characteristics and Possible Underlying Causes

Level of Uropathy	Most Distal Ultrasound Finding	Possible Underlying Causes
High	Pyelectasis Hydronephrosis	PUJ stenosis, polyuria, duplication
Mid	Hydroureter	VUJ stenosis, VUR, congenital megaureter, ureterocele
Low	Megacystis	Urethral atresia, PUV, obstructive ureterocele, polyuria, VUR, complex cloacal malformations

PUJ, Pyeloureteral junction; PUV , posterior urethral valves; VUJ, vesicourethral junction; VUR, vesicoureteral reflux.

Mild Isolated Pyelectasis

Mild pyelectasis is a common and usually benign finding (see Fig. 33.6 ). In some cases, however, it may be secondary to vesicoureteral reflux (VUR) or obstruction. Prenatal ultrasound follow-up should be performed to ensure that the dilation does not increase with gestation. Postnatal ultrasound is advocated 6 weeks after birth unless symptomatology suggestive of urinary tract involvement occurs (e.g., fever).

The prevalence of mild pyelectasis is somewhat greater in fetuses with trisomy 21 than in euploid fetuses, and this finding has been used for screening. In the presence of midtrimester pyelectasis, other soft markers for fetal aneuploidy should be sought and the risk for aneuploidy, especially trisomy 21, calculated. Male fetuses tend to have a larger renal pelvis. Therefore the likelihood ratio for aneuploidy associated with this finding is smaller in male than in female fetuses.

Ureteropelvic Junction Stenosis

Ureteric obstruction at the ureteropelvic junction (UPJ) is the most common lesion of the fetal urinary tract, occurring in 1 in 2000 newborns. The cause can be intrinsic (e.g., abnormal muscle arrangement at the UPJ, anomalous collagen collar or urothelial fold) or extrinsic (e.g., compression of the ureter by a crossing vessel). UPJ stenosis can be bilateral in approximately 30% of cases. The typical ultrasound presentation is severe hydronephrosis without ureteral dilation and with a normal bladder ( Fig. 33.8 ). A severely dilated renal pelvis can rupture and evolve to a perinephric urinoma ( Fig. 33.9 ).

• Fig. 33.9, Severe ureteropelvic junction stenosis with leakage of urine into the retroperitoneal space: perirenal urinoma. Arrow indicates anteriorly displaced, hydronephrotic kidney.

Obstruction at the Vesicoureteral Junction (VUJ) (Vesicoureteral Junction Stenosis) and Megaureter

Obstruction at the VUJ can be uni- or bilateral. On prenatal ultrasound, the ureter (hydroureter, Fig. 33.10A ) and renal pelvicalyceal system are dilated. The cause can be an anatomical abnormality of the vesicoureteral junction (stricture or valve), or the obstruction can be functional. A primary megaureter ( Fig. 33.10B ) is most frequently the result of an aperistaltic distal ureteral segment, but megaureters can also be seen in high grade VUR or in cases of ectopic insertion in the bladder.

• Fig. 33.10, Ultrasound appearance of hydroureter ( A ) and megaureter ( B ).

Ureterocele

A ureterocele is a cystic dilation of the distal intravesical ureter. Most ureteroceles arise from an abnormal location of the ureteral meatus in the bladder and are therefore termed ectopic . Ureteroceles are often associated with a double ureter and kidney (duplex system), the ureterocele at the lower ureteric orifice draining the upper pole of the duplex kidney. The lesion may be associated with obstruction accounting for the dilation of the corresponding ureter or renal pelvis. On ultrasound, the ureterocele is visible as a ‘bubble’ in the fetal bladder ( Fig. 33.11 ). A large ureterocele may obstruct the bladder neck, the disease then resembling an infravesical obstruction (see under lower urinary tract obstruction (LUTO)). In these cases, successful prenatal drainage has been described.

Obstruction of the Bladder Outlet (Lower Urinary Tract Obstruction)

Obstruction of the bladder outlet usually occurs in the urethra and can lead to bladder dilation (megacystis or megabladder) with muscle hypertrophy and secondary hydroureteronephrosis ( Fig. 33.12 ). The kidneys may ultimately become dysplastic, resulting in a variable association with chronic renal failure. Longstanding oligo- or anhydramnios will ultimately result in lethal fetal pulmonary hypoplasia.

• Fig. 33.12, Typical ultrasound appearance of severe lower urinary tract obstruction: megacystis (star) ( A ), bilateral hydronephrosis and signs of renal dysplasia (arrows) ( B ), dilated proximal urethra or ‘keyhole’ sign ( C ). Signs of bladder wall hypertrophy and trabeculation are shown in D (arrows) .

Sonographically, a persistently dilated bladder is visualised between the two umbilical arteries using colour-flow Doppler. The dilation is usually round in shape but can be larger above the umbilical vessels, evoking the shape of a cork or champagne bottle. The image of a dilated proximal urethra (keyhole) is suggestive of posterior urethral valves (PUVs) in a male fetus ( Fig. 33.12C ). PUVs are the most common cause of bladder obstruction, occurring exclusively in male fetuses. The ‘valves’ consist of folds of mucosa along the posterior wall of the urethra, most often extending from the veru montanum and resulting in a very narrow urethral lumen. Urethral atresia can be seen in both male and female fetuses. This condition is less common than PUV and most frequently results in fetal lethality with anuria in the first and early second trimesters.

Vesicoureteral Reflux

Vesicoureteral reflux is a common disorder that is associated with dilation of the ureters and calyceal collecting systems and is usually confirmed postnatally ( Fig. 33.13 ). Direct imaging of the reflux is sometimes possible during real-time two-dimensional ultrasonography. In the most severe cases, the bladder and ureters appear dilated because of a functional increase of the urinary outflow. The potential benefit of prenatal diagnosis of such cases is to avoid postnatal urinary infection and subsequent kidney damage. Postnatal assessment is essential, and postnatal surgery may be required in the severe forms of VUR.

Complex Cloacal Anomalies

These anomalies result from the failure of the urogenital sinus to divide properly. Therefore fistulae form in vesicovaginal or urethrovaginal locations in females or urethrorectal locations in males. The association with anorectal atresia is frequent.

Sonographically, the diagnosis can be quite difficult, and sonographic signs may only appear late in pregnancy. In case of a uroenteric fistula, there may be bowel dilation containing echogenic material. Direct visualisation of a duplicated and enlarged vagina is suggestive for a cloacal malformation ( Fig. 33.14 ). Although the anal sphincter can be visualised on ultrasound, this does not rule out anal atresia.

• Fig. 33.14, A and B, Cloacal malformations. Dilated uterus with uterine septum (large arrow) , urinary ascites (stars) and hydronephrosis (arrow) in a fetus with a persistent cloaca.

Microcolon-Megacystis-Intestinal Hypoperistalsis Syndrome (MMIHS)

This syndrome is caused by an anomaly in the acetylcholine receptor secondary to a variant of the ACTG2 gene. The disorder is inherited as an autosomal dominant disorder but in many cases occurs as a de novo mutation. It should be suspected when nonobstructive megacystis is visualised in combination with ileal or large bowel dilation and normal amniotic fluid. The condition has a poor prognosis in the postnatal period because of the poor intestinal function.

Prenatal Management of Fetal Obstructive Uropathies

In first trimester megacystis, further detailed fetal anatomy scanning and karyotyping are warranted because the risk for an underlying chromosomal syndrome is increased. With a longitudinal bladder diameter of 7 to 15 mm, there is a risk for about 25% of a chromosomal defect. In the chromosomally normal group, there is spontaneous resolution of the megacystis in about 90% of cases. If the bladder diameter is greater than 15 mm, the risk for chromosomal defects is about 10%, and in this chromosomally normal group, the condition is almost invariably associated with progressive obstructive uropathy ( Table 33.4 ). If the fetal bladder is not visualised during the first trimester, renal agenesis should be actively excluded. This may require repeated (transvaginal) scanning.

TABLE 33.4

Outcome of First Trimester Megacystis

Adapted from Liao AW, Sebire NJ, Nicolaides KH, et al. Megacystis at 10-14 weeks of gestation: chromosomal defects and outcome according to bladder length. Ultrasound Obstet Gynecol 21 (4):338–341, 2003.

	Longitudinal bladder length (mm)
	7–15	>15
Total	110	35
Abnormal karyotype	26	4
Normal karyotype with follow up	79	30
Spontaneous resolution	71	0
LUTO	8	30

LUTO, Lower urinary tract obstruction.

When a fetal obstructive uropathy is suspected during the second trimester , a detailed assessment of the genitourinary tract should be performed, including bladder size, renal size, shape and parenchyma. Amniotic fluid volume and associated anomalies should be evaluated. If there is severe oligohydramnios limiting transabdominal ultrasound imaging, transvaginal ultrasound, magnetic resonance imaging (MRI) and amnioinfusion can be used to better visualise the fetus and urinary tract. When the diagnosis of obstructive uropathy is clear and associated malformations have been excluded, the prognosis should be established.

Factors associated with a poor prognosis include:

Diagnosis before 24 weeks
Severe oligohydramnios
Renal dysplasia (hyperechogenic parenchyma, cortical cysts)
Associated structural or chromosomal malformations
Female gender (indicating urethral atresia or more complex cloacal plate anomalies)

Evaluation of the Fetus With an Obstructive Uropathy

Genetic Testing for Obstructive Uropathies

Overall, the incidence of fetal chromosomal anomalies is as high as 10% to 15% in fetal renal defects, with the combination of renal and extrarenal malformations carrying the highest risk. In isolated uropathies, the risk is lower, but most clinicians offer invasive genetic testing including karyotyping or preferably microarrays. No studies have specifically explored the added value of microarrays compared with conventional karyotyping in cases with LUTO. However, because chromosomal abnormalities are frequent in LUTO cases and genomic imbalances are frequent in children with chronic kidney disease, it seems appropriate to screen fetuses with the highest available scrutiny before invasive maternal procedures are considered.

Prediction of Fetal Renal Function

After a diagnosis of a uropathy is confirmed by ultrasound, an attempt should be made to access the short- and long-term outcomes. In unilateral disease, renal function is generally preserved, and a conservative approach is warranted during pregnancy, provided that the contralateral kidney is normal. Postnatal management is dependent on the remaining function of the diseased kidney. In bilateral uropathies, the prognosis and management depend on the predicted damage to renal function, which is usually predicted based on detailed renal imaging supplemented by sampling of fetal urine, serum or renal tissue, when imaging alone is uncertain. In some cases, such as LUTO, the ultrasound appearance of the fetal kidneys and the urinary biochemistry are not strongly correlated, so both ultrasound and biochemistry need to be taken into account.

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