Antenatal Diagnosis and Management of Renal Problems

R Bhimma
Renal Agenesis
Renal agenesis may be unilateral or bilateral; the latter also known as Potters syndrome, Potters sequence or oligohydrammios sequence, coined by the pathologist Edith Potter [8-11].
Bilateral renal agenesis is the congenital absence of both kidneys and is incompatible with life in most cases as it is a lethal congenital anomaly [12]. Bilateral renal agenesis can be detected by ultrasound after 16 weeks of gestation as severe oligohydramnios (markedly decreased amniotic fluid in the amniotic cavity) because at this stage foetal urine production is the main source of amniotic fluid production as compared to transmembrane flow in earlier gestation [13]. The genetic aspects of this condition have not yet been fully investigate and the estimated incidence is 0.1 per 1000 live births [14]. Maternal factors associated with bilateral renal agenesis include a body mass index greater than 30kg/m² prior to pregnancy, smoking and binge drinking particular during the second month of pregnancy [15]. Although serial amnioinfusions have been used to improve foetal pulmonary development, it is not an appropriate intervention in cases of severe renal agenesis [16, 17].
Bilateral renal agenesis may be associated with structural abnormalities in over 50% of cases including a variety of syndromes associated with chromosomal anomalies, caudal dysgenesis and the VACTERL association (Vertebral anomalies, Anal atresia, Cardiac defects, Tracheo-oesophageal fistula, Renal defects and Limb defects) [18]. Crossed fused ectopic occurs when both kidneys fuse and are located on the same side of the midline. It occurs predominantly on the left side and in males [19]. Most patients are asymptomatic. Complications include urinary tract infection, VUR, pelviureteric function obstruction and urolithiasis. The estimated prevalence is in 2000 live births although this may be an underestimate due to many cases being asymptomatic [1].
Unilateral agenesis is the congenital absence of one kidney and these patients usually have a normal lifespan unless there is co-existing renal anomalies that progress to end-stage kidney disease. These include ureterovisical junction obstruction, bladder dysfunction, vesicoureteric reflux (VUR), ureteropelvic junction obstruction, duplicated collecting system with severe reflux and an ectopic kidney with severe reflux [1, 20]. These patients also have an increased risk of hypertension [21, 22]. This condition is more common than bilateral renal agenesis with an incidence of about 1 in 2000 [21].

Renal hypoplasia is failure of development of part of the kidneys with normal morphology but decreased number of nephrons. The incident is about 1 in 400 live births and it can progress to end-stage kidney disease in childhood if bilateral and severe [1, 23].

The incidence of ectopic kidneys is about 1 per 1000 pregnancies [24, 25]. The commonest site is the pelvis. Other forms of renal ectopia include horseshoe kidneys, crossed (fused) ectopia and intrathoracic kidney [25]. Horseshoe kidney is the commonest type of renal fusion anomaly with an incidence of 1 in every 400 births and is more common in males [26]. The mechanism of development is thought to be due to fusion of birth kidney held by a fibrous isthmus during organogenesis. Alternatively fusion may be due to abnormal migration of the parenchymatous isthmus, resulting in a teratogenic event [27, 28]. Although the majority of patients are asymptomatic when symptoms are present they include nausea, vomiting, recurrent episodes of urinary tract infection usually associated with reflux and renal calculi with obstructive uropathy [29].
Fused pelvic kidney results from failure of the kidney to ascend during fetal development and results in the kidney being fixed in the pelvis. It is also known as a pancake kidney [30, 31].

Renal malrotations are rare and the exact incidence unknown as patients are usually asymptomatic. The condition is sometimes known as abnormal renal rotation and is an anatomical variation in the position of the kidneys, particularly the orientation of the renal hilum [32].

Solitary kidney may be the result of complete renal agenesis of one kidney or involution of a dysplastic kidney [33]. Associated abnormalities include VUR and obstruction (ureteropelvic junction or ureterovesical junction obstruction). Infants with a normal post-natal ultrasound and solitary kidney do not require extensive imaging studies. However if any abnormality is detected a voiding cystourethrogram and diuretic urography should be performed. These children must be monitored for the development of hypertension and for proteinuria as this predisposes to chronic kidney disease [34-36].
A duplex kidney is when two pelvicaliceal systems drain a single kidney [37]. This kidney usually is more elongated and contributes a higher percentage to total kidney function on split function renography [38]. Postnatal care involves close monitoring for urinary tract infections to prevent loss of renal function as several of these children have severe VUR or some form of obstructive uropathy [39].

Multicystic kidney disease (MCKD) is characterised by the presence of non-communicating cysts of various sizes, lack of normal renal parenchyma and atretic proximal ureters [7]. The incidence is about 1 in 4300 live births [47]. In 25-40% of cases the contralateral kidney is also abnormal, reflux being the most frequently associated anomaly. Bilateral MCDK occurs in about 10-20% of cases and is a lethal condition [48]. High quality ultrasonography done antenatally is diagnostic of MCDK and only if the postnatal ultrasound suggests the possibility of function renal parenchyma should a Dimercaptosuccinic acid (DMSA) scan be done [49, 50]. VUR in patients with unilateral MCDK and a normal contralateral kidney on postnatal ultrasonography is usually low grade and these patients can be managed conservatively without routine voiding cystourethrogram (VCUG) screening [51, 52]. Abnormalities of the contralateral kidney (hydronephrosis, small size, lack of corticomedullary differentiation, dilated ureter) should be investigated with a VCUG. If this is normal, a diuretic renogram should be performed [7]. Families of patients with unilateral MCKD should be counseled on the signs and symptoms of UTI to allow prompt diagnosis and treatment [53]. Infants with postnatal confirmed moderate or severe hydronephrosis (SPU 3-4, renal anteroposterior diameter >10mm) or dilated ureter should receive antibiotic prophylaxis whilst awaiting evaluation. Those with VUR grade III-V should also receive antibiotic prophylaxis [54, 55].

MCKD is characterised by slowly progressive kidney disease due to interstitial fibrosis with progression to end-stage kidney disease in adulthood. This has an autosomal dominant pattern of inheritance. There are several gene defects that can result in MCKD: Type 1 MCKD is due to mutations in the MUC 1 gene resulting in excessive deposition of mucin 1 protein in the distal nephron; Type 2 is due to mutations in the UMOD gene resulting in a mutant form of uromodulin protein that cannot exit the endoplasmic reticulum and this results in abnormal accumulation of protein, which causes tubular cell death and chronic kidney disease [56, 57].

Polycystic Kidney disease can occur in both adults and children. The term polycystic kidney disease is reserved for the following hereditary conditions.
• Autosomal recessive polycystic kidney disease (ARPKD) characterised by cystic dilations of the renal collecting ducts and congenital hepatic fibrosis with an autosomal recessive pattern of inheritance.
• Autosomal dominant polycystic Kidney disease (ADPKD) characterised by cystic dilations in all parts of the nephron with cysts in several other organs (e.g. liver, pancreas, spleen, and intestine) with an autosomal dominant pattern of inheritance.

ADPCK occurs in one in every 400-1000 live births and accounts for more than 5% of cases of end-stage kidney disease in Western countries [58]. Mutations in the PKD1 gene (MIM 173900) account for 85% of cases. This gene is located on chromosome 16p13.3 and encodes for the polycystic 1 protein. Most other patients have a mutation in the PKD 2 gene (MIM *173910), which encodes polycystic 2 protein and is located on chromosome 4q21, involved in cell calcium signaling and localizes to the primary cilia of renal epithelial cells [59, 60].

The disease is rarely seen in foetal life. Prenatal ultrasound may show kidneys that are moderately enlarged (+1 -2SD) with hyperechoic cortex and hypoechoic medullar or absent or decreased corticomedullary differentiation, although in some cases ultrasonography may be normal [61]. Most children with the condition are asymptomatic. Symptomatic children present similar to adults (gross or microscopic haematuria, hypertension, proteinuria, infection of cysts, urinary tract infection, abdominal, flank or back pain and rarely, renal insufficiency) [62-64].

No specific treatment has been proven to prevent or delay progression to end-stage kidney disease. Promising therapies which are being tested in clinical trials include Vasopressin receptor antagonists, mammalian target of rapamycin (mTOR) and rigorous control of blood pressure with angiotensin receptor blockers or antagonists with maximal inhibition of the renin angiotensin receptor antagonists [65]. Children with significant nephromegaly should avoid contact sport. The use of non-steroid anti-inflammatory drugs is discouraged because of the increased risk of haemorrhage into cysts. In patients who develop cysts infection, sulphanamides and Ciprofloxacin are the antibiotics of choice as they have better cysts penetration and are effective against gram negative bacteria that are the most frequent causative agents [66]. Children diagnosed with ADPCKD are likely to preserve kidney function until the fourth decade of life. However symptomatic children may progress more rapidly to end-stage kidney disease [67].

Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in the PKHD1 gene located on chromosome 6p21. This gene encodes fibrocystic (polyductin), a large internal membrane protein (4074 amino acids) and has at least 66 exons [68, 69]. The gene is found on chromosome 6 and is expressed on the cilia of the renal and bile ducts [70]. It is much less frequent than ADPKD with an estimated frequency if 1:20000 live births [71]. Prenatally the condition can be detected after 24 weeks gestation. The characteristic finding is markedly enlarged echogenic kidneys with poor corticomedullary differentiation [72, 73]. Occasionally discreet cysts between 5-7mm may be defected. Cysts >10mm are unusual and more compatible with a diagnosis of multicystic dysplasia. There if often concomitant oligohydrannios and absence of urine in the fatal bladder [72, 73]. Absence of abnormal ultrasound findings does not exclude the diagnosis and similar findings may be present in other condition associated with renal cysts. The presence of other system involvement usually suggests cystic disease associated with syndromic ciliopathies e.g. Bardet-Biedl and Jourbet syndromes. Ultrasound of both parents should be done to exclude ADPKD or HNF1B–related cystic kidney disease, both of which are autosomal dominant disorders.

Neonatal presentation varies from those with severe ARPKD associated with Potter syndrome and severe respiratory distress, to those less severely affected with renal dysfunction but no signs of respiratory distress. The degree of pulmonary hypoplasia is the major determinate of compatibility of life even with mechanical ventilation [74, 75]. Patients with ARPKD who survive and on renal replacement therapy are at risk of hepatobiliary complications such as progressive portal hypertension, bacterial cholangitis, reduced level of fat soluble vitamins and increased risk of infection by encapsulated organism (pneumococcus, hemophilic influenza type B and meningococcus). Prophylactic immunization is advised [76, 77].

Renal tumours can be diagnosed at about 18-20 weeks gestation using ultrasound or fetal magnetic resonance imaging (MRI). The most common is mesoblastic nephroma (a renal stromal neoplasm) that represents 3-10% of all pediatric tumors [78]. It usually accompanies oligohydramnios and has a favorable outcome following nephrectomy [79]. Other tumors that may be diagnosed antenatally include: Wilms tumor, rhabdoid tumor, clear cell sarcoma, harmatomas (e.g. angiolipomia), and ossifying tumor of infancy [80].

The common ureteral abnormalities diagnosed antenatally are shown in Table 3.

a. Ectopic Ureter
Also known as ureteral ectopia, it is more common in females than males, resulting from abnormal migration of the ureteral bud during its insertion to the bladder. In males the ectopic ureter may insert itself into the lower urinary bladder, posterior urethra or outside the urinary tract (e.g. seminal vesicles vas deferens, or ejaculating duct) [81-83]. In females its insertion is into the lower urinary bladder, urethra, or vagina [81-83]. Common presenting symptoms postnatally include dribbling urinary incontinence, urinary tract infection, abdominal pain, and progression to chronic kidney disease [82, 84].

b. Congenital Mega Ureter
This condition is present in 6–10% of infants diagnosed antenatally with hydronephrosis [85] and presents as primary non-obstructed, non-refluxing megaureter. This must be differentiated from primary obstructed megaureter which is associated with high complication rates, including infections, stone formation and progression to chronic kidney disease [86]. The cause is taught to be an abnormality in the (Wolffian) duct and ureteric buds [87].

c. Duplication of Ureters
This condition occurs when two separate ureteric buds arise from a single Wolffian duct. It is one of the most commonly diagnosed renal anomalies antenatally, occurring in about 1% of the population [88]. Incomplete forms of ureteric duplication are clinically silent but complete forms can result in VUR, ectopic ureterocoele, or ectopic ureteral insertion [89, 90]. It is estimated that about 10% of children diagnosed with urinary tract infections have ureteral duplication [88]. For patients with ureteral duplication with a severely dilated ureter, management is surgical correction [91].

c. Ureterocoele
This condition is characterised by cystic pouching of the distal ureter into the urinary bladder. The condition can be diagnosed by antenatal ultrasound but postnatally MRI may be needed to clarify the diagnosis [92-94]. The condition is more common in females [95]. Management is surgical and often includes endoscopic ureteral incision, ipisilateral ureterostomy, and ureterocele moiety heminephrectomy. Endoscopic puncture is also a safe and effective treatment for symptomatic children with both single system and duplex system intravesical ureterocoeles [96].

Table 3: Commonly diagnosed ureteral anomalies.
Ectopic Ureter
Duplication of Ureters
Congenital Mega Ureter
Uretropelvic Junction Obstruction

This condition is characterized by herniation of the urinary bladder through and anterior abdominal wall defect [97]. This is due to a developmental defect of the cloacal membrane that results in the protrusion of the bladder mucosa as a mass lesion. The diagnosis is usually made prenatally during routine US examination [98]. MRI is useful in planning optimal surgery postnatally [99]. The incidence is 1 in 10 000 to 50 000 and is more common in males [1].

This is a congenital disorder seen almost exclusively in males, found in 1.7% live births and in characterized by an out-pouching from the bladder wall [98, 100]. The defect arises as a result of weakness of the ureterovesical junction or posterior ureteral valve causing high intravesical pressure with voiding. If sufficiently severe, the lesion can be detected antenatally on US. Due to the potential for carcinomatous change, diverticular excision is recommended [101]. Bladder diverticulum and VUR, along with neurological problems is sometimes associated with Menkes syndrome, first described in 1962 [102]. This is an X-linked neurodegenerative disorder characterized by impairment of copper transport where there is a reduction in the function of ATP7A function, which decreases copper transport [103, 104].

This condition arises when the Allantois fails to breakdown and results in an opening between the bladder and umbilical cord. The condition is diagnosed antenatally using US and is seen as a tubular connection between the bladder and umbilical cord. Postnatally treatment is surgery with removal of the patent urachus and repair to the bladder [105-107].

First described by Berdon in 1976, the condition is characterized by largely a dilated non-obstructed urinary bladder, microcolon, and decreased or absent intestinal peristalsis [108]. Often diagnosed antenatally on US and as the condition is fatal, termination of pregnancy is advised [109]. The pathogenesis is thought to be due to mutations in ACTG2 resulting in a smooth muscle myopathy with an autosomal recessive pattern of inheritance [110, 111]. It is recommended that when a female foetus is found to have megacystis associated with polyhydramnios on antenatal US, this condition should be considered [112].

Hydronephrosis is defined as dilatation of the renal pelvis and calyces whilst pyelectases involves dilatation of the renal pelvis only. Grading the severity of renal pelvic dilatation is most often done using the maximal antero-posterior diameter of the renal pelvis on a transverse scan of the foetal abdomen [40, 41]. An alternative grading system is that proposed by the Society of Fetal Urology (SFU) that classifies hydronephrosis in 4 degrees (grade 0-4) and takes into account the degree of pelvic dilatation, the number of calyces seen and the presence or seventy of renal parenchymal thinning or atrophy [42]. This grading system is more subjective and therefore less often used.
An anteposterior diameter of <10mm equate to SPU grade 1-2 and >10mmHg equates to the SPU grade 3-4.
There should be an ideal threshold value for renal anteroposterior diameter that differentiates foetuses with physiological and transient hydronephrosis from those at risk for congenital anomalies of the GU. Unfortunately, as consensus is lacking, thresholds vary between 4-10 in the second trimester and between 7 and 10mm in the third trimester. In a systemic review and meta-analysis of the outcome of isolated antenatal hydronephrosis, it was found that anteroposterior diameter of the renal pelvis <12mm (grade 1-2 in SPU grading) showed stabilization of pelviectasis in 98% of patients whilst there >12mm (grade 3-4 SPM) the resolution rate was 51%, with grade 1-2 being 5 times more likely to stabilize than grade 3-4. This provides strong evidence that patients with mild degrees of isolated antenatal hydronephrosis (<12mm), the condition is self-limiting.
Hydronephrosis may be detected as early as the 12th to 14th week of gestation [43] and is seen in 1-5% of pregnancies [44]. The condition presents in about 30-75% of infants and may result in obstruction to the urinary tract [45]. The aetiology of hydronephrosis is transient (48%) or physiological (15%) in the majority of cases with only in a minority of cases with significant pathology of the urinary tract being detected [25]. The latter includes inter alia, ureter pelvic junction stenosis, VUR, vesico-ureteric junction stenosis and mega-ureter, multicystic kidney disease, ureterocele or duplex collecting system and posterior urethral valves. Rare causes are an ectopic ureter, prune belly syndrome, urachal cyst and urethral atresia [46]. Severe forms are more likely associated with underlying pathology (>10mm in the 2nd trimester and >15mm in the 3rd trimester) [41]. The classification of antenatal hydronephrosis, based on renal pelvic anteroposterior diameter is shown in Table 2.

Table 2: Classification of renal antenatal hydronephrosis based on renal pelvic anteroposterior diameter [113]
Classifications Renal pelvic anteroposterior diameter, APD
Second Trimester Third Trimester
Mild 4-6 mm 7-9 mm
Moderate 7-10 mm 10-15 mm
Severe >10 mm > 15mm
Adapted with permission [1]

Figure 1: Algorithm for postnatal evaluation of antenatal hydronephrosis.
Algorithm for postnatal evaluation of antenatal hydronephrosis

The main aim of antenatal diagnosis of renal problems is to detect the type of anomaly as accurately as possible, exclude associated malformations and screen for parameters that will predict a poor renal outcome. In this way, perinatal diagnosis of kidney anomalies and urinary tract malformations allows for improved perinatal management to ensure improved prognosis.

Antenatal Diagnosis and Management of Renal Problems Antenatal Diagnosis and Management of Renal Problems 04/04/2016
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