Congenital Anomalies of the Kidney and Urologic System

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66 Congenital Anomalies of the Kidney and Urologic System

This chapter reviews several common congenital and inherited anomalies of the kidney and urologic system. Congenital abnormalities are a frequent cause of renal failure in children, accounting for more than 30% of end-stage renal disease (ESRD). Congenital anomalies can be subdivided into three categories based on the stage of the primary abnormality in renal embryologic development (Figure 66-1). The first category refers to a failure to form a functional nephron, leading to renal parenchyma malformations, such as renal agenesis or cystic dysplasia. The second group of defects relates to a failure of the developing kidney to migrate to its appropriate destination. This may lead to renal ectopy (pelvic or thoracic kidneys) or fusion abnormalities, such as a horseshoe kidney. The third category describes defects of the urinary collecting system, such as double ureters or posterior urethral valves (PUVs). Here, changes of the renal parenchyma (hydronephrosis, dysplasia) are often secondary to obstructive uropathy or urinary reflux disease. Inherited conditions such as the polycystic kidney diseases (PKD) are the result of specific genetic mutations that may present with detectable renal abnormalities at birth or may not develop until later in life. The following sections detail common and exemplary conditions representative of these subcategories.

Figure 66-1 Congenital anomalies categories.

Polycystic Kidney Disease

PKDs are a group of genetically inherited conditions in which cyst formation and renal parenchymal replacement can occur at anytime from fetal life to adulthood. There are two major forms, autosomal dominant PKD (ADPKD) and autosomal recessive PKD (ARPKD) (Table 66-1). In addition, a number of rare pleiotropic disorders exist, which are loosely associated because of similar clinical and pathophysiologic features, including renal cystic and hepatobiliary disease (Table 66-2). All of these disorders share ciliary dysfunction as a common principle in their pathogenesis. PKD proteins have been localized to the cilia or basal body, and loss or abnormalities of cilia in the kidney are associated with cyst development (Figure 66-2).

Table 66-1 Autosomal Recessive Polycystic Kidney Disease versus Autosomal Dominant Polycystic Kidney Disease

	Autosomal Recessive Polycystic Kidney Disease	Autosomal Dominant Polycystic Kidney Disease
Gene	Chromosome 6p21.2-p12	Chromosome 16p13.3, chromosome 4q13-q23
Protein	Fibrocystin	Polycystin 1, polycystin 2
Age of presentation	Commonly prenatally, childhood, adolescence	Highly variable
Renal cysts	Radial pattern	Anywhere in kidney, varying size
Extrarenal manifestations	Biliary obstruction, hepatic fibrosis with portal hypertension, liver failure	Liver cysts, pancreas cysts, vascular cysts (“Berry aneurysms”)
Things in common	Renal cysts do not communicate. Disease may present at any age, including prenatally. Gene defect leads to malfunction of the ciliary body. The kidneys are usually enlarged. Usually bilateral disease (exception: early diagnosis ADPKD in childhood with positive family history)

Table 66-2 Overview of the Ciliopathies*

Figure 66-2 Renal cystic diseases.

Autosomal Recessive Polycystic Kidney Disease

ARPKD typically presents early in life and is commonly detected in utero by routine prenatal ultrasound. Severe cases may be associated with the Potter sequence (i.e., oligohydramnios with subsequent lung hypoplasia and characteristic limb and facial abnormalities resulting from decreased intraamniotic space). ARPKD is reported to have an incidence of one in 20,000. The phenotype can be quite variable. One-third of identified patients do not survive beyond the neonatal period mainly because of respiratory insufficiency. Of those who survive infancy, approximately one-third will need chronic renal replacement therapy. In addition to the renal manifestations, cystic biliary dysgenesis is another hallmark of ARPKD. It can result in congenital hepatic fibrosis and may present later in childhood or adolescence, even in adults. Characteristically, patients presenting later in life have less severe renal disease and more prominent hepatic fibrosis. Hepatic fibrosis may lead to portal hypertension, gastrointestinal bleedings from esophageal varices, cholangitis, and hepatic failure. The gene identified with ARPKD is on the short arm of chromosome 6 and encodes fibrocystin (polyductin). Fibrocystin is expressed on the cilia of renal and bile duct epithelial cells and is thought to be critical in the maintenance of normal tubular architecture in the renal and biliary systems.

The diagnosis is established based on classical radiographic features. The classic sonographic appearances in newborns are large kidneys, increased echogenicity of the parenchyma, and loss of corticomedullary differentiation. There may be macrocysts that are less than 2 cm in diameter. The cysts are subcapsular extensions of radially oriented ectatic spaces. In addition to the sonographic findings, the diagnosis of ARPKD requires one or more of the following: (1) absence of renal cysts in both parents, (2) a previously affected sibling, (3) consanguinity, or (4) hepatic fibrosis.

Treatment is largely supportive. The primary prognostic determinant in the newborn period is the degree of lung hypoplasia. Renal failure and portal hypertension are treated with medications, dialysis, or transplant depending on an individual patient’s symptoms. In childhood, the most common features are renal failure, electrolyte abnormalities, and hypertension. The hypertension is usually responsive to angiotensin-converting enzyme inhibitors. Hepatic fibrosis may cause portal hypertension with resulting esophageal varices, gastrointestinal bleedings, and hypersplenism with thrombocytopenia. Liver failure may in some cases require liver transplant. Cholelithiasis is common. Ascending cholangitis is a potentially life-threatening concern.

Autosomal Dominant Polycystic Kidney Disease

In contrast to ARPKD, ADPKD is usually diagnosed in adulthood, although it may be detected at any age, including prenatally. With an estimated incidence between one in 400 and one in 1000, it is one of the more common genetic disorders. There is a high degree of phenotypic variation, ranging from infants presenting in renal failure to asymptomatic elderly patients with adequate renal function. The disease may commonly lead to ESRD. In the United States, 4.4% of adult patients requiring renal replacement therapy have ADPKD. Morphologically, both kidneys show progressive bilateral development and enlargement of focal cysts. ADPKD is a systemic disease, with cysts occurring in the liver, pancreas, and vasculature. In contrast to ARPKD, the liver disease is predominantly cystic, and hepatic failure is rare. Extrarenal manifestations of ADPKD are uncommon in children; however, intracranial aneurysms (intracranial saccular aneurysms, or “Berry aneurysms”) and male fertility problems can occur in adulthood.

Two genes have been identified with ADPKD. The PKD1 gene on chromosome 16p13.3 encodes polycystin 1 and accounts for 85% of all ADPKD cases. PKD2 on chromosome 4q13-q23 encodes for polycystin 2. Both affected proteins are involved with the ciliary apparatus. A small number of cases could not be linked to either gene, suggesting the involvement of other genes.

Children with ADPKD may present with flank pain, hematuria, renal colic, urinary tract infections (UTIs), or hypertension, or they may be asymptomatic. ADPKD can be diagnosed by renal ultrasound, computed tomography, or magnetic resonance imaging. Multiple renal parenchymal cysts are generally visible and usually increase in size and number with age. The finding of a single cyst in a child may merit further observation. In general, the combination of a parent with ADPKD and more than one cyst in a child is considered diagnostic for ADPKD. Rarely, ADPKD may arise sporadically. Diagnosing ADPKD in a presymptomatic, otherwise healthy child may not always be in the patient’s best interest given the financial and psychosocial implications. Because of the complexities of these issues, pediatric practitioners should refer asymptomatic children to a pediatric nephrologist before undertaking any diagnostic investigations.

Analogous to ARPDK, the treatment of ADPKD is largely symptomatic. Notably, UTIs are relatively common in patients with ADPKD. A UTI in ADPKD may be difficult to diagnose because the infection may be contained within a cyst and may not provide diagnostic pyuria or bacteriuria. Conversely, a ruptured cyst may show hematuria and pyuria in the absence of a UTI. Furthermore, traditional first-line antibiotic agents for UTIs such as a cephalosporin or an aminoglycoside may be ineffective because of poor cyst penetration. A sulfonamide or quinolone is usually preferred. Screening for extrarenal manifestations, such as intracranial aneurysms, is not routinely recommended in children, and magnetic resonance angiography is usually reserved for symptomatic patients and those with a strong family history of cerebrovascular disease.

Horseshoe Kidney

Horseshoe kidney is the most prevalent fusion abnormality of the developing kidney. The fusion occurs commonly at the lower poles, and two separate excretory urinary systems are maintained (Figure 66-3) The incidence is reported between one in 400 and one in 1600. The isthmus may be located at or lateral to the midline (symmetric vs. asymmetric horseshoe kidney). It may contain actual parenchyma or a fibrous band. The kidneys arrest during their embryologic ascension toward the dorsolumbar position, usually between the fourth to ninth weeks of gestation. This is caused by the inferior mesenteric artery holding the isthmus and preventing further rostral migration. As a consequence, blood supply of the fused kidney is variable and may come from the iliac arteries or aorta or at times, the hypogastric and middle sacral arteries. Horseshoe kidneys may occur in isolation or as part of a syndrome, such as Turner syndrome, trisomy 18, or less commonly trisomy 13 and 21. It is occasionally associated with other genitourinary findings, such as bicornuate or septate uterus in girls and hypospadias and undescended testis in boys. Most patients with horseshoe kidneys are asymptomatic and are diagnosed incidentally by ultrasonography. However, some patients may present with pain, hematuria, obstruction, or UTIs. Hydronephrosis may be seen in up to 80% of children with horseshoe kidneys. The etiologies include vesicoureteral reflux (VUR), obstruction of the collecting system by external ureteric compression (from blood vessels, renal calculi), or ureteropelvic junction (UPJ) obstruction caused by a relatively high insertion of ureters. Twenty percent of patients have urolithiasis.

Figure 66-3 Horseshoe kidney.

Patients with an isolated horseshoe kidney have a slightly increased risk of developing a Wilms tumor. The overall incidence of Wilms’ tumor is 7.6 cases per million in children younger than 15 years and 14.9 per million (1.96 times higher) in children with horseshoe kidney. Because the risk still remains well less than 0.002%, screening for Wilms’ tumor in patients with horseshoe kidney is not routinely done. The diagnostic evaluation of a horseshoe kidney is aimed at identifying VUR. These initial investigations include renal ultrasound and voiding cystourethrography (VCUG). The ultrasound may demonstrate the presence or absence of hydronephrosis. A voiding cystourethrogram should be done to exclude the possibility of reflux. A technetium 99m-labeled diethylenetriaminepentaacetic acid (DTPA) scan should be done if there is evidence of an obstruction on ultrasonography.

In most patients with a horseshoe kidney, no specific treatment is necessary. If VUR or obstructive uropathy has been identified, these patients should be referred to a pediatric urologist. Antibiotic prophylaxis and corrective surgery may be necessary.

Urologic Malformations

Double Ureter

Double ureters are part of a duplicated collecting system complex, defined as two pyelocaliceal systems within one renal unit. Both ureters may either drain separately or jointly over a single orifice into the bladder. Double ureters can be unilateral or bilateral and can be associated with a variety of congenital genitourinary tract abnormalities. Most patients are asymptomatic, with double ureters being detected incidentally on imaging studies. Double ureters occur when two ureteral buds arise from the Wolffian duct. In cases of complete duplication, the lower renal unit typically drains into the normal ureteric insertion and the ureter of the upper renal unit drains ectopically in the bladder, urethra, or elsewhere. The ectopic ureter usually enters the bladder inferiorly and medially to the normal ureter. In girls, if the ectopic ureter inserts into the vagina, urethra, or uterus, urinary dribbling or incontinence may be the presenting sign. Most patients are asymptomatic. Symptoms usually occur in ureteric duplication if there is reflux into the ureter of the lower renal unit or if the ectopic upper renal unit ureter becomes obstructed (Figure 66-4). The typical complications observed with complete double ureter systems are summarized in Table 66-3. Recurrent UTIs can occur in obstructed or refluxing ureters. It is noteworthy that up to 80% of ureteroceles are associated with double ureters. In duplex kidneys, ureteroceles are usually an outgrowth of the ectopic ureter. Double ureters are common and noted to occur in 0.2% of live births. There is a 12% chance of a double ureter occurring in first-degree relatives of persons with this condition. Bilateral duplication is noted in 15% to 40% of individuals with complete duplication. The diagnostic evaluation includes renal ultrasound and VCUG. The goal of imaging is to identify VUR, ureteroceles, and obstructive uropathy. If these are found, surgical correction may be indicated.

Figure 66-4 Ureterocele.

Table 66-3 Double Ureter: Associated Pathology

Renal upper pole	Urinary obstruction from ectopic insertion of the ureter leading to upper pole hydronephrosis Ureterocele
Renal lower pole	Urinary reflux from maldevelopment of the ureter’s valve mechanism

Ureteropelvic Junction Obstruction

UPJ obstruction is the most common cause of antenatally detected hydronephrosis. It is found in one of 500 live births on routine fetal ultrasound. UPJ obstruction is more commonly found in boys and more commonly on the left than on the right side. The UPJ diameter enlarges as a result of a partial restriction of urinary flow, resulting in hydronephrosis. The hydronephrosis may be progressive, arrest, or improve spontaneously, depending on both the reason for UPJ obstruction and the ability of the renal pelvis to expand and compensate for increased urinary pressure. Most patients are asymptomatic and found to have antenatal hydronephrosis on routine prenatal ultrasonography. Occasionally, newborns may present with abdominal masses or renal insufficiency if the obstruction is bilateral. The standard evaluation of a newborn with prenatal ultrasound findings suggestive of UPJ obstruction includes a confirmatory postnatal renal ultrasound. If the UPJ is persistent a VCUG to assess for urinary reflux disease should be considered. Urolithiasis and UTIs are possible complications of a UPJ obstruction. If patients are symptomatic, surgical intervention is frequently indicated. The surgical options include a reconstructive pyeloplasty or temporary nephrostomy tubes to alleviate pressure more acutely. If patients are managed by observation alone, antibiotic prophylaxis is usually not needed unless there is evidence of vesicoureteral reflux.

Posterior Urethral Valves

PUVs are the most common cause of lower urinary tract obstruction in male neonates (Figure 66-5). The reported incidence ranges from one in 8000 to one in 25,000 live births. The etiology of PUV is still disputed. Autopsy studies on stillborn fetuses with PUVs have found a congenital obstructing posterior urethral membrane (COPUM). It is possible that the valves classically seen on ultrasound and VCUG occur as a result of the perforation of the COPUM by an advancing Foley catheter.