Pediatric Polycystic Kidney Disease Workup

Previously, molecular genetic testing was by direct mutation and linkage analysis, but this has changed. Advances in genome sequencing (targeted next-generation sequencing) have resulted in less expensive and faster automated high-throughput tests to look for known mutations in PKHD1 (ARPKD) and PKD1 and PKD2 (ADPKD). 

Blood and urine studies are useful in evaluating patients with both types of polycystic kidney disease, although none is diagnostic. Based on the patient's clinical presentation, these studies are performed at diagnosis and are repeated as appropriate during the disease course.

The glomerular filtration rate (GFR) is measured with various tests. The most common is the serum creatinine level test. Creatinine is a product of creatine and phosphate metabolism in the muscle and is therefore produced in quantities directly proportional to muscle mass. Normal values of creatinine depend on the patient's muscle mass and, therefore, age and build of the children. Acute or gradual loss of renal function causes an increase in the serum creatinine concentration.

Blood urea nitrogen (BUN) levels in plasma are also increased in renal dysfunction. However, this is not as reliable a test as the serum creatinine level test, because BUN levels are also elevated in cases of intravascular depletion, increased protein intake, catabolism, and GI hemorrhage and may be reduced in chronic liver disease.

Liver function is usually normal. However, liver function test findings are often abnormal in the later stages of the disease, particularly in ARPKD.

Serum albumin levels may be low (< 3.5 g/dL) because of a number of factors, including the following:

• Urinary protein losses

• Malnutrition - Often due to poor appetite in patients with renal insufficiency

• Liver dysfunction - Can cause protein malabsorption

• Decreased hepatic synthesis in patients with advanced liver disease

Urine analysis findings can be normal. Microhematuria or macrohematuria may be present. Macrohematuria is more common in ADPKD. Gross hematuria often develops after minor trauma to the flank. Proteinuria, pyuria, and, sometimes, evidence of urinary concentrating defects, such as prerenal azotemia, may be present. Metabolic acidosis may be present.

Maternal alpha fetoprotein (AFP) is increased, and amniotic fluid trehalase activities are potential markers for ARPKD in utero. Liver hydroxyiminodiacetic acid (HIDA) imaging and transient liver elastography may aid in the diagnosis of ARPKD.

Brain imaging is used in the diagnosis of ADPKD. Left ventricular hypertrophy and early ramifications are revealed using echocardiography; diastolic dysfunction is present, even in normotensive patients. Renal biopsy in polycystic kidney disease is not usually indicated, particularly when the family history is positive.

Serum electrolyte levels may reveal further evidence of glomerular and tubular dysfunction in polycystic kidney disease. Reduced glomerular filtration results in intravascular fluid overload, which can cause hyponatremia. Hyponatremia related to fluid overload in patients with oliguria resolves with time. It can also be associated with hyperkalemia, hyperphosphatemia, and metabolic acidosis. Reduced renal function causes abnormalities in the conversion of vitamin D into its active form, leading to hypocalcemia. Alkaline phosphatase levels may be normal or can be elevated secondary to the hyperparathyroidism triggered by hypocalcemia. Tubular dysfunction can also cause electrolyte abnormalities.

Autosomal recessive polycystic kidney disease

Abdominal radiography may reveal enlarged neonatal kidneys, abdominal distension, and centrally deviated, gas-filled bowel loops. Chest radiography reveals pulmonary hypoplasia, which manifests as a small thorax. Pneumothorax can occur in infants after birth.

Autosomal dominant polycystic kidney disease

Radiographic findings in ADPKD include the following (see also the images below):

• Grossly enlarged kidneys with lobular appearance

• Distorted calyces secondary to nonopacified cysts with smooth or irregular indentations

• Numerous bilateral cysts of various sizes

• Intravenous pyelogram findings - May be normal or show abnormalities in one or both kidneys

  Frontal excretory urogram of autosomal dominant polycystic kidney disease (ADPKD) shows a spider-legs configuration of the collecting system secondary to compression due to cysts.

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  Lateral excretory urogram of autosomal dominant polycystic kidney disease (ADPKD) shows a spider-legs configuration of the collecting system secondary to compression due to cysts.

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Autosomal recessive polycystic kidney disease

Prenatal findings include the following:

• Bilaterally enlarged, echogenic kidneys

• Small or nonvisualized bladder with absence of urine

• Large renal masses

• Oligohydramnios - Usually not observed before 30 weeks' gestation

Neonatal findings include the following:

• Bilaterally smooth, enlarged kidneys, which are diffusely echogenic with poor corticomedullary differentiation

• Microcysts that are difficult to visualize and account for the diffuse echogenicity

• Hypoechoic macrocysts, which may be visualized in worsening disease

• Hepatic parenchymal echogenicity - May be diffusely increased with fibrous tissue that causes poor depiction of peripheral portal veins

Patients are most commonly diagnosed based on prenatal ultrasonographic findings. In older children who present late, renal ultrasonographic findings may be less reliable. Hepatic features are often the prominent presenting feature.

Enlarged kidneys in older children with ARPKD differ from enlarged kidneys in younger children with the disease in that the hyperechogenicity is mainly in the medulla because of focal tubular cysts.

Renal macrocysts are more common in older children. Also in this age group, the liver is often enlarged, with heterogeneously or homogenously increased echogenicity, macrocysts in the liver and pancreas are often visualized, and splenomegaly is observed. Macroscopic liver cysts are uncommon in older children, although choledochal cysts have been reported. When present, biliary duct dilatation is indistinguishable from Caroli disease.

The reversal of hepatic venous blood flow in older children, revealed by Doppler ultrasonography, suggests portal hypertension.

Adult ultrasonographic findings include the following:

• Multiple small cysts, typically in normal-sized kidney

• Increased cortical echogenicity

• Loss of corticomedullary differentiation

Autosomal dominant polycystic kidney disease

Ultrasonography should be the first line of imaging in patients who are at risk for ADPKD. It is limited in the differentiation of hemorrhage of the cyst and infection, as both the conditions show internal echoes, fluid debris levels, and thickened walls. (See the images below.)

Sonogram shows cysts with bilaterally enlarged kidneys. These findings are compatible with a diagnosis of autosomal dominant polycystic kidney disease (ADPKD).

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Sonogram shows cysts with bilaterally enlarged kidneys. These findings are compatible with a diagnosis of autosomal dominant polycystic kidney disease (ADPKD).

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Sonogram shows cysts with bilaterally enlarged kidneys. These findings are compatible with a diagnosis of autosomal dominant polycystic kidney disease (ADPKD).

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Occasionally, prenatal ultrasonography reveals renal cysts. Multiple bilateral macrocysts smaller than 2 cm may be present. Renal cysts combined with a positive family history suggest ADPKD. In families with known ADPKD, routine screening ultrasonography often reveals cysts in asymptomatic children.

Kidneys are usually normal in size, with normal echogenicity. Infants may have large, hyperechoic kidneys, with or without macrocysts, with varying degrees of renal insufficiency. In patients with renal insufficiency, nephromegaly and loss of corticomedullary differentiation has been observed.

Less commonly, prenatal ultrasonographic findings and ultrasonographic findings in infants may be indistinguishable from findings in patients with ARPKD.

Routine ultrasonographic screening that demonstrates even one cyst is highly predictive of the development of symptomatic ADPKD later in life in a child with a family history of the disease.

Ovarian cysts may be present in patients with autosomal dominant polycystic kidney disease. Pancreatic cysts are found exclusively in patients with PKD1 and are usually asymptomatic.

Multicystic kidney disease differs from polycystic kidney disease in that it is unilateral, with multiple noncommunicating macrocysts of varying size.

CT scanning

Computed tomography (CT) can be helpful for distinguishing between cystic wall calcifications and calculi.

With combined enhanced and unenhanced CT scanning, cystic walls can be evaluated for signs of infection, bleeding, or malignancy. CT scanning also helps in the evaluation of perinephric extension of a bleeding or infected cyst..

In ARPKD, noncontrast CT scanning reveals smooth, enlarged kidneys.

With intravenous contrast, kidneys have a striated appearance due to the accumulation of contrast in dilated tubules. Depending on the degree of renal insufficiency, a proportionate delay in the arrival of contrast to the kidneys is observed. Macrocysts may appear as well-circumscribed, lucent defects. The bladder may be opacified. See the image below.

CT shows bilaterally smooth enlarged kidneys. These findings are compatible with a diagnosis of autosomal recessive polycystic kidney disease (ARPKD).

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In autosomal dominant polycystic kidney disease, well-delineated cysts that do not enhance following intravenous contrast administration may be present in both kidneys. Over time, kidneys and cysts often grow and this can be measured by CT scanning.

If a cyst hemorrhage is present, it can be observed as a high-density cyst on nonenhanced images, with sharp contours and interface and no contrast enhancement.

If it is an infected cyst, the density is close to water or has mildly increased attenuation, presenting ticked walls and enhancement.

CT scanning also allows detection of complications such as emphysematous pyelonephritis, which is highly sensitive by the presence of intracystic air. See the image below.

CT shows bilateral renal and liver cysts with enlarged kidneys and remaining renal cortex enhancement compatible with a diagnosis of autosomal dominant polycystic kidney disease (ADPKD).

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MRI

MRI is the best imaging tool in polycystic kidney disease to determine renal/cyst size and volume and to help in the evaluation of cystic bleeding and infection. Even though the association with renal cell carcinomas is controversial, its incidence is higher in these patients, in whom MRI can play a role showing restricted diffusion and morphological changes.

MRI findings in ARPKD include the following (see image below):

• Enlarged kidneys with T2-weighted imaging that show increased signal intensity

• A characteristic hyperintense, linear, radial pattern in the cortex and medulla

  T2-weighted MRI shows bilateral smooth enlarged kidneys with a hyperintense, linear, radial pattern in the cortex and medulla, compatible with autosomal recessive kidney disease.

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Findings in autosomal dominant polycystic kidney disease include the following:

• The presence of a single cyst in childhood can lead to the diagnosis, as simple cysts are extremely rare in this age group

• Enlarged kidneys with low T1-weighted and high T2-weighted signal cysts

• Morphological changes and restricted diffusion in high cellularity areas help in the diagnosis of associated renal cell carcinomas and sarcomas, which are not associated but occur more frequently in these patients

• Signal changes on hemorrhagic cysts usually present hyperintense on T1-weighted images, with varied signals in all sequences, depending on the age of the hemorrhage, and they often show fluid hematic or iron levels

• Infected cysts commonly present hypointense on T1-weighted images and hyperintense on T2-weighted images, with marked mural thickening

Note the images below.

T1- and T2-weighted MRIs demonstrating a superior left kidney cyst with high T1 and intermediary T2 signal compatible with a bleeding cyst in autosomal dominant polycystic kidney disease (ADPKD).

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T1- and T2-weighted MRIs demonstrating bilateral renal and liver cysts compatible with autosomal dominant polycystic kidney disease (ADPKD).

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The definitive method for the diagnosis of ARPKD is molecular genetic testing. Targeted next-generation sequencing is the most cost-effective approach to detect the underlying genetic variants.

The large size and complexity of PKD1 and marked allelic heterogeneity are obstacles to molecular testing by direct DNA analysis.

Mutation scanning by methods such as denaturing high-performance liquid chromatography (DHPLC) in research settings has yielded mutation detection rates of around 65-70% for PKD1 and PKD2. Higher rates of around 85% are possible by direct sequencing. However, because most mutations are unique and as many as one third of PKD1 changes are missense, the pathogenicity of some changes is difficult to prove.

Prenatal diagnosis in ADPKD represents an ethical dilemma, because symptoms may not present until well into adulthood. Making such an early diagnosis is a potential cause of "vulnerable child" syndrome. The parents view the child as prematurely sick, and this thought process is transferred to the child, leading to behavioral and psychological changes. Until effective treatments become available, the adverse effects from presymptomatic diagnosis in children (removal of the choice to know or not know; psychological, educational, and career implications; insurability issues) outweigh the benefits.