Pediatric Polycystic Kidney Disease 

Updated: Apr 26, 2018
Author: Priya Verghese, MD, MPH; Chief Editor: Craig B Langman, MD 

Overview

Practice Essentials

Polycystic kidney disease, a disorder that can be diagnosed in adult and pediatric patients, is an inherited disease that involves bilateral renal cysts without dysplasia. The condition is broadly divided into 2 forms: autosomal recessive polycystic kidney disease, previously known as infantile polycystic kidney disease, and autosomal dominant polycystic kidney disease, previously known as adult polycystic kidney disease. The nomenclature of infantile versus adult is no longer used because it is not an accurate description. (See the image below.)

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

Autosomal recessive polycystic kidney disease and autosomal dominant polycystic kidney disease can involve the presence of renal cysts at any time during an affected person's life, from the prenatal period to adolescence or older. The clinical and radiologic manifestations of both types of polycystic kidney disease have considerable overlap. (See Clinical and Workup.)

Autosomal recessive polycystic kidney disease

Autosomal recessive polycystic kidney disease is characterized by cystic dilatation of renal collecting ducts associated with hepatic abnormalities of varying degrees, including biliary dysgenesis and periportal fibrosis. Autosomal recessive polycystic kidney disease was first recognized in 1902; however, the histology was not reported until 1947. In 1964, Osathanondh and Potter classified autosomal recessive polycystic kidney disease as type 1 cystic kidney disease.[1, 2] Eventually, because neither parent had the disease and no sex predilection was observed, this disease was concluded to have an autosomal recessive mode of inheritance. (See the image below.) (See Etiology.)

Sonogram shows enlargement of both kidneys, diffus Sonogram shows enlargement of both kidneys, diffuse increased echogenicity, and loss of corticomedullary differentiation. These findings are compatible with a diagnosis of autosomal recessive polycystic kidney disease (ARPKD).

Autosomal recessive polycystic kidney disease was originally described as 4 separate clinical entities based on age of presentation. This classification is no longer considered valid because of the large degree of overlap among the different groups and the wide range of possible presentations, regardless of age.

Autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease is the most common inherited kidney disease in humans. It is a multisystem disorder characterized by progressive cystic dilatation of both kidneys (see the image below), with variable extrarenal manifestations in the gastrointestinal (GI) tract, cardiovascular system, reproductive organs, and brain.[3] (See Etiology.)

Pathologic specimen of end-stage autosomal dominan Pathologic specimen of end-stage autosomal dominant polycystic kidney disease (ADPKD) with deformed lobulated kidneys.

Hepatic cysts are possible in autosomal dominant polycystic kidney disease, although they are less common than in autosomal recessive polycystic kidney disease. Autosomal dominant polycystic kidney disease has a wide clinical spectrum. It may present asymptomatically as an incidental finding or, similar to autosomal recessive polycystic kidney disease, it may present with severe neonatal manifestations. (See Clinical and Workup.)

Etiology

The 3 basic processes involved in renal cyst formation and progressive enlargement are as follows[4, 5] :

  • Tubular cell hyperplasia

  • Tubular fluid secretion

  • Abnormalities in tubular extracellular matrix and/or function

Tubular cell hyperplasia

This may be mediated by factors that control cell proliferation (eg, epidermal growth factor, transforming growth factor-α), dysregulation of apoptosis, or the balance between the 2.

Tubular fluid secretion

The solid tumor cell nests produced by the cell hyperplasia described above are transformed into fluid-filled cysts by the secretion of fluid by the tubular cells associated with efferent tubular obstruction or slow or absent afferent flow. This accounts for the fluid within the cysts of kidneys in patients with autosomal dominant polycystic kidney disease, 70% of which have no afferent or efferent tubular connections.

Abnormalities in tubular extracellular matrix and/or function

These are thought to be responsible for amplifying tubular cell hyperplasia and tubular fluid secretion. Interstitial inflammation and fibrosis are responsible for progression in all forms of polycystic kidney disease.

Autosomal recessive polycystic kidney disease

In 1994, the autosomal recessive polycystic kidney disease gene (PKDHD1) was localized to the short arm of chromosome 6.[6] Fibrocystin/polyductin, a protein encoded by PKDHD1, is expressed on the cilia of renal and bile duct epithelial cells and is thought to be crucial in maintaining the normal tubular architecture of renal tubules and bile ducts. However, the precise function of this protein has yet to be completely studied or understood. The protein strengthens the theory that the primary defect in autosomal recessive polycystic kidney disease is linked to ciliary dysfunction.[7]

Autosomal recessive polycystic kidney disease is characterized by nonobstructive, bilateral, symmetrical dilatation and elongation of 10-90% of the renal collecting ducts, focally accounting for a wide variability of renal dysfunction. As the number of ducts involved increases, the kidneys enlarge. However, at autopsy, the reniform shape is maintained, because the abnormality is in the collecting ducts and the cysts are usually minute (< 3 mm). In older patients, cysts as large as 1 cm may be seen. (See the images below.)

Excretory urogram shows minimal bilateral tubular Excretory urogram shows minimal bilateral tubular changes caused by a mild form of autosomal recessive polycystic kidney disease (ARPKD).
Excretory urogram shows enlarged kidneys with bila Excretory urogram shows enlarged kidneys with bilateral distortion of the collecting system (spider-legs configuration). These findings are compatible with a diagnosis of autosomal recessive polycystic kidney disease (ARPKD).
Excretory urogram shows the typical mottled (spong Excretory urogram shows the typical mottled (spongelike) contrast pattern in autosomal recessive polycystic kidney disease (ARPKD).
Excretory urogram shows the typical mottled (spong Excretory urogram shows the typical mottled (spongelike) contrast pattern in autosomal recessive polycystic kidney disease (ARPKD).
Excretory urogram shows the typical mottled (spong Excretory urogram shows the typical mottled (spongelike) contrast enhancement pattern in autosomal recessive polycystic kidney disease (ARPKD).

At autopsy, gross examination of a kidney in patients with autosomal recessive polycystic kidney disease reveals multiple minute cystic spaces throughout the capsular surfaces. Cut sections of the kidney show that these cystic structures are subcapsular extensions of radially oriented cylindrical or fusiform ectatic spaces, with poor corticomedullary differentiation due to the extension of the elongated and dilated collecting ducts from the medulla to the cortex.

All patients with autosomal recessive polycystic kidney disease have congenital hepatic fibrosis (CHF), which may have a more severe clinical manifestation than the renal disease. The CHF results from malformation of the developing ductal plate. The liver biopsy findings reveal enlarged, fibrotic portal tracts and hyperplastic, dilated, and dysgenetic biliary ducts with normal hepatocytes. The ductules can show true cystic changes, and, when the changes are macroscopic, autosomal recessive polycystic kidney disease can be indistinguishable from Caroli disease. The portal hypertension secondary to the CHF can be clinically debilitating, with splenomegaly, varices, and GI hemorrhage.[8]

The results from one study noted that characteristics of CHF are similar in both autosomal dominant and autosomal recessive polycystic kidney diseases.[9]

In a study designed to better understand the complications of autosomal recessive polycystic kidney disease, researchers at the NIH analyzed clinical, molecular and imaging data from 73 patients (ages 1-56 years old, average 12.7) with mutations in PKHD1 and kidney and liver involvement. The findings identified platelet count as the best predictor of the severity of portal hypertension, which has early onset but is underdiagnosed in patients with autosomal recessive polycystic kidney disease.[10]

Autosomal dominant polycystic kidney disease

The genes responsible for autosomal dominant polycystic kidney disease were localized to the short arm of chromosome 16 (PKD1) in 85% of cases and the long arm of chromosome 4 (PKD2) in most of the remaining cases. The proteins encoded by PKD1 and PKD2 are polycystin 1 and polycystin 2, respectively. These proteins are expressed in the developing kidney, and their functions overlap considerably.

The dysfunction of these proteins is thought to be pathogenetically responsible for the manifestations of autosomal dominant polycystic kidney disease, primarily by renal ciliary dysfunction. Whether a third gene accounts for a small number of unlinked families is uncertain. Homozygous or compound heterozygous genotypes have been thought to be lethal in utero. Individuals heterozygous for PKD1 and PKD2 mutations usually survive to adulthood but have more severe renal disease.

Autosomal dominant polycystic kidney disease differs from autosomal recessive polycystic kidney disease in that cysts associated with autosomal dominant polycystic kidney disease develop anywhere along the nephron. Upon clinical presentation, kidneys are usually enlarged, with numerous large, round nodules on the external surface of the kidney, causing the loss of its original reniform shape, which is different from kidneys in patients with autosomal recessive polycystic kidney disease.

Cysts of varying sizes containing pale fluid or blood are randomly distributed throughout the parenchyma and involve any segment along the nephron. The cysts have thickened basement membranes with pericystic interstitial fibrosis, and their epithelium maintains active secretion and reabsorption. It has been hypothesized that patients with an associated marked epithelial hyperplasia may have a higher rate of malignant transformation than does the general population.

Epidemiology

Occurrence in the United States

The exact incidence of autosomal recessive polycystic kidney disease is unknown because of varying reports in patient autopsies versus survivors, as well as the possibility of affected children who die perinatally without a definitive diagnosis. The frequency of autosomal recessive polycystic kidney disease has been reported as one case per 10,000-40,000 births, although the frequency of the gene in the general population is estimated to be 1 case per 70 population.

Because of the recessive inheritance of autosomal recessive polycystic kidney disease, both parents are unaffected. The recurrence risk in subsequent pregnancies is 25%. Unaffected siblings have a 66% chance of being carriers. Carriers or heterozygotes are asymptomatic.

The estimated prevalence of autosomal dominant polycystic kidney disease is 1 case per 200-1000 population. Autosomal dominant polycystic kidney disease is responsible for 6-10% of cases of end-stage renal disease in North America. Because of the autosomal dominant inheritance, one parent is usually affected, and each offspring has a 50% chance of inheriting the gene, with a penetrance of almost 100%.

With education, better quality of prenatal ultrasonography, awareness, and gene testing, more accurate reports regarding the incidence and prevalence of autosomal recessive polycystic kidney disease and autosomal dominant polycystic kidney disease will hopefully be available soon.

International occurrence

Autosomal dominant polycystic kidney disease is responsible for 6-10% of cases of end-stage renal disease in Europe.

Race- and sex -related demographics

Both forms of polycystic kidney disease affect all racial and ethnic groups and both equally affect males and females.

Prognosis

Determining the prognosis of polycystic kidney disease is difficult; however, with advances in medical management and continued progress in end-stage renal disease therapy in young infants, further improvements in survival and rehabilitation can be expected.

Autosomal recessive polycystic kidney disease

The clinical manifestations of autosomal recessive polycystic kidney disease vary depending on the number of collecting ducts involved, as well as the degree of interstitial fibrosis. Fetuses with severe impairment of renal function and reduced fetal urinary output present with oligohydramnios, which may result in pulmonary hypoplasia. Most of these infants die from pulmonary complications after birth.

Babies with less severe renal manifestations who survive the neonatal period may still develop chronic kidney disease, which occurs at varying ages depending on the degree of renal involvement. Pulmonary insufficiency with respiratory distress due to oligohydramnios that is worsened by large renal masses is a major cause of morbidity and mortality in neonates.

In patients who survive the neonatal period, renal prognosis has improved over time because of renal transplantation. CHF still causes considerable morbidity, even in patients who have received transplants; some die from GI hemorrhage secondary to portal hypertension. Oliguric acute renal failure (ARF) often improves as the pulmonary function improves.

Autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease can also present prenatally but usually does not involve the severe renal impairment seen in autosomal recessive polycystic kidney disease. In adults, it more commonly causes chronic kidney disease that progresses to further cystic development of the renal cortex, often with transition into end-stage renal disease. Thus, the chance of end-stage renal disease is 2% in patients younger than age 40 years and increases to 50% by the seventh decade of life.

Autosomal dominant polycystic kidney disease is a multisystem disorder, and some patients develop associated intracranial aneurysms, which can cause stroke and intracranial hemorrhage. Much of the morbidity of autosomal dominant polycystic kidney disease is due to chronic hypertension. Autosomal dominant polycystic kidney disease can manifest in utero with the Potter phenotype, with death from pulmonary hypoplasia.[11]

Patient Education

The Polycystic Kidney Disease (PKD) Foundation is devoted to determining the cause of polycystic kidney disease, improving its clinical treatment, and discovering a cure. To become members, patients, family members, friends, physicians, and allied health professionals can contact the foundation at the following:

1001 E. 101st Terrace, Suite 220

Kansas City, MO, 64131 

Toll-free phone: 1.800.PKD.CURE (753.2873)

Local phone: 816.931.2600

Email: pkdcure@pkdcure.org

 

Additional information can be obtained by contacting the National Kidney Foundation at the following:

National Kidney Foundation

30 East 33rd Street

New York, NY 10016

 

Presentation

History

Autosomal recessive polycystic kidney disease

At birth, babies may present with large palpable flank masses that may cause difficulty in delivery. These babies may have classic Potter facies and abnormal extremities.

Parents or pediatricians may discover abdominal masses in older infants. Older infants may have abdominal distension secondary to renal masses or hepatosplenomegaly.

All patients with autosomal recessive polycystic kidney disease can present with urinary concentrating defects that can cause polyuria and polydipsia.

Autosomal dominant polycystic kidney disease (ADPKD)

The initial presentation in older children includes the following:

  • Abdominal pain

  • Urinary tract infections - These may manifest as pain, perinephric abscess, hemorrhage, chronic pyelonephritis, sepsis, and death

  • Abdominal or inguinal hernias

  • Renal insufficiency (rarely occurs in childhood)

  • Concentrating defects that cause polydipsia and polyuria (more common in autosomal recessive polycystic kidney disease)

  • Extrarenal manifestations of autosomal dominant polycystic kidney disease (more common in adults but can occur in children as young as age 1 y)

Physical Examination

Autosomal recessive polycystic kidney disease

Patients present prenatally with massively enlarged kidneys and oligohydramnios. In infants, Potter facies with low-set, flattened ears; short, snubbed nose; deep eye creases; and micrognathia, all secondary to oligohydramnios, can be found. Clubfoot commonly occurs secondary to oligohydramnios because of pressure effect in utero.

An abdominal mass may manifest after the newborn period because of renal masses or hepatosplenomegaly. Impaired renal function is present in 70-80% of infants. Renal cysts in children may be an incidental finding.

Hepatic involvement is present in all children with autosomal recessive polycystic kidney disease but may not manifest in neonates (50-60%).

Hypertension may be severe and may be a presenting feature, even in patients with normal renal function. The pathophysiology is unknown, because renin levels are within the reference range. Cardiac hypertrophy and congestive heart failure (which may develop in patients with poorly managed hypertension) can also occur, and there can be evidence of portal hypertension.

Autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease commonly presents as low back pain with or without abdominal pain.[12] Hypertension can present in patients of all age groups (even in patients with normal renal function), as a result of increased activation of the renin-angiotensin system, reduced renal blood flow, and sodium retention. In addition, patients may have signs of portal hypertension and CHF (although this is rare compared with autosomal recessive polycystic kidney disease).

Other presentations include the following:

  • Manifestations of stroke secondary to cerebral hemorrhage of ruptured aneurysms

  • Renal involvement - Often asymmetrical but usually bilateral

  • Renal masses

  • Hepatic cysts - These are usually asymptomatic in children, unlike in adults, in whom pain, infection, and hepatomegaly are present

  • Cerebral vessel aneurysms

  • Cardiovascular system manifestations - Mitral valve prolapse and, in children as well as adults, endocardial fibroelastosis

  • Increased left ventricular mass with diastolic dysfunction , even in normotensive children

  • Coronary aneurysms - Exclusively in adults

 

DDx

 

Workup

Approach Considerations

Previously molecular genetic testing was by direct mutation and linkage analysis but this has now changed. There have been advances in the field of genome sequencing (targeted next-generation sequencing) which have resulted in cheaper 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 are 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 autosomal recessive polycystic kidney disease.

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 autosomal dominant polycystic kidney disease. 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 autosomal recessive polycystic kidney disease in utero. Liver hydroxyiminodiacetic acid (HIDA) imaging and transient liver elastography may aid in the diagnosis of autosomal recessive polycystic kidney disease.

Brain imaging is used in the diagnosis of autosomal dominant polycystic kidney disease. 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.

Electrolytes

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.

Radiography

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 autosomal dominant polycystic kidney disease 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 1 or both kidneys

    Frontal excretory urogram of autosomal dominant po 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.
    Lateral excretory urogram of autosomal dominant po 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.

Ultrasonography

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 ultrasonography findings may be less reliable. Hepatic features are often the prominent presenting feature.

Enlarged kidneys in older children with autosomal recessive polycystic kidney disease 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 autosomal dominant polycystic kidney disease, especially in patients older than 30 years. In patients younger than 30 years, ultrasonography may not reveal manifestations, and linkage analysis may be more sensitive. 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 kid Sonogram shows cysts with bilaterally enlarged kidneys. These findings are compatible with a diagnosis of autosomal dominant polycystic kidney disease (ADPKD).
Sonogram shows cysts with bilaterally enlarged kid Sonogram shows cysts with bilaterally enlarged kidneys. These findings are compatible with a diagnosis of autosomal dominant polycystic kidney disease (ADPKD).
Sonogram shows cysts with bilaterally enlarged kid Sonogram shows cysts with bilaterally enlarged kidneys. These findings are compatible with a diagnosis of autosomal dominant polycystic kidney disease (ADPKD).

Occasionally, prenatal ultrasonography reveals renal cysts. Multiple bilateral macrocysts smaller than 2 cm may be present. Renal cysts combined with positive family history findings suggest autosomal dominant polycystic kidney disease. In families with known autosomal dominant polycystic kidney disease, 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 ultrasonography findings and ultrasonography findings in infants may be indistinguishable from findings in patients with autosomal recessive polycystic kidney disease.

Routine ultrasonographic screening that demonstrates even 1 cyst is highly predictive of the development of symptomatic autosomal dominant polycystic kidney disease later in life in a child with a family history of autosomal dominant polycystic kidney 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.

Cross-Sectional Imaging - CT Scanning and MRI

CT scanning

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

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

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 enla 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).

MRI

MRI is the best imaging tool in polycystic kidney disease to determinate 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 autosomal recessive polycystic kidney disease 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 ki 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.

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

Genetic Testing

Genetic testing in autosomal recessive polycystic kidney disease has improved because of haplotype-based molecular analysis. It is performed only if the patient's family has at least 1 established index case of the disease.

Genetic testing can be used when the imaging results are equivocal or when a definite diagnosis is required in a younger individual, such as a living, related potential kidney donor.

Genetic testing can be done by linkage or sequence analysis. In linkage analysis, polymorphic markers are used to flank the location of the known disease gene and to track the disease. Linkage analysis uses highly informative microsatellite markers flanking PKD1 and PKD2 and requires accurate diagnosis, as well as willingness of sufficient affected family members to be tested. Therefore, linkage analysis is suitable in fewer than 50% of families. It can reveal disease and carrier status in the fetus or newborn.

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 now 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.

Ethical Diagnostic Considerations

Prenatal diagnosis in autosomal dominant polycystic kidney disease 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.

 

Treatment

Approach Considerations

Autosomal recessive polycystic kidney disease

Survival of neonates depends on neonatal artificial ventilation and intensive care, as well as the degree of pulmonary hypoplasia. In order to optimize ventilation, fluid overload can be managed with diuretics, continuous renal replacement therapy, and nephrectomy.

If evidence of concentrating defects is observed in infants without significant renal insufficiency, thiazides may be useful. Bicarbonate supplements may be necessary for correction of metabolic acidosis.

Systemic hypertension should be aggressively treated with antihypertensive medication. Angiotensin-converting enzyme (ACE) inhibitors are the drugs of choice. Calcium channel blockers, beta blockers, and the judicious use of diuretics are also potential options. Antibiotics are used to treat urinary tract infections.

Once children with autosomal recessive polycystic kidney disease develop chronic kidney disease, they require management of anemia with iron and erythropoietin; prevention of metabolic bone disease with calcium supplements, phosphate binders, and parathyroid-suppressing medication; and growth hormone to counter the growth-limiting effects of uremia.

Because of the large size of the kidneys, unilateral or bilateral nephrectomy is often performed if respiratory compromise is present in the neonatal period or if failure to thrive is present because of the large, bilateral, space-occupying masses that prevent appropriate nourishment.

Once children are in end-stage renal disease, dialysis or transplantation is the only option. Renal transplantation may be necessary in a large number of patients with autosomal recessive polycystic kidney disease.

With better renal care, the course of children with autosomal recessive polycystic kidney disease is further complicated by the hepatic complications described earlier, which require specific therapy by specialists. A large number of hepatic complications require surgical management (eg, sclerotherapy for esophageal varices or portocaval and splenorenal shunt placement).

Autosomal dominant polycystic kidney disease

Medical care in autosomal dominant polycystic kidney disease is directed at reducing morbidity and mortality due to the complications of the disease and includes management of hypertension, renal insufficiency, and end-stage renal disease, similar to autosomal recessive polycystic kidney disease.

Renal insufficiency is less common in children with autosomal dominant polycystic kidney disease than in those with the recessive form, but hemodialysis or peritoneal dialysis or transplantation may be required, as in patients with autosomal recessive polycystic kidney disease.

Long-Term Monitoring

The primary care physician and consulting nephrologist should participate in the care of children and adults with polycystic kidney disease. Once polycystic kidney disease is diagnosed, the frequency of outpatient follow-up with the nephrologist depends on the degree of renal dysfunction and on complicating features, such as a failure to thrive, nutritional and feeding difficulties, hypertension, electrolyte disturbances, urinary infections, and hepatic fibrosis (ie, portal hypertension).

In addition to the significant medical problems, the psychosocial stress on the patient and family can be overwhelming. A team approach in which the skills of the nephrologist are used together with those of other medical specialists (eg, gastroenterologist), specialized nurses, nutritionists, social workers, psychiatrists, and other support staff provides optimal comprehensive care.

 

Medication

Medication Summary

Drug therapy is not currently a component of the standard of care in this condition. Medications are used only to treat the complications that arise from the disease process.

Because of the availability of animal models, preclinical trials have been developed, and promising candidate drugs have been identified for clinical trials.[13] The role of cyclic adenosine monophosphate (cAMP) in cystogenesis provided the rationale for preclinical trials of vasopressin V2 receptor antagonists. One of these drugs, OPC-31260, substantially reduced concentrations of cAMP and inhibited cyst development in models of both types of polycystic kidney disease and nephronophthisis.

Tolvaptan (Jynarque), a selective vasopressin V2-receptor antagonist, was approved in the U.S. in April 2018 for adults at risk of rapidly progressing ADPKD. Approval was based on two phase 3 clinical trials that showed improvement of GFR and slow the increase in total kidney volume and the decline in kidney function.[14, 15, 16] Because of the potential for serious liver injury, Jynarque is available only through a restricted distribution program.

Other drugs shown to be effective in preclinical trials for the treatment of human polycystic kidney disease include inhibitors of epidermal growth factor receptor, Erb-B2 tyrosine kinase, and Src kinase.[17, 18]

Once children with autosomal recessive polycystic kidney disease develop chronic kidney disease, they require management of anemia with iron and erythropoietin; prevention of metabolic bone disease with calcium supplements, phosphate binders, and parathyroid-suppressing medication; and growth hormone to counter the growth-limiting effects of uremia.

If evidence of concentrating defects is observed in infants without significant renal insufficiency, thiazides may be useful. Bicarbonate supplements may be necessary for correction of metabolic acidosis.

Systemic hypertension should be aggressively treated with antihypertensive medication. Angiotensin-converting enzyme (ACE) inhibitors are the drugs of choice. Calcium channel blockers, beta blockers, and the judicious use of diuretics are also potential options. Antibiotics are used to treat urinary tract infections.

Iron Salts

Class Summary

Iron salts are used to replenish iron stores. The body stores iron in compounds called ferritin and hemosiderin for future use in the production of hemoglobin. Iron absorption is a variable of the existing body iron stores, the form and quantity in foods, and the combination of foods in the diet. The ferrous form of inorganic iron is more readily absorbed.

Ferrous sulfate (Feosol, MyKidz Iron, Fer-Iron)

Ferrous sulfate is a source of iron for hemoglobin synthesis in the treatment of anemia of chronic renal failure. This agent is used with erythropoietin to prevent iron stores depletion. Oral solutions and chewable tablet formulations of ferrous iron salts are available for use in pediatric populations.

Sodium ferric gluconate complex (Ferrlecit, Nulecit)

Sodium ferric gluconate complex is used to treat microcytic hypochromic anemia due to iron deficiency when oral administration is unfeasible or ineffective as well as to replenish iron stores in individuals on erythropoietin therapy who cannot take or tolerate oral iron supplementation.

Iron sucrose (Venofer)

Iron sucrose is a polynuclear iron (III) hydroxide in sucrose for intravenous use. This agent contains no preservatives or dextran polysaccharides. Iron sucrose is used to treat microcytic hypochromic anemia due to iron deficiency when oral administration is unfeasible or ineffective, as well as to replenish iron stores in individuals on erythropoietin therapy who cannot take or tolerate oral iron supplementation.

Colony Stimulating Factors

Class Summary

Colony stimulating factors are used to stimulate blood cell production. Endogenous erythropoietin stimulates red blood cell (RBC) hematopoiesis. Recombinant human erythropoietin (epoetin alfa) and darbepoetin stimulate erythropoiesis in anemic conditions.

Epoetin alfa (Epogen, Procrit)

Epoetin alfa stimulates the division and differentiation of committed erythroid progenitor cells and induces the release of reticulocytes from the bone marrow into the blood stream.

Darbepoetin alfa (Aranesp)

Darbepoetin alfa stimulates the division and differentiation of committed erythroid progenitor cells and induces the release of reticulocytes from the bone marrow into the blood stream.

Phosphate Binders

Class Summary

Phosphate binding agents are indicated if phosphate elevation is uncontrolled by dietary phosphate restriction. Calcium phosphate binders are typically the initial therapy for hyperphosphatemia. Calcium supplements and calcitriol may also possibly be used for hypocalcemia.

Calcium acetate (Eliphos, PhosLo)

Calcium acetate is indicated for the treatment of hyperphosphatemia secondary to chronic renal failure. This agent combines with dietary phosphorus to form insoluble calcium phosphate, which is excreted in feces. One caplet or tablet of calcium acetate 667 mg is equivalent to 169-mg elemental calcium (ie, 1 g calcium acetate equivalent to 250-mg of elemental calcium).

Calcium carbonate (Caltrate, Tums, Alcalak)

Calcium carbonate is used to treat hyperphosphatemia in chronic renal failure. This agent combines with dietary phosphorus to form insoluble calcium phosphate, which is excreted in feces. Calcium carbonate is also indicated for hypocalcemia. Calcium carbonate 1 g is equivalent to 400 mg of elemental calcium.

Sevelamer (Renagel, Renvela)

Sevelamer is indicated to reduce serum phosphorous in patients with end-stage renal disease (ESRD). This agent binds dietary phosphate in the intestine, thus inhibiting its absorption as well as reduces the incidence of hypercalcemic episodes in patients on hemodialysis compared with patients receiving calcium acetate treatment.

Vitamin D Analogues

Class Summary

Hyperparathyroidism is treated with calcitriol or other active vitamin D analogues. These drugs may also be used to treat hypocalcemia.

Calcitriol (Rocaltrol, Calcijex, Vectical)

Calcitriol is a primary active metabolite of vitamin D-3. This agent increases calcium levels in serum by promoting absorption of calcium in the intestines and retention in the kidneys. Calcitriol decreases excessive serum phosphatase levels and parathyroid levels as well as decreases bone resorption.

Calcitriol should be used in patients with renal failure who are unable to convert the inactive prohormone forms to the active metabolite. This agent is available in oral and parenteral formulations. This active form of vitamin D is used in cases of proximal renal tubular acidosis (pRTA) as multitherapy with large quantities of alkali and potassium supplementation and is also used to suppress parathyroid production and secretion in secondary hyperparathyroidism and for treatment of hypocalcemia in chronic renal failure by increasing intestinal calcium absorption.

Paricalcitol (Zemplar)

Paricalcitol, an active form of vitamin D, is formed through the removal of the 19th carbon group and modifications to the side chain of calcitriol, thus reducing the calcemic effect. This agent has been reported to suppress parathyroid hormone (PTH) without significant impact on calcium, phosphorus, or calcium-phosphorus product. Paricalcitol increases calcium levels in serum by promoting absorption of calcium in intestines and retention in kidneys, decreases excessive serum phosphatase levels and PTH levels, and decreases bone resorption.

This agent should be used in patients with renal failure who are unable to convert the inactive prohormone forms to the active metabolite. It is also used to suppress parathyroid production and secretion in secondary hyperparathyroidism and for treatment of hypocalcemia in chronic renal failure by increasing intestinal calcium absorption. Paricalcitol is available in oral and parenteral formulations.

Doxercalciferol (Hectorol)

Doxercalciferol is a vitamin D analogue (1-alpha-hydroxyergocalciferol) that does not require activation by the kidneys but does require hydroxylation in the liver to be converted to an active vitamin D metabolite. This agent controls intestinal absorption of dietary calcium, tubular reabsorption of calcium by the kidneys, and in conjunction with parathyroid hormone, the mobilization of calcium from skeleton. Doxercalciferol is indicated for the treatment of secondary hyperparathyroidism in end-stage renal disease (ESRD).

Growth Hormones

Class Summary

Growth hormones are used pharmacologically as growth-promoting agents to help optimize growth in developing children with chronic kidney disease (CKD).

Growth hormone (Nutropin, Saizen, Genotropin)

Growth hormone is a human growth hormone (hGH) produced by recombinant DNA technology and whose use results in stimulation of linear growth. This agent stimulates erythropoietin, which increases red blood cell mass.

Growth hormone is currently widely available in subcutaneous (SC) injection form. Adjust the dose gradually based on clinical and biochemical responses assessed at monthly intervals, including body weight, waist circumference, serum insulinlike growth factor-1 (IGF-1), insulinlike growth factor binding protein-3 (IGFBP-3), serum glucose, lipids, thyroid function, and whole body dual-energy x-ray absorptiometry (DEXA). In children, assess treatment response based on height and growth velocity. Continue treatment until the child's final height or epiphysial closure or both have been recorded.

Calcimimetic Agents

Class Summary

Calcimimetic agents reduce parathyroid hormone (PTH) levels.

Cinacalcet (Sensipar)

Cinacalcet directly lowers intact parathyroid hormone (iPTH) levels by increasing the sensitivity of the calcium-sensing receptor on chief cell of the parathyroid gland to extracellular calcium. This process also results in concomitant serum calcium decrease. Cinacalcet is indicated for secondary hyperparathyroidism in patients with chronic kidney disease on dialysis.

Diuretic Agents

Class Summary

These agents are used to remove excess fluid in children with edema secondary to renal disease and are administered as an adjunct to manage hypertension and excess fluid.

Furosemide (Lasix)

Furosemide is a loop diuretic. It is often effective in removing fluid even when the glomerular filtration rate is reduced secondary to nephritis. This agent increases the excretion of water by interfering with the chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle and the distal renal tubule.

Hydrochlorothiazide (Microzide)

Hydrochlorothiazide (HCTZ) acts on the distal nephron to impair sodium reabsorption, enhancing sodium excretion. It has been in use for more than 40 years and is generally an important agent for the treatment of essential hypertension.

ACE Inhibitors

Class Summary

These agents reduce the systemic arterial blood pressure, reducing injury caused by elevated blood pressure. They may not only reduce cardiovascular risk but also slow progression of renal failure. ACE inhibitors may also slow progression of renal failure by lowering intraglomerular pressure or other intrarenal mechanisms.

A dry cough is a common adverse effect of ACE inhibitors. If the cough occurs with one ACE inhibitor, it is likely to occur with another. A reasonable substitute for an ACE inhibitor if a cough develops is an ARB, such as losartan, valsartan, or candesartan.

Captopril

Captopril, a competitive ACE inhibitor, prevents the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, increasing levels of plasma renin and reducing aldosterone secretion. It has been clinically used for more than 20 years and is effective in experimental radiation nephropathy. Captopril may slow the progression of renal failure by lowering intraglomerular pressure or other intrarenal mechanisms.

Enalapril (Vasotec)

A competitive ACE inhibitor, enalapril reduces angiotensin II levels, decreasing aldosterone secretion. The drug lowers systemic arterial blood pressure, reducing injury caused by elevated blood pressure. It may slow the progression of renal failure by lowering intraglomerular pressure or other intrarenal mechanisms. Enalapril may be used every day or twice per day, which may improve compliance in comparison with a 3-time-per-day medication, such as captopril.

Angiotensin II Receptor Antagonists

Class Summary

ARBs antagonize the action of angiotensin II at the type 1 receptor, reducing systemic arterial blood pressure and blunting the intrarenal effect of angiotensin II. If ACE inhibitors cause cough, ARBs may be substituted.

Losartan (Cozaar)

Losartan is a prototype ARB. It is specific for the type 1, as opposed to type 2, angiotensin receptor. It may induce more complete inhibition of the renin-angiotensin system than do ACE inhibitors. Losartan does not appear to affect bradykinin and is less likely to be associated with cough and angioedema. Use it in patients who are unable to tolerate ACE inhibitors.

Valsartan (Diovan)

Valsartan is a prodrug that directly antagonizes angiotensin II receptors. It displaces angiotensin II from the AT1 receptor and may lower blood pressure by antagonizing AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses. Valsartan may induce more complete inhibition of the renin-angiotensin system than do ACE inhibitors. It does not affect bradykinin and is less likely to be associated with cough and angioedema. Valsartan is for use in patients who are unable to tolerate ACE inhibitors.

Calcium Channel Blockers

Class Summary

Antihypertensive agents other than or in addition to ACE inhibitors and ARBs may be needed for blood pressure control in many subjects with hypertension and chronic renal failure. The same is true for subjects with radiation nephritis. No evidence indicates that one type of calcium channel blocker is preferred over another for radiation nephritis. However, one should avoid verapamil, because the use of this drug in a subject with hyperkalemia may cause atrial arrest.

Nifedipine (Procardia, Adalat, Nifedical XL)

Like other calcium channel blockers, nifedipine causes peripheral arterial vasodilation by inhibiting calcium influx across vascular smooth-muscle cell membranes. Long-acting formulations are used for control of blood pressure.

Beta Adrenergic Blockers

Class Summary

These agents inhibit chronotropic, inotropic, and vasodilatory responses to beta-adrenergic stimulation

Esmolol (Brevibloc)

An ultra–short-acting beta-1-blocker, esmolol is particularly useful in patients with elevated arterial pressure, especially if surgery is planned. It may be useful as a means to test beta-blocker safety and tolerance in patients with history of obstructive pulmonary disease who are at uncertain risk for bronchospasm from beta-blockade. The elimination half-life of esmolol is 9 min.

Labetalol (Trandate)

Labetalol blocks alpha-1 beta 1-, and beta 2-adrenergic receptor sites, decreasing BP.

Propranolol (Inderal, InnoPran XL)

A class II antiarrhythmic nonselective beta-adrenergic receptor blocker, propranolol has membrane-stabilizing activity and decreases automaticity of contractions. Propranolol is not suitable for emergency treatment of hypertension. Do not administer IV in hypertensive emergencies.

Metoprolol (Lopressor, Toprol-XL)

Metoprolol is a selective beta 1–adrenergic receptor blocker that decreases automaticity of contractions. During IV administration, carefully monitor BP, heart rate, and ECG. When considering conversion from IV to oral (PO) dosage forms, use the ratio of 2.5 mg PO to 1 mg IV metoprolol.

Alkalinizing Agents

Class Summary

Sodium bicarbonate is used as a gastric, systemic, and urinary alkalinizer and has been used in the treatment of acidosis resulting from metabolic and respiratory causes, including, diarrhea, kidney disturbances, and shock. Alternatively, THAM is a buffering agent that increases pH without increasing levels of PaCO2. It may be used to correct metabolic acidosis if sodium bicarbonate is contraindicated.

Sodium bicarbonate

Sodium bicarbonate serves as a buffering agent for metabolic acidosis when significant bicarbonate losses have occurred.