Pediatric Polycystic Kidney Disease

The three 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 two.

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 ADPKD, 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 ARPKD 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 ARPKD is linked to ciliary dysfunction. ^[7]

ARPKD 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 10 mm may be seen. (See the images below.)

At autopsy, gross examination of a kidney in patients with ARPKD 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 ARPKD 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, ARPKD 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 ARPKD, researchers at the National Institutes of Health (NIH) analyzed clinical, molecular, and imaging data from 73 patients (aged 1-56 years; average, 12.7 years) 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]

A study that included 304 patients with ARPKD found that biallelic null variants in PKHD1 are associated with severe disease and a poor prognosis. For example, variants that affect amino acids 2625-4074 of fibrocystin are linked to worse hepatic outcomes. ^[11]

Autosomal dominant polycystic kidney disease

The genes responsible for ADPKD 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 ADPKD, 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.

ADPKD differs from ARPKD in that cysts associated with ADPKD 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 ARPKD.

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.

United States statistics

Autosomal recessive polycystic kidney disease

The exact incidence of ARPKD 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 ARPKD has been reported as 1 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 ARPKD, 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.

Autosomal dominant polycystic kidney disease

The estimated prevalence of ADPKD is 1 case per 200-1000 population. ADPKD 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%.

International statistics

ADPKD 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.

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 ARPKD 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. ^[12]

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

ADPKD can also present prenatally but usually does not involve the severe renal impairment seen in ARPKD. 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.

ADPKD is a multisystem disorder, and some patients develop associated intracranial aneurysms, which can cause stroke and intracranial hemorrhage. Much of the morbidity of ADPKD is due to chronic hypertension. A study by Seeman et al showed that the prevalence of hypertension rose from 20% to 38%, along with an increase in the number of kidney cysts, during a median 6-year follow-up period in children. ^[13] ADPKD can manifest in utero with the Potter phenotype, with death from pulmonary hypoplasia. ^[14]

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 

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