AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

Section 2 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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Background

Polycystic kidney disease (PKD) is an inherited disorder that involves bilateral renal cysts without dysplasia. PKD is broadly divided into 2 forms: autosomal recessive polycystic kidney disease (ARPKD), previously known as infantile polycystic kidney disease, and autosomal dominant polycystic kidney disease (ADPKD), previously known as adult polycystic kidney disease. The nomenclature of infantile versus adult is no longer used because it is not an accurate description. Both ARPKD and ADPKD 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 radiological manifestations of both types of PKD have considerable overlap.

ARPKD is characterized by cystic dilatation of renal collecting ducts associated with hepatic abnormalities of varying degrees, including biliary dysgenesis and periportal fibrosis. ARPKD was first recognized in 1902; however, the histology was not reported until 1947. In 1964, Osathanondh and Potter classified ARPKD as type 1 cystic kidney disease. Eventually, given that neither parent had the disease and that no sex predilection was present, this disease was demonstrated as having an autosomal recessive mode of inheritance. ARPKD was originally described as 4 separate clinical entities based on age of presentation. This classification is no longer considered valid, given the large degree of overlap among the different groups and the wide range of possible presentations, regardless of age.

ADPKD is the most common inherited kidney disease in humans. It is a multisystem disorder characterized by progressive cystic dilatation of both kidneys with variable extrarenal manifestations in the gastrointestinal tract, cardiovascular system, reproductive organs, and brain. Hepatic cysts are possible in ADPKD, although they are less common than in ARPKD. ADPKD has a wide clinical spectrum. It may present asymptomatically as an incidental finding or may present as severe neonatal manifestations similar to ARPKD.

Pathophysiology

The 3 basic processes involved in renal cyst formation and progressive enlargement are as follows:

• Tubular cell hyperplasia: This may be mediated by factors that control cell proliferation (eg, epidermal growth factor, transforming growth factor- a), 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 PKD.

Autosomal recessive polycystic kidney disease

In 1994, the ARPKD gene (PKDHD1) was localized to the short arm of chromosome 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.

ARPKD is characterized by nonobstructive, bilateral, symmetric 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. At autopsy, gross examination of a kidney in patients with ARPKD shows 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 more severe clinical manifestation than the renal disease. The CHF results from malformation of the developing ductal plate. The liver biopsy shows 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 gastrointestinal hemorrhage.

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.

ADPKD differs from ARPKD in that cysts associated with ADPKD develop anywhere along the nephron. At 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, which contain 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. Some have hypothesized that patients with an associated marked epithelial hyperplasia may have a higher rate of malignant transformation than the general population.

Frequency

United States

• ARPKD: The exact incidence 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 one case per 10,000-40,000 births, although the frequency of the gene in the general population is estimated to be 1 per 70. Because of the recessive inheritance of ARPDK, 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.
• ADPKD: The estimated prevalence of ADPKD is one 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%.
• With education, better quality of prenatal ultrasound, awareness, and gene testing, more accurate reports regarding the incidence and prevalence of ARPKD and ADPKD will hopefully be available soon.

International

ADPKD is responsible for 6-10% of cases of end-stage renal disease in Europe.

Mortality/Morbidity

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. 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 gastrointestinal hemorrhage secondary to portal hypertension. Oliguric acute renal failure (ARF) often improves as the pulmonary function improves.

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 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. ADPKD can manifest in utero with the Potter phenotype, with death from pulmonary hypoplasia.

Race

Both forms of PKD affect all racial and ethnic groups.

Sex

ARPKD and ADPKD equally affect males and females.

Age

Because it is a genetic disease, PKD begins at conception. In both ARPKD and ADPKD, the renal manifestations may occur prenatally or later in life. ARPKD usually presents in the neonatal period or in childhood. Rare reports have described initial presentations in late adolescence and even in early adulthood. ADPKD most often initially presents in adults aged 20-40 years.

CLINICAL

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History

• Autosomal recessive polycystic kidney disease
• • Presentation 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.
  • Presentation in infancy
  • • Parents or pediatricians may discover abdominal masses in older infants.
    • Older infants may have abdominal distension secondary to renal masses or hepatosplenomegaly.
  • Presentation in all patients: Urinary concentrating defects include polyuria and polydipsia.
• Autosomal dominant polycystic kidney disease
• • 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 ARPKD)
    • Extrarenal manifestations of ADPKD (more common in adults but can occur in children as young as age 1 y)

Physical

• Autosomal recessive polycystic kidney disease
• • Presents 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
  • Clubfoot commonly seen secondary to oligohydramnios because of pressure effect in utero
  • Abdominal mass (This may manifest after the newborn period because of renal masses or hepatosplenomegaly.)
  • Hypertension (This 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 (may develop in patients with poorly managed hypertension)
  • Evidence of portal hypertension
  • Hepatic involvement (present in all children with ARPKD but may not manifest in neonates [50-60%])
  • Impaired renal function (present in 70-80% of infants)
  • Renal cysts in children (may be an incidental finding)
• Autosomal dominant polycystic kidney disease
• • Commonly presents as abdominal pain with or without abdominal pain
  • Hematuria
  • The pathophysiology of hypertension, which can present in patients of all age groups (even in patients with normal renal function), is as follows:
    • Increased activation of renin-angiotensin system
    • Reduced renal blood flow
    • Sodium retention
  • May have signs of portal hypertension and CHF (rare compared with ARPKD)
  • Manifestations of stroke secondary to cerebral hemorrhage of ruptured aneurysms
  • Renal involvement (often asymmetric 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
    • Endocardial fibroelastosis in children as well as adults
    • Increased left ventricular mass with diastolic dysfunction, even in normotensive children
    • Coronary aneurysms, exclusively in adults

Causes

PKDs are genetically transmitted multisystem diseases found in 2 forms (see Background). In 1994, Zerres et al localized the ARPKD gene (PKDHD1) to the short arm of chromosome 6; PKDHD1 is responsible for the expression of the ciliary protein fibrocystin. In ARPKD, the mutant fibrocystin is found to be completely destabilized and rapidly degraded, leading to ciliary dysfunction and the features of ARPKD.

The genes responsible for ADPKD are found at the tip of the short arm of chromosome 16 (PKD1) in 85% of the cases and the long arm of chromosome 4 (PKD2) in most of the remaining cases. The PKD1 gene encodes for a protein called polycystin-1, and the PKD2 gene encodes for a protein called polycystin-2, both of which are widely expressed in the kidney and are thought to play an important role in tubular architecture. The loss of these proteins may cause altered differentiation in affected cells, with dysfunction of the renal primary cilium that leads to clinical manifestations of ADPKD. Some families have no linkage to PKD1 or PKD2, suggesting that other loci for this disease may exist.

DIFFERENTIALS

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Other Problems to be Considered

Glomerulocystic kidney disease

WORKUP

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Lab Studies

• Blood and urine studies are useful in evaluating patients with both types of PKD, 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.
• BUN levels in plasma are also increased in renal dysfunction. However, this is not as reliable as the serum creatinine level test because BUN levels are also elevated in cases of intravascular depletion, increased protein intake, catabolism, and gastrointestinal hemorrhage and may be reduced in chronic liver disease.
• Serum electrolyte levels may reveal further evidence of glomerular and tubular dysfunction in PKD. 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 and 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 this hypocalcemia. Tubular dysfunction can also cause electrolyte abnormalities.
• Liver function is usually normal.
• Metabolic acidosis may be present.
• Gross or microscopic hematuria may be present. Gross hematuria often develops after minor trauma to the flank.
• 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
• Liver function test findings are often abnormal in the later stages of the disease, particularly in ARPKD.
• • Urine analysis findings can be normal. Microhematuria or macrohematuria may be present. Macrohematuria is more common in ADPKD. Proteinuria, pyuria, and, sometimes, evidence of urinary concentrating defects such as prerenal azotemia may be present.

Imaging Studies

• Ultrasonography findings in autosomal recessive polycystic kidney disease
• • Prenatal findings
  • • 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
  • • 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 (This may be diffusely increased with fibrous tissue that causes poor depiction of peripheral portal veins.)
  • Patients are most commonly diagnosed based on prenatal ultrasonography findings. In older children who present late, renal ultrasonography findings may be less reliable. Hepatic features are often the prominent presenting feature. Findings in older children include the following:
  • • Enlarged kidneys in older children with ARPKD differ from enlarged kidneys in younger children with ARPKD in that the hyperechogenicity is mainly in the medulla because of focal tubular cysts.
    • Renal macrocysts are more common in this age group.
    • The Liver is often enlarged with heterogeneously or homogenously increased echogenicity.
    • Macrocysts in the liver and pancreas are often visualized.
    • Splenomegaly is also observed.
    • The reversal of hepatic venous blood flow revealed by Doppler ultrasonography suggests portal hypertension.
    • Macroscopic liver cysts are uncommon, although choledochal cysts have been reported.
    • When present, biliary duct dilatation is indistinguishable from Caroli disease.
  • Adult findings
  • • Multiple small cysts, typically in normal-sized kidney
    • Increased cortical echogenicity
    • Loss of corticomedullary differentiation
• Ultrasonography findings in autosomal dominant polycystic kidney disease
• • Ultrasonography should be first line of imaging in patients who are at risk for ADPKD, especially patients older than 30 years. In patients younger than 30 years, ultrasonography may not reveal manifestations, and linkage analysis may be more sensitive.
  • Ultrasonography findings in patients with ADPKD include the following:
  • • 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 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 ultrasonography findings and ultrasonography findings in infants may be indistinguishable from findings in patients with ARPKD.
    • Routine ultrasonography 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 ADPKD.
    • Multicystic kidney disease differs from PKD in that it is unilateral with multiple noncommunicating macrocysts of varying size.
    • Pancreatic cysts are found exclusively in patients with PKD1 and are usually asymptomatic.
    • Ovarian cysts may be present.
• MRI findings in autosomal recessive polycystic kidney disease
• • Enlarged kidneys with T2-weighted imaging that shows increased signal intensity
  • Characteristic hyperintense, linear, radial pattern in cortex and medulla
  • MRI is not routinely performed in patients with ADPKD.
• CT scanning is not a diagnostic procedure of choice in either form of PKD.
• • In ARPKD, noncontrast CT scanning reveals smooth, enlarged kidneys. With intravenous contrast, kidneys have a striated appearance due to accumulation of contrast in dilated tubules. Depending on degree of renal insufficiency, a proportionate delay in arrival of contrast to kidneys is observed. Macrocysts may appear as well-circumscribed lucent defects. The bladder may be opacified.
  • In ADPKD, well-delineated cysts that do not enhance following intravenous contrast administration may be present in both kidneys. Over time, kidneys and cysts often grow as revealed by CT scanning. If a cyst hemorrhage is present, it can be observed as a high-density cyst.
• Radiographic findings in 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.
• Radiographic findings in autosomal dominant polycystic kidney disease
• • Intravenous pyelogram findings may be normal or have abnormalities of one or both kidneys
  • Grossly enlarged kidneys with lobular appearance
  • Distorted calyces secondary to non-opacified cysts with smooth or irregular indentations
  • Numerous bilateral cysts of various sizes

Other Tests

• Maternal atrial filling pressure (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 diagnosis of ARPKD.
• Brain imaging is used in the diagnosis of ADPKD.
• Genetic testing in autosomal recessive polycystic kidney disease
• • Genetic testing in ARPKD has improved because of haplotype-based molecular analysis. It is performed only if the patient's family has at least one established index case of ARPKD.
  • One of the techniques used is linkage analysis, which uses polymorphic markers to flank the location of the known disease gene and to track the disease. It can reveal disease and carrier status in the fetus or newborn.
• Prenatal diagnosis in ADPKD represents an ethical dilemma, given that symptoms may not present until well into adulthood and that 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.
• Another consideration in early diagnosis in patients not yet symptomatic is the label of ADPKD, which affects their medical insurance coverage and could have profound financial implications. Because of these reasons, genetic testing for ADPKD to identify PKD1 or PKD2 was not routinely performed in the United States. However, commercial laboratories in the United States and other genetic laboratories now perform genetic testing for ADPKD using polymerase chain reaction (PCR) and bidirectional sequencing techniques. Careful consideration must be made prior to testing, given psychosocial and financial concerns.
• Left ventricular hypertrophy and early ramifications mentioned above are revealed using echocardiography. Diastolic dysfunction is present, even in normotensive patients.

Histologic Findings

Renal biopsy is not usually indicated, particularly when the family history is positive.

TREATMENT

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Medical Care

• Medical care in 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. 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 ARPKD 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.
  • Once children with ARPKD are in end-stage renal disease, dialysis or transplantation is the only option.
  • With better renal care, the course of children with ARPKD is further complicated by the hepatic complications listed above, which require specific therapy by specialists.
• Medical care in ADPKD includes management of hypertension, renal insufficiency, and end-stage renal disease, similar to ARPKD.

Surgical Care

• Surgical care in autosomal recessive polycystic kidney disease
• • 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.
  • In patients who require dialysis, peritoneal dialysis requires surgery for the placement of peritoneal dialysis catheters, and hemodialysis requires surgery for access.
  • Renal transplantation may be necessary in a large number of patients with ARPKD.
  • A large number of hepatic complications require surgical management (eg, sclerotherapy for esophageal varices or portocaval and splenorenal shunt placement).
• Surgical care in autosomal dominant polycystic kidney disease: Renal insufficiency is less common in children with ADPKD, but hemodialysis or peritoneal dialysis or transplantation may be required, as in patients with ARPKD.

Diet

The medical management of ARPKD is supportive. Infants and young children without significant renal insufficiency need close follow-up. Adequate nutrition (protein and energy) is essential.

• Salt supplementation is necessary only if salt wasting occurs.
• Alkali therapy with sodium bicarbonate or sodium citrate is required in patients with metabolic acidosis.
• The risk of severe dehydration due to urinary concentration defects, particularly during episodes of intercurrent illnesses that can increase insensible water losses (eg, fever), that can limit free water intake (because of nausea), or that can increase extrarenal water losses (diarrhea), can be overcome with oral or parenteral intake of generous amounts of salt and water.

  The treatment of chronic kidney disease among children with ARPKD is similar to the treatment for any child with chronic kidney disease. Supplemental energy intake and nasogastric or gastrostomy tube feedings should optimize the management of nutrition. These measures must be considered to improve growth and overall health of the child.

  The natural history of the presymptomatic child with proven ADPKD remains largely unknown. Close monitoring is recommended, and the treatment of hypertension, renal insufficiency, and end-stage renal disease should be treated as in ARPKD.

MEDICATION

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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.

A recent study suggests that kidney enlargement due to cyst expansion in ADPKD is associated with a decline in renal function, which warrants study into therapies that would slow the progression of cyst growth and renal enlargement in this disease.

FOLLOW-UP

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Further Outpatient Care

• The primary care physician and consulting nephrologist should participate in the care of children and adults with PKD. Once PKD 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.

Prognosis

• Determining the prognosis is difficult, but, 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.

Patient Education

• The Polycystic Kidney Research (PKR) Foundation is devoted to determining the cause of PKD, 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:

  PKR Foundation
  4901 Main Street
  Suite 200
  Kansas City, MO 64112-2634
  Telephone: 1-800-PKD-CURE
  Fax: (816) 931-8655
  Email: pkdcure@pkrcure.org

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

  National Kidney Foundation
  30 East 33rd Street
  1111th Floor
  New York, NY 10016

• For excellent patient education resources, visit eMedicine's Kidneys and Urinary System Center. Also, see eMedicine's patient education articles Chronic Kidney Disease and Kidney Transplant.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Molecular genetic testing by direct mutation screening is clinically available; however, sometimes a relatively large number of affected family members need to be tested in order to establish which 2 of the 2 possible genes is responsible within each family. The large size and complexity of PKD1 and PKD2 genes, as well as marked allelic heterogeneity, present obstacles to molecular testing by direct DNA analysis.
• Because of other potential mutations of known or unknown significance that may arise as incidental findings, sequencing an entire gene carries a significant risk of medical liability. Consequently, clear family history with known allelic mutations is preferred.

MULTIMEDIA

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Media file 1:  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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Media file 2:  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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Media file 3:  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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Media file 4:  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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Media file 5:  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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Media file 6:  Pathologic specimen of end-stage autosomal dominant polycystic kidney disease (ADPKD) with deformed lobulated kidneys.
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Media file 7:  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).
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Media file 8:  Excretory urogram shows minimal bilateral tubular changes caused by a mild form of autosomal recessive polycystic kidney disease (ARPKD).
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Media file 9:  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).
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Media file 10:  Excretory urogram shows the typical mottled (spongelike) contrast pattern in autosomal recessive polycystic kidney disease (ARPKD).
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Media file 11:  Excretory urogram shows the typical mottled (spongelike) contrast pattern in autosomal recessive polycystic kidney disease (ARPKD).
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Media file 12:  Excretory urogram shows the typical mottled (spongelike) contrast enhancement pattern in autosomal recessive polycystic kidney disease (ARPKD).
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REFERENCES

Section 11 of 11

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• Follow-up
• Miscellaneous
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• Abuelo JG. Initial laboratory studies. In: Abuelo JG, ed. Renal Failure: Diagnosis and Treatment. Dordrecht, The Netherlands:. Kluwer Academic Publishers;1995:25-34.
• Anand SK, Chan JC, Lieberman E. Polycystic disease and hepatic fibrosis in children. Renal function studies. Am J Dis Child. Jul 1975;129(7):810-3. [Medline].
• Athena Diagnostics, Inc. PKD Molecular Diagnostic Testing Service. Available at: http://www.nephrocast.com/site/content/clincal_overview.asp. Accessed March 5, 2003. [Full Text].
• Bajwa ZH, Gupta S, Warfield CA, Steinman TI. Pain management in polycystic kidney disease. Kidney Int. Nov 2001;60(5):1631-44. [Medline].
• Bear JC, McManamon P, Morgan J, et al. Age at clinical onset and at ultrasonographic detection of adult polycystic kidney disease: data for genetic counselling. Am J Med Genet. May 1984;18(1):45-53. [Medline].
• Begleiter ML, Smith TH, Harris DJ. Ultrasound for genetic counselling in polycystic kidney disease. Lancet. Nov 19 1977;2(8047):1073-4. [Medline].
• Bernstein J, Evan AP, Gardner KD Jr. Epithelial hyperplasia in human polycystic kidney diseases. Its role in pathogenesis and risk of neoplasia. Am J Pathol. Oct 1987;129(1):92-101. [Medline].
• Blickman JG, Bramson RT, Herrin JT. Autosomal recessive polycystic kidney disease: long-term sonographic findings in patients surviving the neonatal period. AJR Am J Roentgenol. May 1995;164(5):1247-50. [Medline].
• Blyth H, Ockenden BG. Polycystic disease of kidney and liver presenting in childhood. J Med Genet. Sep 1971;8(3):257-84. [Medline].
• Boal DK, Teele RL. Sonography of infantile polycystic kidney disease. AJR Am J Roentgenol. Sep 1980;135(3):575-80. [Medline].
• Bosniak MA, Ambos MA. Polycystic kidney disease. Semin Roentgenol. Apr 1975;10(2):133-43. [Medline].
• Caroli J, Carlos V. Maladies des voies biliaries intrahepatiques segmentaries. Paris, France:. Maison et Cie;1964:59-156.
• Carone FA, Makino H, Kanwar YS. Basement membrane antigens in renal polycystic disease. Am J Pathol. Mar 1988;130(3):466-71. [Medline].
• Carter CO. Genetics of polycystic disease of the kidneys [Commentary]. Birth Defects. 1973;6: 11.
• Chilton SJ, Cremin BJ. The spectrum of polycystic disease in children. Pediatr Radiol. 1981;11(1):9-15. [Medline].
• Churchill DN, Bear JC, Morgan J, et al. Prognosis of adult onset polycystic kidney disease re-evaluated. Kidney Int. Aug 1984;26(2):190-3. [Medline].
• Cole BR, Conley SB, Stapleton FB. Polycystic kidney disease in the first year of life. J Pediatr. Nov 1987;111(5):693-9. [Medline].
• D''Agata ID, Jonas MM, Perez-Atayde AR, Guay-Woodford LM. Combined cystic disease of the liver and kidney. Semin Liver Dis. Aug 1994;14(3):215-28. [Medline].
• Daoust MC, Reynolds DM, Bichet DG, Somlo S. Evidence for a third genetic locus for autosomal dominant polycystic kidney disease. Genomics. Feb 10 1995;25(3):733-6. [Medline].
• De Vos M, Barbier F, Cuvelier C. Congenital hepatic fibrosis. J Hepatol. Apr 1988;6(2):222-8. [Medline].
• Dell KM, McDonald R, Watkins S. Polycystic kidney disease. Pediatr Nephrol. 2004;675-699.
• Desmet VJ. Congenital diseases of intrahepatic bile ducts: variations on the theme "ductal plate malformation". Hepatology. Oct 1992;16(4):1069-83. [Medline].
• Desmet VJ. What is congenital hepatic fibrosis?. Histopathology. Jun 1992;20(6):465-77. [Medline].
• Elkin M, Bernstein J. Cystic diseases of the kidney--radiological and pathological considerations. Clin Radiol. Jan 1969;20(1):65-82. [Medline].
• Fauvert R, Benhamou J. Congenital Hepatic Fibrosis. New York, NY:. Intercontinental Medical;1974:283-8.
• Fick GM, Gabow PA. Hereditary and acquired cystic disease of the kidney. Kidney Int. Oct 1994;46(4):951-64. [Medline].
• Gardner KD. Pathogenesis of human cystic renal disease. Annu Rev Med. 1988;39:185-91. [Medline].
• Ghishan FK, Younoszai MK. Congenital hepatic fibrosis: a disease with diverse manifestations. Am J Gastroenterol. Apr 1981;75(4):317-20. [Medline].
• Grantham JJ, Geiser JL, Evan AP. Cyst formation and growth in autosomal dominant polycystic kidney disease. Kidney Int. May 1987;31(5):1145-52. [Medline].
• Grantham JJ, Gabow PA. Polycystic kidney disease. In: Schrier RW, Gottschalk CW, eds. Diseases of the kidney. Boston, Mass:. Little Brown;1988:583-615.
• Grantham JJ, Torres VE, Chapman AB, et al. Volume progression in polycystic kidney disease. N Engl J Med. May 18 2006;354(20):2122-30.
• Grossman H, Rosenberg ER, Bowie JD, et al. Sonographic diagnosis of renal cystic diseases. AJR Am J Roentgenol. Jan 1983;140(1):81-5. [Medline].
• Guay-Woodford LM. Autosomal recessive polycystic kidney disease: clinical and genetic profiles. In: Watson ML, Torres VE, eds. Polycystic Kidney Disease. New York, NY:. Oxford University Press;1996:237-82.
• Gunay-Aygun M, Avner ED, Bacallao RL, et al. Autosomal recessive polycystic kidney disease and congenital hepatic fibrosis: summary statement of a first National Institutes of Health/Office of Rare Diseases conference. J Pediatr. Aug 2006;149(2):159-64.
• Gupta S, Seith A, Sud K, et al. CT in the evaluation of complicated autosomal dominant polycystic kidney disease. Acta Radiol. May 2000;41(3):280-4. [Medline].
• Hayden CK Jr, Swischuk LE, Smith TH, Armstrong EA. Renal cystic disease in childhood. Radiographics. Jan 1986;6(1):97-116. [Medline].
• Hoeffel JC, Jacottin G, Bourgeois JM. Apropos of a family associating cases of renal polycystic disease of juvenile and adult type [French]. Ann Radiol (Paris). Mar-Apr 1971;14(3):205-9. [Medline].
• Kaariainen H, Koskimies O, Norio R. Dominant and recessive polycystic kidney disease in children: evaluation of clinical features and laboratory data. Pediatr Nephrol. Jul 1988;2(3):296-302. [Medline].
• Kaplan BS, Kaplan P, Rosenberg HK, et al. Polycystic kidney diseases in childhood. J Pediatr. Dec 1989;115(6):867-80. [Medline].
• Kaplan BS, Fay J, Shah V, et al. Autosomal recessive polycystic kidney disease. Pediatr Nephrol. Jan 1989;3(1):43-9. [Medline].
• Kimberling WJ, Kumar S, Gabow PA, et al. Autosomal dominant polycystic kidney disease: localization of the second gene to chromosome 4q13-q23. Genomics. Dec 1993;18(3):467-72. [Medline].
• Kuizon BD, Salusky IB. Nutritional management of the child with renal insufficiency. In: Kopple JD, Massry SG, eds. Nutritional Management on Renal Disease. Baltimore, Md:. Williams and Wilkins;1997:687-711.
• Lambert P. Polycystic disease of the kidney. Arch Pathol. 1947;44: 34-58.
• Lee WM. Medical management of acute liver failure. In: Lee WM, Williams R, eds. Acute Liver Failure. New York, NY:. Cambridge University Press;1997:115-31.
• Lieberman E, Salinas-Madrigal L, Gwinn JL, et al. Infantile polycystic disease of the kidneys and liver: clinical, pathological and radiological correlations and comparison with congenital hepatic fibrosis. Medicine (Baltimore). Jul 1971;50(4):277-318. [Medline].
• Lipschitz B, Berdon WE, Defelice AR, Levy J. Association of congenital hepatic fibrosis with autosomal dominant polycystic kidney disease. Report of a family with review of literature. Pediatr Radiol. 1993;23(2):131-3. [Medline].
• Lonergan GJ, Rice RR, Suarez ES. Autosomal recessive polycystic kidney disease: radiologic-pathologic correlation. Radiographics. May-Jun 2000;20(3):837-55. [Medline]. [Full Text].
• Lundin PM, Olow I. Polycystic kidneys in newborns, infants and children. A clinical and pathological study. Acta Paediatr. Mar 1961;50:185-200. [Medline].
• MacDermot KD, Saggar-Malik AK, Economides DL, Jeffery S. Prenatal diagnosis of autosomal dominant polycystic kidney disease (PKD1) presenting in utero and prognosis for very early onset disease. J Med Genet. Jan 1998;35(1):13-6. [Medline].
• Main D, Mennuti MT, Cornfeld D, Coleman B. Prenatal diagnosis of adult polycystic kidney disease. Lancet. Aug 6 1983;2(8345):337-8. [Medline].
• McHugh K, Stringer DA, Hebert D, Babiak CA. Simple renal cysts in children: diagnosis and follow-up with US. Radiology. Feb 1991;178(2):383-5. [Medline].
• Mehrizi A, Rosenstein BJ, Push A. Myocardial infarction and endocardial fibroelastosis in children with polycystic kidneys. Bull Johns Hopkins Hosp. 1964;115:95-8.
• Melson GL, Shackelford GD, Cole BR, McClennan BL. The spectrum of sonographic findings in infantile polycystic kidney disease with urographic and clinical correlations. J Clin Ultrasound. Feb 1985;13(2):113-9. [Medline].
• Milutinovic J, Schabel SI, Ainsworth SK. Autosomal dominant polycystic kidney disease with liver and pancreatic involvement in early childhood. Am J Kidney Dis. Apr 1989;13(4):340-4. [Medline].
• Murray-Lyon IM, Ockenden BG, Williams R. Congenital hepatic fibrosis--is it a single clinical entity?. Gastroenterology. Apr 1973;64(4):653-6. [Medline].
• Niaudet P. Autosomal recessive and dominant polycystic kidney disease in children. Available at: http://www.uptodate.com. UpToDate 2006. Last updated on 5/7/2006;[Full Text].
• Niaudet P. Renal Cystic Diseases in Children. Available at: http://www.uptodate.com. UpToDate 2006. [Full Text].
• Nicolau C, Torra R, Badenas C, et al. Autosomal dominant polycystic kidney disease types 1 and 2: assessment of US sensitivity for diagnosis. Radiology. Oct 1999;213(1):273-6. [Medline]. [Full Text].
• Nicolau C, Torra R, Badenas C, et al. Sonographic pattern of recessive polycystic kidney disease in young adults. Differences from the dominant form. Nephrol Dial Transplant. Sep 2000;15(9):1373-8. [Medline]. [Full Text].
• Nishi T, Iwasaki M, Yamoto M, Nakano R. Prenatal diagnosis of autosomal recessive polycystic kidney disease by ultrasonography and magnetic resonance imaging. Acta Obstet Gynecol Scand. 1991;70(7-8):615-7. [Medline].
• Nishi T. Magnetic resonance imaging of autosomal recessive polycystic kidney disease in utero. J Obstet Gynaecol. Oct 1995;21(5):471-4. [Medline].
• Osathanondh V, Potter EL. Pathogenesis of polygenesis of polycystic kidneys. Historical survey. Arch Pathol. May 1964;77:459-65. [Medline].
• Osathanondh V, Potter E. Pathogenesis of polycystic kidneys: type I due to hyperplasia of interstitial portions of collecting tubules. Arch Pathol. 1964;77:466-73.
• Ozcan T, Singh RB. Prenatal Sonographic Diagnosis of Cystic Renal Disease. Available at: http://www.uptodate.com. UpToDate 2006. [Full Text].
• Perrone R. Imaging progression in polycystic kidney disease. N Engl J Med. May 18 2006;354(20):2181-3.
• Peters DJ, Spruit L, Saris JJ, et al. Chromosome 4 localization of a second gene for autosomal dominant polycystic kidney disease. Nat Genet. Dec 1993;5(4):359-62. [Medline].
• Potter E. Normal and abnormal development of the kidney. Chicago, Ill:. Year Book Medical;1972:6-112.
• Proesmans W, Van Damme B, Casaer P, Marchal G. Autosomal dominant polycystic kidney disease in the neonatal period: association with a cerebral arteriovenous malformation. Pediatrics. Dec 1982;70(6):971-5. [Medline].
• Rabinowitz R, Segal AJ, Rao HK, Pathak A. Computed tomography in diagnosis of infantile polycystic kidney disease. J Urol. Nov 1978;120(5):616-7. [Medline].
• Rahill WJ, Rubin MI. Hypertension in infantile polycystic renal disease. The importance of early recognition and treatment of severe hypertension in polycystic renal disease. Clin Pediatr (Phila). Apr 1972;11(4):232-5. [Medline].
• Ravine D, Gibson RN, Walker RG, et al. Evaluation of ultrasonographic diagnostic criteria for autosomal dominant polycystic kidney disease 1. Lancet. Apr 2 1994;343(8901):824-7. [Medline].
• Ravine D, Gibson RN, Donlan J, Sheffield LJ. An ultrasound renal cyst prevalence survey: specificity data for inherited renal cystic diseases. Am J Kidney Dis. Dec 1993;22(6):803-7. [Medline].
• Reeders ST, Breuning MH, Davies KE, et al. A highly polymorphic DNA marker linked to adult polycystic kidney disease on chromosome 16. Nature. Oct 10-16 1985;317(6037):542-4. [Medline].
• Romero R, Cullen M, Jeanty P, et al. The diagnosis of congenital renal anomalies with ultrasound. II. Infantile polycystic kidney disease. Am J Obstet Gynecol. Oct 1 1984;150(3):259-62. [Medline].
• Rosenfield AT, Lipson MH, Wolf B, et al. Ultrasonography and nephrotomography in the presymptomatic diagnosis of dominantly inherited (adult-onset) polycystic kidney disease. Radiology. May 1980;135(2):423-7. [Medline].
• Sanders RC, Hartman DS. The sonographic distinction between neonatal multicystic kidney and hydronephrosis. Radiology. Jun 1984;151(3):621-5. [Medline].
• Saunders AJ, Denton E, Stephens S, Reid C. Cystic kidney disease presenting in infancy. Clin Radiol. Jun 1999;54(6):370-6. [Medline].
• Sessa A, Righetti M, Battini G. Autosomal recessive and dominant polycystic kidney diseases. Minerva Urologica e Nefrologica / The Italian journal of Urology and Nephrology. 2004;56(4):329-338. [Medline].
• Sharp AM, Messiaen LM, Page G, et al. Comprehensive genomic analysis of PKHD1 mutations in ARPKD cohorts. J Med Genet. Apr 2005;42(4):336-49. [Medline]. [Full Text].
• Sise C, Kusaka M, Wetzel LH, et al. Volumetric determination of progression in autosomal dominant polycystic kidney disease by computed tomography. Kidney Int. Dec 2000;58(6):2492-501. [Medline].
• Striker GE, Striker LJ. Renal cysts in polycystic kidney disease. Am J Nephrol. 1986;6(3):161-4. [Medline].
• Sweeney WE, Chen Y, Nakanishi K, et al. Treatment of polycystic kidney disease with a novel tyrosine kinase inhibitor. Kidney Int. Jan 2000;57(1):33-40. [Medline].
• Sweeney WE, Avner ED. Molecular and cellular pathophysiology of autosomal recessive polycystic kidney disease (ARPKD). Cell and tissue research. 2006;1-15. [Medline].
• Torra R, Darnell A, Cleries M, et al. Polycystic kidney disease patients on renal replacement therapy: data from the Catalan Renal Registry. Contrib Nephrol. 1995;115:177-81. [Medline].
• Walker FC, Loney LC, Root ER, et al. Diagnostic evaluation of adult polycystic kidney disease in childhood. AJR Am J Roentgenol. Jun 1984;142(6):1273-7. [Medline].
• Ward CJ, Yuan D, Masyuk TV, et al. Cellular and subcellular localization of the ARPKD protein; fibrocystin is expressed on primary cilia. Hum Mol Genet. Oct 15 2003;12(20):2703-10. [Medline]. [Full Text].
• Yoder BK, Mulroy S, Eustace H, et al. Molecular pathogenesis of autosomal dominant polycystic kidney disease. Expert Rev Mol Med. 2006;8(2):1-22. [Medline].
• Zand MS, Strang J, Dumlao M, et al. Screening a living kidney donor for polycystic kidney disease using heavily T2-weighted MRI. Am J Kidney Dis. Mar 2001;37(3):612-9. [Medline].
• Zeier M, Geberth S, Ritz E, et al. Adult dominant polycystic kidney disease--clinical problems. Nephron. 1988;49(3):177-83. [Medline].
• Zerres K, Mucher G, Bachner L, et al. Mapping of the gene for autosomal recessive polycystic kidney disease (ARPKD) to chromosome 6p21-cen. Nat Genet. Jul 1994;7(3):429-32. [Medline].
• Zerres K, Weiss H, Bulla M, Roth B. Prenatal diagnosis of an early manifestation of autosomal dominant adult-type polycystic kidney disease. Lancet. Oct 30 1982;2(8305):988. [Medline].
• Zerres K, Hansmann M, Mallmann R, Gembruch U. Autosomal recessive polycystic kidney disease: problems of prenatal diagnosis. Prenatal Diagn. 1988;8:215-229. [Medline].
• Zerres K, Senderek J, Rudnik-Schoneborn S, et al. New options for prenatal diagnosis in autosomal recessive polycystic kidney disease by mutation analysis of the PKHD1 gene. Clinical Genetics. 2004;66:53-57. [Medline].
• de Chaderevian JP, Kaplan BS. Endocardial fibroelastosis, myocardial scarring and polycystic kidneys. Int J Pediatr Nephrol. 1981;2: 273-5.

Article Last Updated: Nov 13, 2006