Autosomal recessive polycystic kidney disease

Synonyms: infantile polycystic kidneys, polycystic kidney and hepatic disease type I

Autosomal recessive polycystic kidney disease (ARPKD) is one of the most common ciliopathies with kidney (nephromegaly, hypertension, renal dysfunction) and liver involvement (congenital hepatic fibrosis, dilated bile ducts). Pulmonary hypoplasia may also occur. Clinical features also include growth failure and neurocognitive impairment.¹

Both autosomal recessive polycystic kidney disease (ARPKD) and autosomal dominant polycystic kidney disease (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.

ARPKD is the most common genetic cystic renal disease occurring in infancy and childhood. However, it is nonetheless a rare disorder and is much less common than ADPKD. It is an autosomal recessive disorder due to mutation of the number 6 chromosome at gene map locus 6p21.1-p12, a gene encoding fibrocystin.²

Mutations in DZIP1L have been identified in a small number of individuals with moderate ARPKD.³

A single gene defect leads to differing degrees of renal and hepatic involvement, with very different phenotypes and clinical outcome within even one affected family.⁴ Kidneys are bilaterally enlarged and contain large numbers of cysts throughout the organ, due to the dilatation and elongation of renal collecting ducts. At birth, the interstitium and the rest of the tubules are normal but they may later develop interstitial fibrosis and tubular atrophy that can cause end-stage kidney disease. There may be hepatic as well as renal involvement:

• Hepatic involvement with bile duct ectasia is sometimes called Caroli's disease.

• Generally, the later the manifestation of the renal disease, the more marked the liver disease. The renal and hepatic disease tend to show opposite degrees of severity

• Severe cases of liver disease may progress to cirrhosis with portal hypertension and oesophageal varices.

How common is autosomal recessive polycystic kidney disease? (Epidemiology)

Studies suggest a prevalence of between 5-10 in 100,000 births (with carrier frequency of between 1 in 50-70).⁵

Autosomal recessive polycystic kidney disease symptoms (presentation)

The presentation of the disease can be highly variable, even within the same family. There are a number of classifications but this is the one that is used most often and is based on age at presentation which is, in turn, related to disease severity:⁵

• Category 1 presents perinatally:
  

  • Infants are born with a very large abdomen due to massive renal enlargement and this may complicate delivery. About 90% of the collecting ducts are dilated but the liver is scarcely involved.

  • Severe renal impairment in utero produces oligohydramnios and subsequent pulmonary hypoplasia. Other clinical findings resulting from oligohydramnios include Potter's facies (flattened nose, micrognathia and large, floppy, low-set ears) and club foot.

  • Approximately 75% of cases result in the death of the baby within a week of birth.

• Category 2 presents neonatally:
  

  • Infants have palpable kidneys at birth.

  • About 60% of the kidney is affected and there is mild liver disease.

  • As renal impairment is often less severe in utero there is less risk of pulmonary hypoplasia but the kidney disease is progressive, usually causing death within a few months.

• Category 3 presents in infancy:
  

  • This tends to present when babies are a few months old.

  • Approximately 25% of renal collecting ducts are dilated, with moderate hepatic periportal fibrosis.

  • There are enlarged kidneys and hepatosplenomegaly on examination.

  • Affected babies and children often develop chronic kidney disease with or without portal and systemic hypertension.

  • The principal cause of mortality is end-stage kidney disease, usually in adolescence.

• Category 4 presents in childhood:
  

  • There is marked liver disease.

  • Fewer than 10% develop end-stage kidney disease.

  • The disease usually presents between 6 months and 5 years.

  • There is variable renal enlargement and hepatosplenomegaly.

  • Significant liver involvement results in portal hypertension.

  • Morbidity and mortality are usually due to portal hypertension, including variceal bleeding and thrombocytopenia or anaemia from hypersplenism.

  • Mortality is the lowest of the four categories, with around 80% surviving beyond the age of 15 years.

Moderate presentation is seen rarely in adults with complications of liver disease or with renal manifestations, such as proteinuria, nephrolithiasis and renal insufficiency.⁶

Differential diagnosis

Distinguish from other causes of renal and hepatic cystic disease and other conditions causing enlargement of the kidneys:

• ADPKD.

• Multicystic dysplasia.

• Bardet-Biedl syndrome (a ciliopathy causing multivisceral abnormalities, including polycystic kidneys).⁷

• Meckel-Gruber syndrome.

• Hydronephrosis.

• Wilms' tumour.

• Renal vein thrombosis.

Investigations⁸

• Ultrasound:
  

  • It is the imaging tool of choice in the perinatal period. With the increased use of routine scanning, approximately 50% of cases are now diagnosed prenatally. Large kidneys may appear 'bright' from about 13 weeks and, between 20-30 weeks, oligohydramnios may be detectable.

  • Prenatal diagnosis is unlikely before the second half of pregnancy unless there are strong reasons to suspect the condition, such as an affected older child. Early ultrasound is not very reliable at detecting the condition.

• In older children, CT and MRI scanning may be used to monitor liver disease:
  

  • Magnetic resonance cholangiography to assess the liver.

  • CT scanning may also show renal calcification that is missed on plain film.

• Plain X-ray:
  

  • Large kidneys and even medial displacement of the bowel are usually visible on AXR.

  • Enlarged liver or spleen may also be seen.

  • In Potter's syndrome, a CXR may show hypoplastic lungs with pneumothorax and elevated diaphragm.

• Intravenous urography:
  

  • This may be used in the older child but the contrast material is nephrotoxic in renal inadequacy.

• Blood and urine investigations:
  

  • These are useful in evaluating and monitoring patients with ARPKD but none is diagnostic. Although normal initially, LFTs are often abnormal in the later stages of the disease.

• Genetic testing in ARPKD:⁹
  

  • • This can be performed using linkage analysis where the patient's family has at least one diagnosed index case. Where this is not possible, direct genetic testing is improving.

  • The suspicion of a diagnosis is based on clinical findings in the proband and the absence of renal disease in the proband's biological parents.

  • Identification of biallelic pathogenic variants in PKHD1 in the affected individual establishes the diagnosis.

Prenatal and pre-implantation diagnosis

• There may be suspicion if there is a family history of the disease but ultrasound, even into the second trimester, is unreliable in many cases.

• Late suspicion may arise from clinical detection of oligohydramnios or noting a large abdomen on routine late scan.

• Where ultrasound is uncertain, MRI can be a useful adjunct.

• When counselling parents, it is important to stress that diagnostic tests are unreliable in this highly variable condition.

Typically genetic testing for prenatal diagnosis is only offered to families with a known risk of ARPKD as the procedure requires chorionic villus sampling or amniocentesis which are invasive. Another option, especially for couples with particularly high recurrence risk, is preimplantation genetic diagnosis.¹⁰

Autosomal recessive polycystic kidney disease treatment and management⁹

Management will depend on clinical severity, but may include:

• Stabilisation of respiratory function by mechanical ventilation.

• Rarely, unilateral or bilateral nephrectomy if massive kidney enlargement impairs movement of the diaphragm.

• Neonates with oliguria or anuria may require peritoneal dialysis within the first days of life. Early recognition and treatment of dehydration and hypertension is critical.

• Management of chronic kidney disease.

• Treatment of biliary dysfunction focuses on malabsorption of nutrients and fat-soluble vitamins and early recognition and treatment of ascending cholangitis. Treatment includes synthetic bile acids.

• In those with progressive portal hypertension, endoscopy with sclerotherapy or banding of varices may be required. Portosystemic shunting and/or consideration of liver transplantation may also be needed.

• Those with end-stage renal disease and severe portal hypertension may be candidates for dual renal/liver transplantation.

Prevention of complications

• Ursodiol treatment may increase the amount of bile acid and/or reduce the development of gallstones.

• Immunisation against encapsulated bacteria in those with severe portal hypertension and splenic dysfunction is recommended.

• Palivizumab (Synagis®) for children younger than age 24 months with chronic lung disease and/or prematurity is recommended.

• Prophylaxis with antibiotics is recommended for those at high risk of developing ascending cholangitis.

Monitoring

• Regular monitoring of blood pressure, renal function, serum electrolyte concentrations, hydration, nutrition, and growth.

• Hepatobiliary dysfunction leading to portal hypertension is monitored by physical examination evaluating for hepatosplenomegaly, regular platelet count, in addition to serum albumin levels, clotting studies, and 25-OH vitamin D, vitamin E levels, and fat-soluble vitamin levels.

• Periodic ultrasound and referral to a hepatologist if hepatomegaly and/or splenomegaly develops.

• Periodic endoscopy to detect oesophageal varices.

• Consideration of MR cholangiography, a more sensitive measurement for biliary ectasia, at baseline and then as indicated.

Evaluation of relatives

• Genetic testing and genetic counselling.

• If the pathogenic variants in the family are not known, high-resolution renal and hepatic ultrasound and monitoring of blood pressure may identify disease in siblings of a proband.

Complications

Apart from complications resulting from renal and liver disease as outlined above, intracranial aneurysms have been reported.¹¹

Prognosis

• ARPKD shows a range of severity, with 30% of individuals dying early and the majority having good prognosis if they survive the first year of life.³

• However, those who survive to adulthood still see progressive deterioration of renal function and risk of hepatic complications.

• Disease progression may have organ-specific patterns.

• In those with pulmonary hypoplasia the outlook is very poor and even ventilation is unlikely to save lives.

• Only a subset of patients may be at risk for developing clinically significant manifestations of periportal fibrosis.¹²