Autosomal recessive polycystic kidney disease

Autosomal recessive polycystic kidney disease (ARPKD) affects about 1-in-20,000 live births and can be clinically very variable. It primarily affects the kidneys and liver and may result in severe in utero complications such as anhydramnios and pulmonary hypoplasia, kidney failure during infancy or childhood, and liver disease such as portal hypertension, cirrhosis and cholangitis. Most cases are diagnosed antenatally due to the presence of enlarged echogenic kidneys, but the diagnosis can be delayed until later childhood or even adulthood. The high early mortality of about 20% is typically due to pulmonary hypoplasia. The 10-year survival rate is over 80%.

Clinical features can be highly variable and determine the likely age of presentation.

In the antenatal and postnatal period (up to one year of age), the main findings are:

• oligohydramnios or anhydramnios;
• abdominal distention due to enlarged cystic kidneys;
• postnatal respiratory failure due to pulmonary hypoplasia;
• chronic kidney disease;
• hypertension;
• liver disease, including congenital hepatic fibrosis, hepatosplenomegaly, bile duct dilatation and cholangitis; and
• failure to thrive.

In patients presenting after one year of age, the kidney and hepatobiliary disease (including portal hypertension, splenomegaly, cirrhosis and varices) tends to be more prominent.

ARPKD is most commonly caused by biallelic pathogenic or likely pathogenic variants in PKHD1. The carrier frequency for variants in PKHD1 in the general population is about 1 in 70. ARPKD caused by biallelic variants in PKHD1 has many clinical similarities to other cystic kidney diseases or ciliopathies. Biallelic variants in DZIP1L and CYS1 can rarely cause an ARPKD phenotype.

• The diagnosis of ARPKD is made based on the typical clinical and radiological findings supported by genomic testing.
• Antenatally, ARPKD is suggested by enlarged hyperechogenic kidneys with poor corticomedullary differentiation. Cysts greater than 10mm in size are rare. Other congenital anomalies are absent. Diagnosis can be confirmed using invasive testing.
• Postnatal diagnosis is typically made using ultrasound to identify enlarged echogenic kidneys and liver disease, congenital hepatic fibrosis, portal hypertension and bile duct disease), with genomic testing for confirmation.

• ARPKD is an autosomal recessive condition that affects about 1-in-20,000 live births and has a carrier frequency of 1 in 70.
• If both parents are carriers of an autosomal recessive condition, with each pregnancy there is a:
  • 25% (1-in-4) chance of a child inheriting the pathogenic variant from each parent and therefore being affected by the condition;
  • 50% (1-in-2) chance of a child inheriting the pathogenic variant from one parent only, and therefore being a carrier, but unaffected themselves; and
  • 25% (1-in-4) chance of a child not inheriting the pathogenic variant from either parent, and therefore being neither affected nor a carrier.
• Genomic testing is offered to parents of a child with ARPKD to determine their carrier status and establish the chance of other children in the family – or future children – having the condition or being carriers themselves. Prenatal diagnosis and preimplantation genetic testing should be discussed with clinical genetics following referral from nephrology.

Management of individuals with ARPKD is complex and should be delivered via a multidisciplinary expert team familiar with the pulmonary, renal and hepatic complications of ARPKD.

National Registry of Rare Kidney Diseases (RaDaR)

Patients with a confirmed diagnosis of ARPKD should be registered on the National Registry of Rare Kidney Diseases (RaDaR).  RaDaR facilitates translational and epidemiological research into rare diseases through a comprehensive clinical database. It is managed by the UK Renal Registry on behalf of the UK Kidney Association. Recruitment is open to all UK hospitals.

• GeneReviews: Autosomal Recessive Polycystic Kidney Disease – PKHD1
• Genomics England: NHS Genomic Medicine Service (GMS) signed off panels resource
• NHS England: National Genomic Test Directory
• US National Library of Medicine StatPearls: Autosomal Recessive Polycystic Kidney Disease

For patients

• Kidney Care UK: Autosomal recessive polycystic kidney disease (ARPKD)
• PKD Charity