Autosomal Recessive Polycystic Kidney Disease

Synonyms: Infantile polycystic kidneys, polycystic kidney and hepatic disease type I, PKD3

This is an autosomal recessive disorder due to mutation of the number 6 chromosome at gene map locus 6p21.1-p12.¹

• A paper from Madrid estimated a prevalence of 10.3 per 100,000 births and calculated a carrier frequency of 1 in 49.²
• Others suggest a gene frequency of 1 in 70, giving a prevalence of 5 in 100,000 births.³

• Both kidneys are enlarged and contain large number of cysts throughout the organ. These are formed by dilated parts of the collecting ducts.
• It is said that the liver is invariably involved but to a lesser extent, with bile duct ectasia, sometimes called Caroli disease.
• Generally, the later the manifestation of the renal disease, the more marked is the liver disease.

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 renal failure.
Severe cases of liver disease may progress to cirrhosis with portal hypertension and oesophageal varices. The renal and hepatic disease tend to show opposite degrees of severity.

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:⁴

• Category 1 is the perinatal form.
  • They are born with a very large abdomen as the kidneys are so big and this may complicate delivery. About 90% of the collecting ducts are dilated but the liver is scarcely involved.
  • Severe renal inadequacy has produced oligohydramnios and subsequent pulmonary hypoplasia. Other clinical findings resulting from oligohydramnios include Potter's face and club foot. Potter's face has a flattened nose, micrognathia and large, floppy, low-set ears in most or all.
  • Most babies do not live longer than a week. Approximately 75% of all cases are this severe.
• Category 2 is the neonatal form.
  • They 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. Progressive renal failure is the salient feature, causing death within a few months.
• Category 3 is the infantile form.
  • This tends to present when a few months old.
  • Approximately 25% of renal collecting ducts are dilated, with moderate hepatic periportal fibrosis. There are large kidneys and hepatosplenomegaly.
  • They often develop chronic renal failure with or without portal and systemic hypertension.
  • The principle cause of mortality is end-stage renal failure, usually in adolescence.
• Category 4 is the juvenile form.
  • There is marked liver disease.
  • Less than 10% have any renal failure or the disease is mild.
  • It may present from 6 months to 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 4 categories, with around 80% surviving beyond the age of 15 years.

An important feature of this condition is that it is bilateral, whilst other conditions are normally unilateral.

• Multicystic dysplasia
• Bardet-Biedl syndrome⁵
• Meckel-Gruber syndrome
• Hydronephrosis
• Wilm's tumour
• Renal vein thrombosis

• Ultrasound may not be very effective at detecting the disease in early intrauterine life, but it may show the cause of an enlarged abdomen in later intrauterine life.
  • It is the diagnostic tool of choice in the perinatal period.
  • Pre-natal diagnosis is unlikely before the second half of pregnancy unless there are strong reasons to suspect the condition, such as an affected older child.
• In older children CT and MRI may be used to monitor liver disease.
  • Magnetic resonance cholangiography is the best tool to assess the liver.⁶
  • CT may also show renal calcification that is missed on plain film.
• Plain x-ray may show large kidneys and even medial displacement of the bowel.
  • Enlarged liver or spleen may be visible.
  • In Potter's syndrome a CXR may show hypoplastic lungs with pneumothorax and elevated diaphragm.
• Intravenous urography may be used in the older child but the contrast material is nephrotoxic in renal inadequacy.

Blood and urine investigations are useful in evaluating and monitoring patients with ARPKD, but none are diagnostic. Although normal initially, liver function tests are often abnormal in the later stages of the disease

• There may be suspicion if there is a family history of the disease but ultrasound, even in the second trimester, is unreliable in many cases.⁷
• 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.⁸
• When counselling parents it is important to stress the unreliability of diagnostic tests in this highly variable condition.⁹

Survival of neonates depends on the degree of pulmonary hypoplasia and the skill of the neonatal intensive care unit.

• Very large kidneys may press on the diaphragm and impede ventilation.
  • To facilitate ventilation nephrectomy may be necessary.¹⁰
  • Fluid overload can be managed with diuretics, and continuous renal replacement therapy.
• Hypertension should be aggressively treated with ACE inhibitors.¹¹
• Urinary tract infections will require antibiotics.
• Development of chronic kidney disease will require:
  • Treatment of anaemia with iron and erythropoietin
  • Prevention of metabolic bone disease with calcium supplements, phosphate binders, and parathyroid-suppressing medication
  • Growth hormone to counter the growth-limiting effects of uraemia
• End-stage renal disease requires dialysis or transplantation.

Hepatic complications will also need to be dealt with.

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

• There is a high mortality rate in the first month of life while the clinical spectrum of surviving patients is much more variable.¹²
• If the neonatal period is survived, the prognosis is much better but there must be attention not just to renal function but to the management of systemic and portal hypertension.
• Disease progression may have organ-specific patterns.
• Only a subset of patients may be at risk for developing clinically significant manifestations of periportal fibrosis.¹²

The first study reporting the long-term outcome of ARPKD patients with defined PKHD1 mutations found that:

• The 1- and 10-year survival rates were 85% and 82% respectively.
• Chronic renal failure was first detected at a mean age of 4 years.
• Renal survival rates, where the end point is defined as start of dialysis/renal transplantation or by death due to end-stage renal disease, were 86% at 5 years, 71% at 10 years, and 42% at 20 years.¹³

Those that survive to adulthood still see progressive deterioration of renal function and risk of hepatic complications.¹⁴