Polycystic kidney disease

Adult autosomal dominant polycystic kidney disease is the most common renal hereditary disorder, and referring family members for genetic counselling is recommended, explains Dr Linda Miller.

Polycystic kidneys: tissue has been replaced by cysts (dark brown)
Polycystic kidneys: tissue has been replaced by cysts (dark brown)

Mr G came to the surgery with his three-year-old daughter. He explained that his 30-year-old wife had been killed in a car accident and a post-mortem had revealed that his wife had polycystic kidneys.

He had not been told much about it except that it could be hereditary and he was worried that his daughter had it. The pregnancy had been normal and uneventful.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disorder, affecting about one in 800 people in the UK.

As it is autosomal dominant, in families with one affected parent the risk of a child inheriting is 50 per cent. It is often asymptomatic up to the age of 30-50 years, although children can develop symptoms. The variation in disease progression rate is determined by both genetic and environmental factors.

Aetiology
Two genes have been identified which cause the condition by transmitting a cell wall defect.

Type 1 ADPKD is more common affecting 85 per cent of ADPKD cases, and is more serious. The milder type 2 affects approximately 15 per cent of cases. There is the possibility that there may be a third genotype. The recognised genes are on chromosomes 16 and 4. They code for the proteins polycystin 1 and 2.

In some cases there is no family history and a spontaneous mutation has arisen (non-hereditary polycystic kidney disease).

The less common autosomal recessive ARPKD presents early in neonates or childhood and affects one in 20,000. The gene is on chromosome 6. A child with both parents as carriers has a 25 per cent chance of inheriting the condition.

Symptoms and complications
Around 50 per cent of people with ADPKD develop hypertension in their twenties or thirties but this may go undetected.

As time passes, multiple cysts develop, exerting pressure on normal renal parenchyma so renal function gradually deteriorates. Renal failure develops between the ages of 40 and 60, with 50 per cent having renal failure by 60 years and 60-70 per cent by 70 years. Patients may present with stage 4 or 5 renal failure with uraemia and end stage renal failure.

Symptoms include fatigue, pruritus, nausea, cramps and oedema. The anaemia normally associated with chronic kidney disease may not be present because cysts cause an increased level of erythropoietin. Large cysts can develop which cause abdominal distension or loin pain. Cysts can bleed causing intermittent haematuria.

Renal calculi and pyelonephritis are more common in ADPKD. Examination may reveal renal enlargement and proteinuria or haematuria. ADPKD causes an increased risk of pre-eclampsia, but many pregnancies are normal.

Comorbidities
The genetically inherited cell wall defect can affect other tissues and organs. There is an association with hepatic cysts, which are more common in women, possibly because of hormonal factors.

These are usually asymptomatic unless they become large and exert pressure. There is a predisposition to herniae and diverticulitis and cysts of the seminal vesicles and pancreas. There may be arachnoid membrane cysts and there is an increased risk of cerebral aneurysms before 50 years and a family history of aneurysm.

Approximately 25 per cent of those with ADPKD have mitral valve prolapse with mitral regurgitation. There is also an association with hereditary ciliopathies and congenital hepatic fibrosis.

Genetic counselling and screening
Screening siblings and children of those with ADPKD can help because attention to BP monitoring and treatment and addressing other factors relevant to cardiovascular risk helps maintain renal function.

Genetic counselling is important for family planning. A DNA analysis test can be done in pregnancy.

Annual ultrasound is offered from late childhood and if scans are negative at age 30 diagnosis of ADPKD is unlikely. A genetic test will be offered to a younger relative if they are potentially a kidney donor.

Mr G was worried about the impact of a possible illness hanging over his daughter as she grew up. He wondered if it would be better not to know, but could see the benefits of monitoring for affected individuals.

Reviewing the incidences, we discussed that one in three people with ADPKD do get to the age of 70 without renal failure. He accepted a referral for genetic counselling and agreed to return for follow up.

  • Dr Miller is a freelance GP in west London
Key Points
  • Refer family members for genetic counselling.
  • Consider renal ultrasound in those with associated problems such as testicular, hepatic or pancreatic cysts or family history of subarachnoid haemorrhage.
  • Consider renal ultrasound for people with recurrent UTIs.
  • In those with ADPKD, monitor eGFR, BP, urine and ultrasound annually.
  • Advise avoiding contact sports, which could result in cyst rupture.
  • Offer lifestyle advice relevant to increased CVD risk.
  • Avoid NSAIDs and other nephrotoxic drugs.
  • Offer influenza and pneumococcal immunisation (CKD 3 or above).

References
1. Ong ACM and Wheatley DW. Polycystic cystic kidney disease - the ciliary connection. Lancet 2003; 361(9359): 774-6.

2. Torres.VE, Harris PC & Pirson Y. Autosomal dominant polycystic kidney disease. Lancet 2007; 369 (9569): 1287-301.

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