Introduction

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited disorder of the kidneys, affecting between 1 in 500 and 1 in 1000 people. It is characterised by the formation of renal cysts and extrarenal manifestations including hepatic cysts, intracranial aneurysms and aortic root dilatation.

Patients with ADPKD typically develop symptoms between the ages of 30 and 60, when the renal cysts are large enough to affect kidney function. Haematuria, loin pain and hypertension are the most common presenting symptoms.

Over 50% of patients with ADPKD will eventually develop end-stage renal disease (ESRD) requiring renal transplantation or dialysis.

Classification

ADPKD is divided into two types based on the genetic cause:
  • Type 1 ADPKD: 85% of cases
    • Caused by a mutation in PKD1 on chromosome 16
    • Symptoms tend to be more severe in this type
  • Type 2 ADPKD: 15% of cases
    • Caused by a mutation in PKD2 on chromosome 4
    • Symptoms tend to be less severe in this type

Epidemiology

  • Incidence: 2.50 cases per 100,000 person-years
  • Peak incidence: 30-40 years
  • Sex ratio: 1:1
<1 1-5 6+ 16+ 30+ 40+ 50+ 60+ 70+ 80+

Pathophysiology

ADPKD is caused by mutation in either PKD1 or PKD2. These genes code for the proteins polycystin 1 and 2, respectively. Polycystin 1 and 2 are membrane proteins, and dysfunction of these proteins results in aberrant cell signalling pathways. This results in disorganised cell growth and fluid secretion within the kidneys, causing fluid accumulation and the formation of renal cysts.

The consequences of renal cyst formation include:
  • Increased kidney volume
  • Compression of normal renal architecture
  • Interstitial fibrosis
  • Tubular atrophy
  • Progressive renal impairment

Clinical features

Patients with ADPKD may present either with symptoms, through screening due to a positive family history, or it may be identified incidentally after abdominal imaging.

Patients with ADPKD usually develop symptoms between the ages of 30 and 60. Whilst both types of ADPKD have the same symptoms, they often present earlier and are more severe in type 1 ADPKD.

Typically, patients with ADPKD present with:
  • Haematuria (65%): both microscopic and macroscopic haematuria are common
  • Loin pain (60%): chronic loin pain may be due to distension of the renal capsule, traction of the renal pedicle, and/or hepatic enlargement. Acute loin pain may be caused by kidney stones, cyst haemorrhage and/or infection.
  • Hypertension (60%)
  • Recurrent UTIs (50%)
  • Kidney stones (20%)
  • Headache (10%): this may be a sign of a ruptured berry aneurysm and subsequent subarachnoid haemorrhage

Signs on examination may include:
  • Palpable kidneys/abdominal mass
  • Hepatomegaly due to hepatic cysts
  • Abdominal wall hernias
    • These are more common in ADPKD, affecting 45% of patients
  • Cardiac murmur
    • This is due to an increased incidence of mitral valve prolapse, mitral regurgitation, aortic regurgitation and dilated aortic root in patients with ADPKD.

Symptoms of renal failure caused by ADPKD typically develop in the 5th decade of life and include:
  • Peripheral oedema
  • Shortness of breath
  • Poor appetite and weight loss
  • Polyuria
  • Pruritus
  • Nausea

Investigations

The first investigation when ADPKD is suspected is often a renal ultrasound scan. It is important to note that creatinine and therefore eGFR is often normal in the early stages and therefore it is not a sensitive test.

Renal ultrasound scan:
  • A renal ultrasound scan is the investigation of choice for patients with a positive family history. There are age-dependent ultrasound criteria for diagnosis known as Ravine's criteria:
    • 15-29 years: presence of 3 or more renal cysts (unilateral or bilateral), which has a sensitivity of 94.3% for type 1 ADPKD and 69.5% for type 2 ADPKD
    • 30-39 years: presence of 2 or more renal cysts (unilateral or bilateral), which has a sensitivity of 96.6% for type 1 ADPKD and 94.9% for type 2 ADPKD
    • 40-59 years: presence of 2 or more cysts in each kidney, which has a sensitivity of 92.6% for type 1 ADPKD and 88.8% for type 2 ADPKD
  • In patients with no family history, ultrasound criteria for diagnosis is >10 cysts in each kidney.

MRI/CT:
  • If renal ultrasound is equivocal, MRI or CT scan may be considered; >10 renal cysts is diagnostic.
  • An MRI scan of the head may be performed to identify intracranial berry aneurysms which occur in up to 40% of cases of ADPKD.

Genetic testing:
  • Genetic testing is not routinely performed for the diagnosis of ADPKD.
  • It may be used to assess potential living related kidney donors with equivocal or negative scan results.

Differential diagnosis

There are a number of conditions which may have similar symptoms to those in ADPKD and must be considered as important differential diagnoses. These include:
  • Autosomal recessive polycystic kidney disease (ARPKD)
    • Similarities: both cause multiple renal cysts with or without hepatic cysts
    • Differences: in ARPKD symptoms present soon after birth and there may be no family history
  • Acquired cystic kidney disease
    • Similarities: both cause renal cysts
    • Differences: acquired cystic kidney disease occurs in patients with pre-existing renal disease, and kidneys are usually smaller than those affected by ADPKD
  • Simple renal cysts
    • Similarities: both cause renal cysts
    • Differences: simple renal cysts do not meet Ravine‚Äôs criteria, they occur in the absence of a family history and are usually asymptomatic
  • Tuberous sclerosis
    • Similarities: both are autosomal dominant conditions which cause multiple renal cysts
    • Differences: tuberous sclerosis is characterised by the presence of other features such as facial angiofibromas, ash-leaf spots, Shagreen patches, subungual fibromas, giant cell astrocytomas and is associated with epilepsy
  • Von-Hippel-Lindau syndrome (VHL)
    • Similarities: both are genetic disorders that cause renal cysts
    • Differences: renal cell carcinoma is strongly associated with VHL but rare in ADPKD
  • Medullary cystic renal disease
    • Similarities: both are autosomal dominant conditions causing renal cysts
    • Differences: in medullary cystic renal disease the kidneys are often smaller than those affected by ADPKD, and recurrent gout is a common feature

Management

There is no cure for ADPKD, therefore treatment focuses on symptom control and management of complications.

In 2015 KDIGO (Kidney Disease: Improving Global Outcomes) published recommendations for the management of ADPKD.
  • Referral to a nephrologist: all patients newly diagnosed with ADPKD should be referred to a nephrologist
  • Blood pressure control: this should be achieved with antihypertensive medications and lifestyle modifications
  • Management of renal pain: underlying causes such as renal stones or cyst haemorrhage should first be excluded before starting analgesic medications
  • Treatment of UTIs:
    • This should be achieved using antibiotics according to culture and sensitivity results and local guidelines
    • A 7-14 day course of antibiotics is recommended
  • Treatment of kidney stones:
    • This is achieved with analgesia and appropriate surgical techniques depending on the composition and size of the stone

Management of ESRD:
  • Renal transplantation is the management of choice for ESRD caused by ADPKD; a living donor is preferable to a cadaveric donor
  • Dialysis is the second-line management of ESRD caused by ADPKD; haemodialysis is preferred to peritoneal dialysis in this group

Tolvaptan for select patient groups:
  • The 2015 NICE Guidelines recommend the use of tolvaptan to slow the progression of cyst formation and renal insufficiency in adults with ADPKD if:
    • They have chronic kidney disease stage 2 or 3 at the start of treatment
    • There is evidence of rapidly progressive disease
  • Tolvaptan is a vasopressin V2 receptor antagonist which has been shown to inhibit cyst growth and preserve kidney function
  • Common side effects of tolvaptan are thirst, polyuria and nocturia

Complications

ADPKD can lead to serious renal and extrarenal complications.

Hepatic cysts
  • 75% of patients with ADPKD have hepatic cysts by the age of 60
  • The majority of hepatic cysts are asymptomatic and do not require treatment
  • Some patients may experience heartburn, nausea, early satiety and an increased abdominal circumference due to hepatomegaly caused by hepatic cysts

Cardiovascular disease
  • Approximately 60% of patients with ADPKD have hypertension which increases the risk of coronary heart disease, stroke and myocardial infarction
  • Mitral valve prolapse, mitral regurgitation, aortic regurgitation and dilated aortic root are also associated with ADPKD

Intracranial aneurysms and subarachnoid haemorrhage
  • Intracranial berry aneurysms can be found in 6% of patients with ADPKD without a family history of brain aneurysms
  • In patients with ADPKD with a family history of brain aneurysms, up to 16% have intracranial berry aneurysms
  • Due to the increased incidence of berry aneurysms in ADPKD, the risk of subarachnoid haemorrhage is increased
  • Subarachnoid haemorrhages cause substantial morbidity and mortality
  • Patients with ADPKD and a family history of subarachnoid haemorrhages are offered a magnetic resonance angiography (MRA) scan at intervals of 1 to 5 years to screen for intracranial aneurysms
  • If aneurysms are detected they may be treated surgically using a clip or coil to prevent rupture

Complications during pregnancy
  • The incidence of gestational hypertension and preeclampsia is higher in women with ADPKD
  • Hypertension during pregnancy increases the risk of adverse fetal and maternal outcomes

End-stage renal disease
  • ADPKD accounts for 4-10% of all cases of ESRD
  • Management involves renal transplantation or dialysis

Prognosis

Over 50% of patients with ADPKD develop ESRD requiring dialysis or renal transplantation.

Factors indicating a poorer prognosis are:
  • Earlier age at diagnosis
  • Male sex
  • Type 1 ADPKD (mutation in PKD1)
  • Rapidly increasing kidney size
  • Hypertension

Cardiovascular disease is the most common cause of death in patients with ADPKD.

Screening and prevention

Screening adults with a positive family history of ADPKD
  • Screening should be offered to asymptomatic adults with a positive family history of ADPKD
  • Screening is most commonly performed using an abdominal ultrasound, but occasionally MRI or CT may be used
  • Although there is no proven treatment to prevent ADPKD developing, screening can help identify hypertension earlier and therefore reduce the risk of cardiovascular disease
Screening children with a positive family history of ADPKD
  • Asymptomatic children with a positive family history of ADPKD may be screened at any age, however, false negative results are higher as imaging may miss small cysts in younger people
  • For this reason, children with a positive family history of ADPKD tend not to be screened unless they are symptomatic
  • This means that children often require additional screening scan/s in adulthood