Autosomal dominant polycystic kidney disease

Synonym: autosomal dominant polycystic kidney disease

What is autosomal dominant polycystic kidney disease (ADPKD)?

This is the most common inherited cause of serious renal disease and is caused by a gene mutation affecting polycystins. Polycystins regulate tubular and vascular development in the kidneys but also in other organs including the liver, brain, arterial blood vessels, and pancreas, causing extra-renal manifestations of the disease.

Who gets autosomal dominant polycystic kidney disease? (Epidemiology)¹

• Approximately 12.5 million individuals are affected in the world and they account for around 10% of patients with end-stage kidney disease (ESKD).

• Between 6 and 9 people per million of the population have ESKD due to ADPKD.

• Sex incidence is equal although males may be slightly more seriously affected.

Transmission of autosomal dominant polycystic kidney disease¹

• ADPKD is transmitted genetically.

• It is an autosomal dominant condition and is thought to be of high or complete penetrance.

• The defect is commonly on chromosome 16 (PKD1, 85% of all ADPKD) or 4 (PKD2, 15% of all ADPKD), with some gene defects probably yet to be discovered²³⁴

• 10 -15% of patients with ADPKD have no family history of the disease, leading to the assumption that there is a significant rate of de novo mutations, although in some cases this may be due to ancestors with ADPKD having gone undiagnosed.⁵

• As with other autosomal dominant diseases:

  • If one parent has the disease there is a 50% chance of transmission to offspring.

  • If both parents have the disease as heterozygotes, there is a 50% chance that the fetus will carry the disease in a heterozygous manner, a 25% chance of normality but a 25% chance of being a homozygote for the disease.

Autosomal dominant polycystic kidney disease symptoms ¹

Most individuals present with complications of autosomal dominant polycystic kidney disease, as symptoms may not present until the 30s or later. However, increasing numbers are being detected by screening individuals who have an affected relative.

Symptomatic patients may present with:

• Haematuria (visible or non-visible).

• Loin pain (the commonest symptom). Loin pain may be due to the condition itself, including cyst haemorrhage, infection, torsion or rupture, or due to associated renal stones.

• Recurrent urinary tract infections, both upper and lower.

• Mass effects from enlarged kidneys, including dyspnoea, early satiety, gastro-oesophageal reflux, low back pain, ascites, oesophageal varices, and obstructive jaundice.

Examination may find an abdominal mass which may represent enlarged kidneys or related hepato- or spleno-megaly.

Complications include:

• Hypertension (sometimes presenting in childhood), with associated left ventricular hypertrophy.

• Renal stones (twice as common as in the general population) and early renal failure.

• Male infertility, which is a rare complication but can be due to cysts in the seminal vesicles and defective sperm motility.

• Recurrent pancreatitis due to pancreatic cysts.

• Intracranial haemorrhage due to arachnoid membrane cysts or berry aneurysms. A ruptured cerebral aneurysm is four times more likely in someone with ADPKD compared to the general population and increases further if there is a personal or family history of cerebral aneurysm or subarachnoid haemorrhage. It is also more common with increasing age and in women than in men and tends to occur at a lower age than in the general population.

• Cardiac complications including cardiomyopathy,⁶ mitral valve prolapse and aortic regurgitation.

• Diverticulosis, present in up to 50% of those with ADPKD.

• Renal cell carcinoma is no more common than in the general population but tends to present at an earlier age.

• Abdominal hernias.

Autosomal dominant polycystic kidney disease screening⁷

ADPKD commences in utero but there may be several decades before symptoms or signs of disease emerge. Screening offers a means of detecting asymptomatic individuals. There should be appropriate counselling prior to screening.

Benefits of screening include:

• Family planning and reproductive choice, particularly with the advent of preimplantation genetic testing.

• Early detection and treatment of disease complications.

• Selection of unaffected family members for living donor transplantation.

Risks of testing include:

• Possible discrimination in terms of insurance and employment.

• Psychological effects of living with a disease without effective treatment, although with the advent of new.

Screening of asymptomatic children is not currently advocated, as the removal of their choice to know and possible adverse effects of the diagnosis are thought to outweigh benefits. However, this is controversial and many argue for earlier screening with more reliable ultrasound scanning and likely benefits of early detection of hypertension.

Screening may be done using ultrasound, CT, or MRI, to look for the characteristic renal cysts, or with genetic testing. Decisions on screening and genetic counselling would always be made in secondary care. The consultant of a patient with ADPKD may write to the GP to ask them to refer certain relatives for a discussion about screening.

Differential diagnosis¹

The differential diagnosis includes the following:

• Acquired and simple cysts of the kidney.

• Autosomal recessive polycystic kidney disease (formerly called polycystic kidney disease of childhood).

• Medullary sponge kidney.

• Tuberous sclerosis.

• Von Hippel-Lindau syndrome.

• Bardet-Biedl syndrome

Autosomal dominant polycystic kidney disease treatment and management^{7 8}

General

• Advice against participating in contact sports which risk abdominal trauma, such as rugby or boxing, as this can provoke haematuria or even cause the rupture of an enlarged kidney.

• Lifestyle advice regarding avoiding smoking, maintenance of a healthy body weight, diet (eg, limiting salt intake), and regular exercise (ideally of a low-impact nature, such as swimming or walking). This is because much of the morbidity and mortality of ADPKD is due to CVD.

Primary care

• Early detection and management of hypertension - ambulatory blood pressure monitoring in young adults or children can reveal raised blood pressure not detected with the one-off blood pressure reading.

• Treatment of urinary tract infections when they occur.

• Being aware of possible complications such as renal colic and for the need to treat this with significant analgesia or referral if there are risks such as infection.

• Ideally, the avoidance of anticoagulants in patients with ongoing haematuria, though the balance of risk and benefits may vary and a discussion between primary and secondary care may be useful.

• Avoidance of nephrotoxic drugs such as non-steroidal anti-inflammatory drugs (NSAIDs).

• Contraceptive considerations; oestrogen may increase the growth of hepatic cysts, so a copper or levonorgestrel intrauterine device or a progestogen only method may be a better choice for this cohort than combined hormonal contraception.⁹

• Management of the menopause - oestrogen may increase cyst size, but this should be balanced against the benefits of hormone replacement therapy on menopausal symptoms, in a cohort who may already have significant cysts and be on the journey to renal transplantation by this age. If in doubt, discuss with the woman's specialist and/or a menopause specialist.

• Referral for obstetrician led care (in conjunction with a renal specialist) if a woman becomes pregnant. Those with pre-conceptual hypertension or renal insufficiency are at higher risk of severe hypertension or pre-eclampsia. Normotensive women generally have uncomplicated pregnancies.

Secondary care

• Tolvaptan, a vasopressin receptor antagonist which has been shown to slow the growth of cystic kidneys and the deterioration of renal function. It is approved by NICE for patients with chronic kidney disease (CKD) 2 or 3 at the start of treatment, who have evidence of rapidly progressing disease.¹⁰

• Annual blood tests and imaging to monitor progression.

• Possible involvement of the pain clinic for chronic unrelenting pain caused by large cysts; a surgical approach to these is also sometimes taken.

• Dialysis or renal transplantation if ESKD occurs. Renal transplantation has similar outcomes for patients with ADPKD as for those without the disease. It is very important to exclude affected relatives as living donors (usually with MRI +/- gene testing).

Autosomal dominant polycystic kidney disease prognosis¹¹

There is great inter-familial and intra-familial variability in the severity of renal and extra-renal manifestations; however:

• 50 - 75% of those with ADPKD will develop ESKD by the age of 70, with 25% having reached this point by the age of 47 in one study.

• Risk factors for progression include:

  • PKD1 genotype.

  • Multiple pregnancies.

  • Afro-Caribbean race.

  • Male sex.

  • Younger age of onset.

  • Large kidneys.

  • Hypertension.

  • Biomarkers which correlate with progression include increased urinary sodium secretion and urine osmolality, and lower HDL-C.