Polycystic kidney disease

Synonym: autosomal dominant polycystic kidney disease

What is polycystic kidney disease?

This is the most common inherited cause of serious renal disease. It is an autosomal dominant condition and is thought to be of high or complete penetrance.

There are three recognised forms of autosomal dominant polycystic kidney disease (ADPKD):

• About 85% are designated as PKD1 with an abnormality on chromosome 16¹ .

• 15% are PKD2 with an abnormality on chromosome 4² .

• A PKD3 has also been described³ . However, the gene locus is not yet identified.

PKD1 and PKD2 cause mutations in polycystin 1 and 2 respectively. 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 polycystic kidney disease? (Epidemiology)

• Clinical registry data show prevalence rates of diagnosed cases ranging from 1 in 543 to 1 in 4,000. Approximately 4-7 million individuals are affected in the world and account for 7% to 15% of patients on renal replacement therapy⁴ .

• It accounts for about 10% of people on dialysis. Annual incidence rates of end-stage kidney disease (ESKD) caused by ADPKD are between 6-8 per million per year in Europe⁵ .

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

• There is no racial predilection.

Transmission of polycystic kidney disease⁶

• Familial transmission is normal for polycystic kidney disease; de novo mutation occurs in only about 5% of cases, although at the time of diagnosis (before familial case finding) 25% will not know of a family history of the disease.

• 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 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. Homozygotes are thought to die in utero⁷ .

Polycystic kidney disease symptoms⁸

Most individuals present with complications of polycystic kidney disease. However, increasing numbers are being detected by screening individuals who have an affected relative.

Complications associated with renal disease

• Impaired urine concentrating capacity is a common early presentation with problems associated with excessive water and salt loss such as nocturia.

• Loin pain is the most common symptom, reported by about 60% of affected adults. It can be caused by renal haemorrhage, stones and urinary tract infections (UTIs). However, chronic loin pain, without an obvious identifiable cause beyond the cysts themselves, develops in a proportion of patients.

• Hypertension is a common presenting feature. 10-15% of affected children are hypertensive, and 50% of affected adults have normal renal function. Hypertension is associated with left ventricular hypertrophy.

• Bilateral kidney enlargement - abdominal examination may reveal enlarged and palpable kidneys. (If other organs are cystic there may be palpable hepatomegaly and even splenomegaly.)

• Gross haematuria following trauma is a classic presenting feature of ADPKD. It occurs in 30-50%. Renal colic due to clots in the collecting system can be severe. Usually the bleeding is quite brief, reverting to microscopic levels in a few days.

• UTI and pyelonephritis may be presenting features.

• Renal stones are twice as common as in the general population. Uric acid stones are more common than calcium oxalate stones.

• Patients sometimes present with kidney failure, usually in the fourth to sixth decade of life.
  

Extra-renal manifestations

• Most polycystic liver disease is asymptomatic. Cysts develop in 80% and tend to be larger in women. Symptoms tend to result from mass effect (eg, dyspnoea, early satiety, gastro-oesophageal reflux, low back pain, ascites, oesophageal varices, obstructive jaundice) or from cyst complications (eg, haemorrhage, infection, torsion or rupture).

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

• Pancreatic cysts can, rarely, cause recurrent pancreatitis.

• Arachnoid membrane cysts are asymptomatic but increase the risk of subdural haematomas.

• Intracranial (berry) aneurysms occur in 6% of patients with a negative family history of aneurysms and 16% of those with a positive family history. They may cause cranial nerve palsies or seizures and have a risk of severe morbidity or mortality (35-55%) if they rupture. Mean age of rupture is lower than in the general population (39 years vs 51 years) and may not be associated with abnormal renal function or blood pressure.

• Aneurysms can also occur elsewhere in the vascular tree (eg, thoracic aorta, cervicocephalic artery, coronary artery) and may cause dissections.

• Cardiac abnormalities are also reasonably common: cardiomyopathy⁹ , mitral valve prolapse is found in up to 25%¹⁰ and aortic insufficiency can occur with aortic root dilatation.

Polycystic kidney disease screening¹¹

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 testing include:

• Family planning and reproductive choice.

• 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.

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.

Investigations

• Urine:
  

  • Urinalysis - check for infection, protein (microalbuminuria occurs in about a third but heavy proteinuria is rare) and haematuria.

  • Urine MC&S - coliforms are the most usual pathogen.

• Blood:
  

  • FBC (polycystic kidneys can produce excess erythropoietin and hence raise Hb).

  • U&E, creatinine, eGFR.

  • Bone profile.

Imaging

This is used to establish the diagnosis and to monitor disease progression. Ultrasound can detect cysts in the kidneys from 1-1.5 cm in diameter. Sensitivity for PKD1 is 100% over the age of 20 but false negatives can occur below this age¹² . It is also possible to scan other organs like the liver or pancreas for cysts.

Individuals at risk (positive family history) are diagnosed on the following criteria¹⁰ :

• At least two unilateral or bilateral renal cysts at age <30 years.

• At least two cysts in each kidney between the ages of 30-59 years.

• At least four cysts in each kidney at age >60 years.

The diagnosis is supported by hepatic or pancreatic cysts. These criteria approach 100% sensitivity for individuals aged 30 years or more and for younger patients with PKD1 mutations. However, they are only 67% sensitive for those with PKD2 mutations who are younger than 30.

For individuals without a family history, diagnosis requires:

• Bilateral renal enlargement and cysts, or the presence of multiple bilateral renal cysts and hepatic cysts.

• No manifestations suggesting an alternative renal cystic disease.

CT is more sensitive in that it can detect cysts down to 0.5 cm in diameter but the dose of radiation is quite high. MRI is an equally sensitive alternative.

Genetic testing

Genetic testing can be done by linkage or sequence analysis:

• Linkage analysis requires accurate diagnosis and availability of sufficient affected family members to be tested and so is suitable in fewer than 50% of cases.

• Sequence analysis is limited, as ADPKD can be caused by hundreds of different PKD1 and PKD2 mutations and current testing can only identify about 70% of known mutations.

• Genetic testing can be used to assist diagnosis when imaging results are equivocal or when a definite diagnosis is required in a younger individual - eg, prior to becoming a potential living related kidney donor.

• Prenatal and pre-implantation testing are possible (within the limitations discussed above)¹³ .

Differential diagnosis¹⁰

• Acquired and simple cysts of the kidney.

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

• Medullary sponge kidney.

• Tuberous sclerosis.

Polycystic kidney disease treatment and management^{11 14}

General

Diagnosis of ADPKD has implications both for the patient and for their family.

• Consider the information needs of the patient and their family members. Provide written information and sources of support relating to the disease and be prepared to discuss the nature of the disease, possible complications and likely prognosis as well as the genetic implications for other family members.

• Screening is usually delayed beyond childhood (see above). However, blood pressure can rise before that age and so should be checked. The option for screening should be given in advance of an individual starting their own family.

• Advise 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.

• Much of the morbidity and mortality of ADPKD is due to CVD. Thus, 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) would seem sensible, even if not studied within the ADPKD population specifically.

• Care and monitoring would usually be undertaken jointly by primary care and renal teams.

Disease modification¹⁴

The TEMPO (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes) 3:4 trial, showed that the vasopressin receptor antagonist tolvaptan slowed the growth of cystic kidneys and the deterioration of renal function. Consequently, the European Medicines Agency in 2015 approved tolvaptan to slow the progression of cyst development and renal insufficiency in ADPKD in adults with CKD stages 1-3 at initiation of treatment and evidence of rapidly progressing disease. TEMPO 4:4 showed that benefit is sustained over time.

Over 6,000 patients with ADPKD are being treated with tolvaptan around the world, but it does have side-effects that include impairing urinary concentrating ability. Patients therefore experience polyuria, nocturia, and polydipsia. Rarely some have drug-induced liver injury.

Monitoring for disease progression

• If blood pressure and blood chemistry are normal then annual blood tests and ultrasound are sufficient to monitor the disease.

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

• Remember that progressive kidney disease will occur over time but serum creatinine concentrations are insensitive measures, only rising once more than 50% of renal parenchyma has been destroyed, and eGFR typically remains within normal range for several decades.

• Ultrasound is a more sensitive means of monitoring progression, as it enables estimate of renal volume.

Medical management¹⁵

Hypertension
Current advice is that blood pressure should be controlled to a target of 130/80 mm Hg. Ongoing research is investigating whether a lower target (110/75 mm Hg) is effective at slowing disease progression in those with preserved function. Where there is significant proteinuria (>1 g/day), a lower target blood pressure is recommended.

Angiotensin-converting enzyme (ACE) inhibitors or angiotensin-II receptor antagonists are the preferred choice (based on limited observational data) but other agents (eg, diuretics) may also be required.

Monitor blood chemistry closely if kidneys are failing and these drugs are used.

Urinary tract infection

• Treat UTIs as they occur, as for the general population.

• Women are more susceptible and more prone to parenchymal and cyst infections.

• Acute pyelonephritis and symptomatic cyst infection require admission for intravenous antibiotic therapy.

• Where fever persists beyond 1-2 weeks of appropriate antibiotic therapy, percutaneous or surgical drainage of infected cysts should be considered. Where there is end-stage disease, nephrectomy may be indicated.

Haematuria

• Treat renal colic with adequate analgesia.

• Bed rest and hydration (sufficient to increase the urinary flow rate to 2-3 litres/day) are recommended.

• Patients should become familiar with self-management for straightforward repeated episodes.

• Avoid anticoagulants (including low-dose aspirin) unless there is a strong indication.

• Renal stones are managed with the same strategies as in the general population.

Renal pain

• Treat the cause where possible - eg, renal stones, infection.

• Avoid long-term use of nephrotoxic drugs - eg, non-steroidal anti-inflammatory drugs (NSAIDs).

• Chronic, unrelenting pain may require the involvement of a pain management specialist. Different strategies have been tried, including transcutaneous stimulation, use of local injections of anaesthetic and renal denervation.

• Depending upon size and accessibility, large, painful cysts of kidneys or other organs may require percutaneous drainage guided by ultrasound, a laparoscopic technique or a more formal operation at laparotomy. Enormous cysts in excess of 40 cm diameter usually require nephrectomy.

• Renal cell carcinoma is a rare cause of pain in ADPKD. It is not more common than in the general population but tends to present at an earlier age.

Kidney disease

• As end-stage kidney disease is reached, dialysis is required.

• Abdominal hernias (common in ADPKD) can complicate peritoneal dialysis.

• Heparin anticoagulation for haemodialysis can be problematic in those with haematuria.

• 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).

Women's health

• Oestrogens appear to provoke the growth of hepatic cysts, so avoid their use in women with ADPKD or, if prescribed, use in the lowest effective dose or with transdermal administration.

• Pregnancies should be overseen by an obstetric physician. Those with pre-conceptual hypertension or renal insufficiency are at higher risk of severe hypertension or pre-eclampsia. Normotensive women generally have uncomplicated pregnancies.

Polycystic liver disease

• Most do not require treatment, as the majority are asymptomatic. Hepatic cysts do not cause liver failure.

• Rarely, symptomatic disease requires interventions to reduce cyst size or hepatic volume. The procedure will depend on the distribution and size of cysts (eg, percutaneous cyst aspiration, laparoscopic cyst fenestration, liver resection or liver transplant).

Intracranial aneurysms

• Magnetic resonance angiography (MRA) is used to detect aneurysms in patients with ADPKD where there is:
  

  • A family history of aneurysm or stroke.

  • Previous aneurysm rupture.

  • New-onset headache or other relevant CNS sign or symptom.

  • Preparation for major surgery.

  • High-risk occupation (eg, airline pilot).

• Routine screening for berry aneurysms in ADPKD patients without a family history is not recommended.

• Where an asymptomatic aneurysm is discovered, the decision to go ahead with intervention is a difficult balance of whether coiling/clipping is technically possible (dependent on site, size, morphology) and the risks of the procedure, versus the risk of spontaneous rupture.

• In many cases, aneurysms can be safely left alone.

Polycystic kidney disease prognosis¹⁶

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

• Around 50% will be in end-stage kidney disease and require dialysis or transplantation by the age of 60 in PKD1 and the age of 75 in PKD2.

• 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.