Adult Polycystic Kidney Disease

Synonyms include: Autosomal dominant polycystic kidney disease, ADPKD, PKD, APKD

This is the commonest inherited cause of serious renal disease. It is an autosomal dominant condition, said to be of high or complete penetrance but a study from Wales found the incidence to be about 1 in 2,500 or about half the expected. They concluded that undiagnosed cases have a benign prognosis.¹

There are 3 recognised forms of adult autosomal dominant polycystic kidney disease:

• About 85% are designated as PKD1 with an abnormality on chromosome 16²
• 15% are PKD2 with an abnormality on chromosome 4³
• A PKD3 has also been described.⁴ The gene locus is not yet identified.

Cysts are not confined to the kidneys and the principle features of this disease are renal cysts, liver cysts and intracranial aneurysm but there is considerable variation even within families.

This condition may affect as many as 1 in 1,000 individuals and accounts for about 10% of people on dialysis. Sex incidence is equal although males may be slightly more seriously affected.

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. However, homozygotes are thought to die in utero.⁵

• Suspicion may have arisen because of a family history of the disease and where a case is identified the family should be screened. However, screening of young people is usually delayed until they are 20.
• Loin pain may be an early feature. It occurs in 50% of patients and is more common as they get older and in those whose kidneys exceed 15cm in length. In the absence of a family history, loin pain may well be the presenting feature.
• Hypertension is often a presenting feature. It usually presents in the 20s or 30s but 10-15% of children may be hypertensive and 60-70% of adults before the onset of chronic renal failure.
• UTI and pyelonephritis may be presenting features.
• Renal stones and haematuria can occur. Haematuria occurs in 30-50% and is usually quite brief, lasting under a week. It may be the presenting feature.
• There may be problems associated with excessive loss of water and salt from the body. Inability to concentrate urine may cause nocturia.
• Patients may sometimes present with renal failure, usually in the fourth to sixth decade of life.
• Stroke in the proband or a relative may prompt screening as berry aneurysms are common in this condition.

Examination:

• Blood pressure may be raised.
• Examination of the abdomen may reveal enlarged and palpable kidneys. If other organs are cystic there may be palpable hepatomegaly and even splenomegaly.
• Physical signs of renal failure are uncommon at presentation. They include pallor, uraemic fetor, dry skin and oedema.

• Microalbuminuria occurs in 35% but heavy proteinuria is rare. Check for haematuria too.
• Urine culture
• FBC. Polycystic kidneys can produce excess erythropoietin and hence raise Hb.
• U&E, creatinine, calcium, phosphate, parathormone level.
• Ultrasound is the modality of choice for imaging the urinary tract. It can detect cysts from 1 to 1.5cm in diameter. Sensitivity for PKD1 is 100% over the age of 20 but false negatives can occur below this age.⁶ The sensitivity for PKD2 is not 100% but the actual figure is not yet established. It is also possible to scan other organs like the liver or pancreas for cysts.
• CT is more sensitive in that it can detect cysts down to 0.5cm diameter but the dose of radiation is quite high. MRI is not often used for the abdomen.
• MRI is used to investigate possible berry aneurysms if there is suggestion in the patient or a relative. It is not usually employed without such a family history.

• Acquired and simple cysts of the kidney
• Autosomal recessive polycystic kidney disease, also called polycystic kidney disease of childhood, usually presents in childhood but may be delayed to adolescence
• Medullary sponge kidney
• Tuberose sclerosis
• Although hepatic cysts may occur in this disease, polycystic liver disease is a different condition.

Diagnostic criteria for APKD1 have been laid down:⁷

• At least 2 cysts in 1 kidney or 1 cyst in each kidney in an at-risk patient under 30 years
• At least 2 cysts in each kidney in an at-risk patient between 30 and 59 years
• At least 4 cysts in each kidney for an at-risk patient over 60 years
• The diagnosis is supported by hepatic or pancreatic cysts.

Advice

• Inform the patient about the nature of the disease and the implications, including the genetic implications for other members of the family.
• Screening other members of the family is usually delayed until the age of 20 as a negative result before then is inconclusive. However, blood pressure can rise before that age and so it should be checked. Screening may be performed earlier if the person is wishing to start a family.
• Contact sport should be avoided as trauma can rupture an enlarged kidney.

Medical Management

• If BP and blood chemistry are normal then annual blood tests and ultrasound are required to monitor the disease.
• If BP is raised it must be controlled. The target should be 130/85 but if proteinuria exceeds 1 gram per day this should be reduced to 125/75.
• ACE inhibitors are the drugs of choice but other agents may also be required. It is possible that the expanding cysts cause ischaemia in the kidney and hence activate the renin-angiotensin-aldosterone system.⁸ If ACE inhibitors are troublesome then angiotensin receptor antagonists may be used but calcium channel blockers are much inferior.⁹
• Monitor blood chemistry closely if kidneys are failing and ACE inhibitors are used.
• Treat UTI as they occur. Women are more susceptible. Distinguish cystitis from infection of the renal parenchyma as management is different.
• If chronic renal failure occurs then remedial action may be required with regard to problems such as hyperkalaemia and secondary hyperparathyroidism.

Interventions

• If cysts are painful, percutaneous drainage and injection of alcohol is effective in 60 to 80%.
• 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 40cm diameter usually require nephrectomy.
• Partial resection of a polycystic liver is a very demanding operation.

• Complications may occur from uncontrolled hypertension.
• Intracerebral aneurysm may rupture and cause subarachnoid haemorrhage. Berry aneurysms occur in 4 to 10% of patients. There is no clinical marker and rupture can occur in the normotensive. The outcome can be death or severe disability.¹⁰ However, most berry aneurysms are small and in the anterior circulation and routine screening for them in this group is not recommended¹¹ and in most cases aneurysms may be safely left alone.¹²
• Simple uncontrolled hypertension may cause stroke.
• Large, cystic kidneys or other organs may rupture with a level of abdominal trauma that would not be alarming for those with normal organs. Bleeding may occur into cysts.
• Renal cell carcinoma is uncommon but more frequent than in the general population and it tends to be bilateral.
• Mitral valve prolapse may occur in as many as a quarter of patients and even in unaffected family members it seems more common.¹³
• There appears to be an increased risk of thoracic aortic aneurysm but not abdominal aortic aneurysm.
• Diverticula of the colon develop in 80%.
• Kidney stones form in 20 to 30% and half are uric acid. Diagnosis by ultrasound may be difficult with large cysts and so IVU is preferred. Consider stones when pain and haematuria present.
• Avoid the use of NSAIDs as they may aggravate renal failure.

• About 50% of patients have cysts in the liver but the figure increases with age.
• Women tend to have larger liver cysts than men. This is thought to be related to oestrogen exposure as it is worse with increasing gravidity and stabilizes after the menopause.
• Liver cysts do not cause liver failure.
• Massive polycystic liver disease may occur, mainly in women. There can be portal hypertension with ascites and oesophageal varices.
• Bilateral nephrectomy in patients with enormous livers may cause portal hypertension and severe ascites.
• Pancreatic cysts occur at a rate of 9% in patients older than 20 years.

• Around 50% will be in end-stage renal failure and require dialysis or transplantation by the age of 60 in APKD1 and age 75 in PKD2.
• Risk factors for progression include PKD1 genotype, multiple pregnancies, Afro-Caribbean race, male sex, large kidneys, and hypertension.
• There is a correlation between the rate of enlargement of renal cysts and decline in renal function.¹⁴
• Whilst PKD2 is less severe it is not to be seen as a benign condition.¹⁵
• The presence of more than one risk factor increases the risk of progression to end stage renal failure.
• The liver may be cystic but it does not fail.

No treatment is available to slow the development of renal cysts but animal studies have shown several potential approaches to modify the disease process. The most advanced therapy is the use of vasopressin V(2) receptor antagonists such as Tolvaptan, which reduce renal cAMP, a known promoter of renal cystic enlargement. Considering the diverse genes that cause renal cysts and the multiorgan involvement of these diseases, multiple therapeutic approaches will eventually be necessary to treat these diseases.¹⁶