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At the heart of general practice since 1960

February 2008: Blood pressure control key in polycystic kidney disease

How can polycystic kidney disease present clinically?

What are the criteria for diagnosing PKD?

How should GPs manage patients with PKD?

How can polycystic kidney disease present clinically?

What are the criteria for diagnosing PKD?

How should GPs manage patients with PKD?

Polycystic kidney disease (PKD) is a common hereditary disorder. It is characterised by multiple renal cysts, slowly enlarging kidneys and a gradual decline in renal function, which results in end-stage renal disease (ESRD) in the majority of patients by the fifth to sixth decade of life.1 It affects between 1 in 400 and 1 in 1,000 people in the UK, so it is likely that a GP with an average list size will care for two to four patients with PKD.

PKD has an autosomal dominant inheritance pattern, with 100% penetrance. Therefore a child of an affected individual has a 50% chance of inheriting the disorder. However, PKD is clinically heterogeneous, with a range of presentations and potential complications.

Eighty-five per cent of mutations occur in the PKD1 gene on chromosome 16. PKD1 encodes for polycystin-1, an integral cell membrane protein localised in renal tubular cells and hepatic ductules. It is overexpressed in most PKD cysts and leads to abnormal cell differentiation, maturation and apoptosis.

Fifteen per cent of mutations occur in the PKD2 gene on chromosome 4, which encodes for polycystin-2. Patients with PKD2 mutations have less severe disease with later onset of ESRD.

The two forms of polycystin proteins are necessary for normal renal tubule development and function.2 They are widely expressed in the body and their normal function includes maintaining tissue strength by cell-to-cell junctions and cell-to-matrix adherence.

Defective polycystin proteins contribute to tissue weakening and cause general tissue laxity. Polycystin mutations can therefore lead to aneurysm formation, a floppy mitral valve, aortic regurgitation, umbilical and inguinal herniae and diverticulosis.

Clinical Presentations

41176181PKD is a multisystem disorder with a variety of renal and non-renal manifestations (see table 1, left).

Renal conditions

Renal features of PKD occur as a direct consequence of the cysts and the progressive renal failure they induce.

Hypertension precedes the onset of renal failure in the majority of patients and is almost universally present in those with established renal failure. Left ventricular hypertrophy is commonly associated with hypertension.3

Loin pain occurs with enlarging cysts, cyst infection or haemorrhage and renal calculi. Although episodes of acute pain are common, chronic severe pain is rare and an alternative explanation should be sought.

Gross haematuria occurs in up to 40% of patients and can be alarming. Potential causes include cyst haemorrhage, infection, renal calculi and, rarely, tumour. Occasionally, cyst rupture can result in a significant retroperitoneal bleed which may require transfusion.

Infection is common and can present as cystitis, pyelonephritis, cyst infection, or rarely, perinephric abscess.

Renal stone disease occurs in around 20% of patients. However, radiological diagnosis may be more difficult because of the altered kidney anatomy.

There are several theories as to why renal stones occur in PKD but there is no well established evidence for any mechanism.

More than 50% of stones in autosomal dominant PKD are composed of uric acid, with most of the remainder composed of calcium oxalate. The predominance of uric acid stones may reflect higher cell turnover/proliferation in the cysts, with the higher cell breakdown contributing to the rise in uric acid excretion.

Although mechanical changes induced by large cysts also contribute, different abnormalities predisposing to stone disease include low urinary volume, low urinary citrate and, less often, hyperuricosuria and hypercalciuria. The mechanism for low urinary citrate is poorly understood.

Patients with undiagnosed PKD may also present late with symptoms or complications of chronic renal failure, such as uraemic fatigue, gastrointestinal upset, anaemia or renal bone disease.

Non-renal conditions

Subarachnoid haemorrhage resulting from a ruptured berry aneurysm is one of the most devastating presentations of PKD and can result in death or severe disability. Risk factors include a family history of subarachnoid haemorrhage, a previous intracerebral bleed and uncontrolled hypertension.

Up to half of patients may have a sentinel bleed days or weeks before. This presents as an acute, severe and transient headache and should prompt urgent investigation. Other, rarer, signs of an impending aneurysm rupture include seizures and cranial nerve abnormalities.

Patients who have a family history of subarachnoid haemorrhage should have a renal ultrasound if they are in their late 20s to try and confirm or exclude PKD. If they have PKD, counselling is required to advise them of the risks and benefits of further neurological assessment, including MRI angiography.

A more common situation is an older patient who has had a cerebral bleed and has hypertension.

If there are pointers to underlying renal disease, such as proteinuria, raised serum creatinine and/or a family history of renal failure, then a renal ultrasound is advisable.

The risk of subarachnoid haemorrhage is independent of the risk associated with hypertension. However, the risk is increased in patients with poorly controlled hypertension.

Polycystic liver disease is the most common non-renal manifestation of PKD. Hepatic cysts usually develop later than renal cysts but do not lead to liver failure. They can be associated with significant morbidity, including pain and infection.

Hepatic cysts are more common in women and massive hepatic cysts occur almost exclusively in women who have had children, suggesting a hormonal aetiology. They become infected less frequently than renal cysts but can be difficult to diagnose and treat and can have serious consequences.

Mitral valve prolapse is the most common valvular abnormality associated with PKD and occurs in up to 25% of patients. Mitral, aortic and tricuspid regurgitation are also more common in patients with PKD. Patients with PKD should have a regular cardiovascular examination and be promptly referred for an ECG if a murmur is detected.

Ovarian cysts are not more common in PKD and fertility is unaffected in women with normal renal function.

Up to 40% of men with PKD have seminal vesicle cysts which, combined with low sperm motility, can cause infertility.

Investigations

Investigations are required to confirm PKD, diagnose complications and guide the management of progressive chronic renal failure.

An abdominal ultrasound scan can detect cysts more than 1cm in diameter. If a patient has a family history of PKD, the following criteria are used to establish diagnosis:4

Positive family history + patient age:

• <30 years: at least two cysts (unilateral or bilateral)
• 30-59 years: at least two cysts in each kidney
• >60 years: at least four cysts in each kidney.

For patients with a PKD1 mutation the sensitivity of these criteria is 97% in patients under 30 years and 100% in those over 30. The specificity is 99%.

As disease caused by a PKD2 mutation has a later onset, there is a higher false negative rate in those under 30 years (4%). Ultrasound scan can therefore confirm a diagnosis of PKD but cannot exclude it in patients under 30.

Up to 25% of patients with PKD have no known family history, either because the gene mutation arose spontaneously (5%) or the affected parent(s) died of other causes before PKD became apparent.

There are no definitive criteria regarding cyst number that provide an unequivocal diagnosis in those without a family history. However, PKD should be strongly suspected if cysts:

• Are bilateral
• Number more than 10
• Are associated with enlarged kidneys or hepatic cysts.

Genetic testing is difficult and not performed routinely.

CT and MRI are more sensitive than ultrasound scan and can detect cysts as small as 0.5cm.

A recent major development has been the use of MRI to detect increased and increasing kidney size and so identify patients at greatest risk of renal failure. Studies have demonstrated that patients with larger kidneys (>1,500ml) at baseline have the greatest loss of glomerular filtration rate (GFR) and have also revealed an inverse correlation between kidney growth rate and GFR.5

Referral

Reasons for referral to specialist nephrology services include:

• To confirm PKD and discuss potential screening of family members. In the absence of a definitive treatment, screening remains controversial as it may confer significant financial penalties (eg life assurance). In adults, the decision whether or not to screen for PKD should be based on the patient's preference and only performed after detailed counselling. Screening children is not recommended.
• To manage complications, including poorly controlled hypertension, frequent urinary tract or cyst infections and recurrent renal calculi.
• If the patient is pregnant or planning a pregnancy. Pregnancy in patients with hypertension and renal impairment is associated with maternal and fetal complications, including pre-eclampsia and preterm delivery. Ideally, pregnancy should be planned for before renal function deteriorates. Patients should be referred to both an obstetrician and a nephrologist.
• To manage progressive renal failure and prepare for ESRD. Both haemodialysis and peritoneal dialysis can be initiated in patients with PKD. As with all patients with renal failure assessed fit for major surgery, a transplant is the optimum renal replacement therapy.

Prognosis

PKD is the fourth most common cause of ESRD in the UK.6 However, it has the best prognosis in terms of patient survival. The average age of progression to ESRD is 53 years for patients with PKD1 and 74 years for PKD2. Renal function decline is linear and ESRD can be predicted and planned for.

Risk factors for earlier development of renal failure include:
• Younger age at diagnosis (in those unscreened)
• Inheritance of a PKD1 mutation
• Hypertension
• Significant proteinuria
• Large kidneys and increasing kidney size
• Male gender
• Gross haematuria.

Management

Cyst complications

Cyst infections can be difficult to treat, as cysts are not always connected with the urinary system, there may be no symptoms of lower urinary tract infection and urine cultures may be negative. Malaise, flank or loin pain, fever and rigors are all potential presenting signs.

Quinolone antibiotics, such as ciprofloxacin, are appropriate as they have good coverage of common urinary pathogens and effective cyst penetration.

For recurrent infection, antibiotics should be continued for at least two weeks. Sometimes a four- to six-week course may be required.

If infection recurs on withdrawal of treatment, GPs should consider Gram-positive antibiotic cover and arrange imaging to exclude renal calculi or perinephric abscess.

Gross haematuria is usually self-limiting and, in the absence of infection or calculi, rarely requires investigation or specific treatment.

If it is persistent and painless, investigations should be performed to exclude malignancy. PKD is not associated with an increased risk of renal cancer.

Chronic renal failure

Patients with PKD and early CKD can be managed in primary care in accordance with CKD guidelines.7 Patients should have a biannual assessment that includes:

• Urinalysis

• Blood pressure

• Renal function (serum creatinine

and estimated GFR)

• Protein estimation (albumin

or protein:creatinine ratio)

• Cardiovascular risk.

Hypertension

Control of blood pressure is arguably the most important management goal. Patients with PKD should have a target blood pressure of 125/75mmHg. There is evidence to suggest that treating patients who are normotensive may reduce the risk of left ventricular hypertrophy.

Effective blood pressure control can limit end organ damage associated with hypertension. ACE inhibitors or angiotensin-II receptor antagonists are appropriate in patients with PKD (unless contraindicated, eg the patient is planning a pregnancy). The rationale for this is that hypertension associated with PKD is at least partially mediated by increased renin and angiotensin-II levels.8

ACE inhibitors and angiotensin-II receptor antagonists can be used safely for hypertension in patients with no evidence of CKD. More frequent monitoring is required for patients with CKD stage three, four or five, because of the risk of emerging hyperkalaemia (resulting from reduced renal function and decreased action of aldosterone secondary to angiotensin blockade).

New developments

Drugs that may modify the natural history of PKD have now entered phase II and III clinical trials. These agents include somatostatin, sirolimus and tolvaptan and all appear to work by reducing cyst growth.9

Currently, sirolimus is only used off licence in clinical trials. Interestingly, patients with PKD who have been treated with sirolimus as part of their kidney transplant immunosuppressive regimen are reported to have had greater shrinkage of their polycystic kidneys than those on non-sirolimus-based immunosuppression.

Such new therapies have the potential to have a radical effect on the long-term prognosis for patients with PKD.

PKD is a common, dominantly inherited renal disorder frequently encountered by GPs. Many clinical aspects are successfully managed in primary care but referral to a nephrologist is advised for long-term follow-up of associated progressive renal failure.

Tab1 PKD Key points Authors

Dr Joanne Shields
MB BCh MRCP
specialist registrar in nephrology

Professor A Peter Maxwell
MD PhD FRCP
Professor of medicine and consultant nephrologist, Regional Nephrology Unit, Belfast City Hospital

Polycystic kidney disease

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