Polycystic kidneys

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121 Polycystic kidneys

Instruction

This patient gives a history of intermittent haematuria, obtain a brief history and examine this patient’s abdomen.

Salient features

History

• Acute loin pain and/or haematuria (from haemorrhage in a cyst, cyst infection or urinary stone formation)

• Loin or abdominal discomfort, caused by increasing size of kidneys

• Family history of polycystic kidney disease (as the condition is autosomal dominant with nearly 100% penetrance)

• Complications of hypertension

• Stroke (as a result of ruptured berry aneurysm)

• Family history of brain aneurysm: the prevalence of intracranial aneurysms increases from 5% to 20% when there is a family history.

Examination

• Arteriovenous fistulae in the arms or subclavian dialysis catheter (remember that polycystic kidneys constitute the third most common cause for chronic renal failure in the UK after glomerulonephritis and pyelonephritis)

• Palpable kidneys: confirm by bimanual palpation and ballottement; there is a resonant note on percussion from overlying colon; the hand can get between the swelling and the costal margin.

Proceed as follows:

• Look for the following signs:

• Enlarged liver as a result of cystic disease
• Transplanted kidney: may be palpable in either iliac fossa
• Third nerve palsy (berry aneurysms are associated with polycystic kidneys).

• Look for anaemia (chronic renal failure) or polycythaemia (increased erythropoiesis)

• Check the BP (hypertension develops in 75%)

• Tell the examiner that you would like to investigate as follows:

• ECG to look for left ventricular hypertrophy (this appears to occur to a greater degree for a given rise in BP in autosomal dominant polycystic kidney disease (ADPKD) than in other renal disorders, and with essential hypertension)
• Microscopic haematuria.

Remember: Polycystic kidney disease is a misnomer as it is a systemic disorder affecting many organs, including the liver, pancreas and, in some rare cases, the heart and brain. Polycystic kidney disease is the most common genetic, life-threatening disease, affecting an estimated 12.5 million people worldwide.

Diagnosis

This patient has polycystic kidney disease (lesion and diagnosis) and is currently on dialysis as evidenced by the arteriovenous fistula in the arm (functional status).

Questions

How may polycystic disease present?

Haematuria, hypertension, urinary tract infection, pain in the lumbar region, uraemic symptoms, subarachnoid haemorrhage associated with berry aneurysm, and complications of associated liver cysts. Kidney stones (more likely to be uric acid rather than calcium oxalate stones) are twice as prevalent as the general population.

Is the kidney involvement usually unilateral or bilateral?

The disease is universally bilateral; unilateral cases reported probably represent multicystic renal dysplasia.

Advanced-level questions

What do you know about the prevalence of this disease?

ADPKD is one of the most common hereditary disorders, being 10 times more common than sickle cell disease, 15 times more common than cystic fibrosis and 20 times more common than Huntington disease. It has a worldwide distribution. In the white population, the disease appears to occur in about 1 in 400 to 1 in 1000 people (Acta Med Scand 1957;328:1–255). Although the disease is rare in Africa and less common in American blacks than American whites, the incidence of end-stage renal disease caused by ADPKD is similar in blacks and whites. ADPKD is an important cause of renal failure, with 77% of patients dying or reaching end-stage renal disease by the age of 70 years (Kidney Int 1992;41:1311–19).

In which other conditions may bilateral renal cysts be observed in an ultrasonographic study?

Multiple simple cysts, autosomal recessive polycystic kidney disease in children, tuberous sclerosis and von Hippel–Lindau syndrome.

What are the criteria for diagnosis of polycystic kidney disease using ultrasonography?

• Individuals at risk and those <30 years: presence of at least 2 renal cysts (unilateral or bilateral) is sufficient to establish a diagnosis in those with a positive family history; 5 cysts bilaterally in those with no such history

• 30–60 years: at least 2 cysts in each kidney in those with a positive family history, 5 cysts bilaterally in those with no such history

• ≥60 years: at least four cysts in each kidney regardless of family history

(Lancet 1994;343:824–7).

How would you like to manage this patient?

• FBC, urea and electrolytes, serum creatinine, urine microscopy, urine culture

• Ultrasonography of the kidneys to confirm the diagnosis. Ultrasound may be equivocal in subjects under the age of 20 years. Ultrasound or renal MRI can also be used to determine total kidney volume, a measure of disease progression

• Contrast-enhanced spiral CT head scan or MRI as a screening test for intracranial aneurysms in patients aged 18–40 years and with a family history of intracranial aneurysms or subarachnoid haemorrhage (N Engl J Med 1992;327:953–5).

In which other organs are cysts seen in this condition?

Liver (in 30% of cases), spleen, pancreas, lungs, ovaries, testes, epididymis, thyroid, uterus, broad ligament and bladder. Women with hepatic cysts. Women with ADPKD may have massive cystic enlargement of the liver, a complication attributed to the role of oestrogens in promoting the growth of cysts. Exogenous oestrogens and repeated pregnancies are also risk factors for this complication; therefore, oral contraceptives and hormone replacement therapy should be avoided.

What are the neurological manifestations of this condition?

Subarachnoid haemorrhage from an intracranial berry aneurysm, causing death or neurological lesions in about 9% of patients. About 8% of ADPKD have an asymptomatic intracranial aneurysm and the prevalence is twice as high with a family history of such aneurysms or of subarachanoid haemorrhage. Typically intracranial aneurysms present as a ‘sentinel’ or ‘thunderclap’ headache.

What is the pathology?

Cysts develop in Bowman’s capsule and at other levels in the nephron, displacing kidney tissue. In the normal kidney, polycystin 1 is an integral membrane glycoprotein involved in cell–cell and/or cell–matrix interaction (J Am Soc Nephrol 1995;6:1125–33); polycystin 2 is similar to a subunit of voltage-activated calcium and sodium channels, which suggests a role in regulating calcium entry (Science 1996;272:1339–42). The polycystins interact through their C-terminal cytoplasmic tails, which suggests that they may function through a common signalling pathway (Bat Genet 1997;16:179–83). As activation of the intracellular calcium pathways inhibits cell proliferation, in ADPKD, with insufficient or abnormal polycystins and impaired calcium entry, the proliferative pathways dominant, resulting in cyst formation and ultimately renal failure. Renal function remains stable until kidney volumes reach a critical size.

What cardiovascular manifestations have been reported in these patients?

• Mitral valve prolapse in 26%

• Other lesions commonly seen are mitral, aortic and tricuspid valve regurgitation: adult polycysic disease of kidney with involvement of liver.

What are the renal manifestations of this disease?

• The main structural change is the formation of cysts. Cysts enlarge, lose their tubular connection and become isolated from the glomerulus, requiring transepithelial transport of solutes and fluids for further expansion. Cyst fluids have different sodium compositions, some high and others low.

• One of the earliest and most consistent functional abnormalities is a decrease in renal concentrating ability.

• There may be altered endocrine function, as reflected by increased secretion of both renin (causing increased predilection to hypertension) and erythropoietin (resulting in better maintained haematocrit in renal failure, unlike in renal failure from other causes; rarely can result in polycythaemia).

What are the causes of abdominal pain in this disease?

Infected cyst, haemorrage into cyst or diverticular perforation.

What are the complications of polycystic kidney disease?

Renal complications

• Hypertension (intrarenal activation of the renin–angiotensin system is said to be the main mechanism and hence ACE inhibitors are first-line-agents to control BP; diuretics should be avoided because hypokalaemia promotes cyst formation)

• Pain: back pain or abdominal pain (cyst decompression may help to relieve pain but does not alter the rate of progression)

• Gross or microscopic haematuria

• Cyst infection (lipophilic antibiotics against Gram-negative bacteria such as co-trimoxazole, fluoroquinolones penetrate the cysts better and are preferred to standard antibacterial agents)

• Renal calculi (seen in 10–20% with ADPKD and are frequently radiolucent and composed of uric acid)

• Urinary tract infection including pyelonephritis

• Proteinuria

• Renal failure (once the glomerular filtration rate (GFR) is <50 ml/min, the rate of progression is more rapid than in other primary renal disorders and there is a reduction in GFR of about 5 ml/min every year). About one half of the patients have normal life with adequate renal function.

Extrarenal manifestations

• Cystic: cysts in the liver, ovary, pancreas, spleen and CNS. Unlike renal cyst formation, liver cysts seem to be influenced by female hormones. Whilst men and women have the same frequency of liver cysts, massive liver cysts are almost exclusively found in women

• Non-cystic:

• Cardiac valvular abnormalities: mitral valve prolapse (seen in ~20% of ADPKD), aortic valve abnormalities
• Intracranial saccular aneurysm or berry aneurysm: MR angiography is the most reliable technique of non-invasive screening among such patients.

• Gastrointestinal: colonic diverticula, herniae of the anterior abdominal wall.

What do you know about the genetic transmission of this disease?

Polycystic kidney disease is an autosomal dominant disorder. Mutations in at least three different genes can lead to ADPKD. The PKD1 gene (encoding polycystin-1) is located on chromosome 16 (Cell 1994;77:881–4). The PKD2 gene (encoding polycystin-2) is situated on chromosome 4. At least one other gene containing mutations that lead to ADPKD is known to exist; its chromosomal location is not known.

Among the European ADPKD population, PKD1 is the cause in about 85% of families and PKD2 the cause is about 15%. Compared with individuals affected by PKD2, those with PKD1 have more severe disease with a higher prevalence of hypertension, an increased risk of progression into renal failure, and shorter life expectancy. Although PKD2-linked disease is clinically milder than PKD1-linked disease, it has a deleterious impact on overall life expectancy and cannot be regarded as a benign disorder (Lancet 1999;353:103–7).

What do you know about screening in this condition?

• The children and siblings of patients with established ADPKD should be offered screening.

• Affected individuals should have their BP checked regularly and offered genetic counselling.

• Genetic linkage analysis can be utilized in many families. Ultrasound is usually not useful before the age of 20 years.

What are the poor prognostic factors in autosomal dominant polycystic kidney disease?

Patients are liable to progress more rapidly if they are male or have PKD1 mutations, early-onset hypertension, episodes of gross haematuria (J Am Soc Nephrol 1997;8:1560–7) or a family history of hypertension in an unaffected person (J Am Soc Nephrol 1995;6:1643–8); however, these only account for a fraction of the variability of disease progression.

What are the causes of death in these patients?

One-third of adult patients die from renal failure; another third die from the complications of hypertension (including heart disease, intracerebral haemorrhage and rupture of berry aneurysm). The remaining third die from unrelated causes.

Are there any special treatments for this condition?

Basis research suggests that patients should be advised to:

• increase their water intake to 3 litres a day (to reduce antidiuretic hormone and cyclic AMP stimulation)

• limit the sodium intake (to control hypertension or kidney cyst formation)

• avoid caffeine or methyxanthine derivatives (since they block phosphodiesterase thereby resulting in more cyclic AMP to stimulate cyst formation)

• avoid situations that could carry a high risk of abdominal trauma, such as high-impact contact sports.

Are there any clinical trials being conducted in autosomal dominant polycystic kidney disease?

• The HALT PKD (Halt Progression of Polycystic Kidney Disease) study funded by NIH is comparing the combination of ACE inhibitor and angiotensin receptor blocker with an ACE inhibitor plus placebo

• The TEMPO (Tolvaptan Efficacy and Safety in Management of Polycystic Diseases and its Outcomes) study

• Studies of mTOR inhibitors: rapamycin as pilot study, everolimus study

• Somatostatin study.

What do you know about hypertension in a pregnant woman with autosomal dominant polycystic kidney disease?

Although ACE inhibitors or an angiotensin receptor blocker are the best choice for hypertension in ADPKD, these drugs are absolutely contraindicated in pregnancy. Normotensive women with ADPKD and creatinine <12 mg/l typically have uncomplicated pregnancies, but 16% get new hypertension and are more likely to develop chronic hypertension (J Am Soc Nephrol 1994;5:1178–85). Pregnant patients with ADPKD have higher frequency of maternal complications (particularly hypertension, oedema and pre-eclampsia) than patients without ADPKD (35% vs 19%, p <0.001).

Further reading

Grantham JJ. Autosomal dominant polycystic kidney disease. N Engl J Med. 2007;359:1477.

Sir W Bowman (1816–1892), Surgeon at the Royal London Ophthalmic Hospital.

EL Potter (1901–), US pathologist. She also described Potter syndrome, with renal agenesis and characteristic of epicanthic folds, receding jaw and low set ears with less cartilage than usual.

OZ Dalgaard’s study in 1957 clarified the autosomal dominant pattern of inheritance of the disease.

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