Polycystic kidney disease (PKD) is a hereditary disorder of renal cyst formation causing gradual enlargement of both kidneys, sometimes with progression to renal failure. Almost all forms are caused by a familial genetic mutation. Symptoms and signs include flank and abdominal pain, hematuria, and hypertension. Diagnosis is by CT or ultrasonography. Treatment is symptomatic before renal failure and with dialysis or transplantation afterward.

Etiology

Inheritance of PKD is autosomal dominant or recessive; sporadic cases occur rarely. Autosomal dominant polycystic kidney disease (ADPKD) has an incidence of 1/1000 and accounts for about 5% of patients with end-stage renal disease requiring replacement therapy. Clinical manifestations are rare before adulthood, but penetrance is essentially complete; all patients ≥ 80 yr have some signs. In contrast, autosomal recessive PKD is rare; incidence is 1/10,000. It frequently causes renal failure during childhood (see Congenital Renal and Genitourinary Anomalies: Autosomal recessive polycystic kidney disease).

In 86 to 96% of cases, ADPKD is caused by mutations in the PKD1 gene on chromosome 16, which codes for the protein polycystin 1; most other cases are caused by mutations in the PKD2 gene on chromosome 4, which codes for polycystin 2. A few familial cases are unrelated to either locus.

Pathophysiology

Polycystin 1 may regulate tubular epithelial cell adhesion and differentiation; polycystin 2 may function as an ion channel, with mutations causing fluid secretion into cysts. Mutations in these proteins may alter the function of renal cilia, which enable tubular cells to sense flow rates. A leading hypothesis proposes that tubular cell proliferation and differentiation are linked to flow rate and that ciliary dysfunction may thus lead to cystic transformation.

Early in the disorder, tubules dilate and slowly fill with glomerular filtrate. Eventually, the tubules separate from the functioning nephron and fill with secreted rather than filtered fluid, forming cysts. Hemorrhage into cysts may occur, causing hematuria; patients are also at higher risk of acute pyelonephritis and urinary calculi (in 20%). Vascular sclerosis and interstitial fibrosis eventually develop via unknown mechanisms and typically affect < 10% of tubules; nonetheless, renal failure develops in about 35 to 45% of patients by age 60.

Extrarenal manifestations are common:

• Most patients have hepatic cysts, which typically do not affect liver function.
• Patients also have a higher incidence of pancreatic and intestinal cysts, colonic diverticula, and inguinal and abdominal wall hernias.
• Valvular heart disorders (most often mitral valve prolapse and aortic regurgitation) can be detected by cardiac ultrasonography in 25 to 30% of patients; other valvular disorders may be due to collagen abnormalities.
• Aortic regurgitation results from aortic root dilation due to arterial wall changes (including aortic aneurysm).
• Coronary artery aneurysms occur.
• About 4% of young adults and up to 10% of elderly patients have cerebral aneurysms. Aneurysms rupture in 65 to 75% of patients, usually before age 50; risk factors include family history of aneurysm or rupture, larger aneurysms, and poorly controlled hypertension.

Symptoms and Signs

ADPKD usually causes no symptoms initially; one half of patients remain asymptomatic, never develop renal insufficiency or failure, and are never diagnosed. Most patients who develop symptoms do so by the end of their 20s. Symptoms include low-grade flank, abdominal, and lower back pain due to cystic enlargement and symptoms of infection. Acute pain, when it occurs, is usually due to hemorrhage into cysts or passage of a calculus; fever is common with acute pyelonephritis. Hepatic cysts may cause right upper quadrant pain if they enlarge or become infected. Valvular disorders rarely cause symptoms but occasionally cause heart failure and require valvular replacement. Symptoms and signs of unruptured cerebral aneurysm can be absent or may include headache, nausea and vomiting, and cranial nerve deficits; these manifestations warrant immediate intervention (see Sidebar 1: Stroke (CVA): Vascular Lesions in the Brain).

Signs are nonspecific and include hematuria and hypertension (each in about 40 to 50%) and proteinuria (in 20%). Anemia is less common than in other types of chronic renal failure, presumably because erythropoietin production is preserved. In advanced disease, the kidneys may become grossly enlarged and palpable, causing fullness in the upper abdomen and flank.

Diagnosis

• Ultrasonography
• Sometimes CT or MRI or genetic testing

The diagnosis is suspected in patients with the following:

• A positive family history
• Typical symptoms or signs
• Cysts detected incidentally on imaging studies

Patients should be counseled before undergoing diagnostic testing, particularly if they are asymptomatic. For example, many authorities recommend against testing asymptomatic young patients because no disease-modifying treatment is effective at this age and diagnosis has potential negative effects on ability to obtain health insurance and on mood. Diagnosis is usually by imaging, showing extensive cystic changes throughout the kidneys and a moth-eaten appearance due to cysts that displace functional tissue. These changes develop with age and are less often present or obvious in younger patients. Ultrasonography is usually done first. If ultrasonography results are inconclusive, CT or MRI, which are both more sensitive (particularly when done using contrast), is done. Urinalysis, renal function tests, and CBC are done, but results are not specific.

Urinalysis detects mild proteinuria and microscopic or macroscopic hematuria. Gross hematuria may be due to a dislodged calculus or to hemorrhage from a ruptured cyst. Pyuria is common even without bacterial infection. Initially, BUN and creatinine are normal or only mildly elevated, but they slowly increase, especially when hypertension is present. Rarely, CBC detects polycythemia.

Patients with symptoms of cerebral aneurysm require high-resolution CT or magnetic resonance angiography. However, there is no consensus on whether asymptomatic patients should be screened for cerebral aneurysm, at what age, and how often. A reasonable approach is to screen patients with ADPKD and a family history of hemorrhagic stroke or cerebral aneurysm.

Genetic testing for PKD mutations is currently reserved for any of the following:

• Patients with suspected PKD and no known family history
• Patients with inconclusive results on imaging
• Younger patients (eg, age < 30, in whom imaging results are often inconclusive) in whom the diagnosis must be made (eg, a potential kidney donor)

Genetic counseling is recommended for 1st-degree relatives of patients with ADPKD.

Prognosis

By age 75, 50 to 75% of patients with ADPKD require renal replacement therapy (dialysis or transplantation). Predictors of more rapid progression to renal failure include the following:

• Earlier age at diagnosis
• Male sex
• Sickle cell trait
• PKD1 genotype
• Larger or rapidly increasing kidney size
• Gross hematuria
• Hypertension

ADPKD does not increase risk of renal cancer, but if patients with ADPKD develop renal cancer, it is more likely to be bilateral. Renal cancer rarely causes death. Patients usually die of heart disease (sometimes valvular), disseminated infection, or ruptured cerebral aneurysm.

Treatment

• Control of risk factors
• Supportive measures

Strict BP control is essential. Typically ACE inhibitors and angiotensin receptor blockers are used; in addition to controlling BP, they help block angiotensin and aldosterone, two growth factors that contribute to renal scarring and loss of renal function. UTIs should be treated promptly. Percutaneous aspiration of cysts may help manage severe pain due to hemorrhage or compression but has no effect on long-term outcome. Nephrectomy is an option to relieve severe symptoms due to massive kidney enlargement (eg, pain, hematuria) or recurrent UTIs. Hemodialysis, peritoneal dialysis, or kidney transplantation is required in patients who develop chronic renal failure. ADPKD does not recur in grafts. With dialysis, patients with ADPKD maintain higher Hb levels than any other group of patients with renal failure.Tolvaptan is a new drug that may become standard of care in ADPKD. Tolvaptan appears to slow increase in renal volume and decline in renal function, but can cause side effects via free water diuresis (eg, thirst,polydipsia, polyuria) that can make adherence difficult.

Last full review/revision July 2009 by Drew C. Cutler, MD