Porth's Essentials of Pathophysiology, 4e

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Disorders of Renal Function

C h a p t e r 2 5

autosomal recessive polycystic kidney disease, and neph- ronophthisis and medullary cystic kidney diseases. Autosomal Dominant Polycystic Kidney Disease Autosomal dominant (adult) polycystic kidney disease (ADPKD) is the most common of all inherited kidney diseases, with 600,000 to 700,000 cases in the United States and about 12.5 million cases worldwide. 6 About 5000 to 6000 new cases are diagnosed in the United States each year, about 40% before the age of 45. 6 About 5% to 10% of these persons develop chronic kidney dis- ease that requires dialysis or kidney transplant. 5 The disorder is characterized by multiple expand- ing cysts of both kidneys that ultimately destroy the surrounding kidney structures and cause renal failure (Fig. 25-2A). There are two genetic forms of ADPKD: polycystin-1I which is caused by mutations in the PKD1 gene and accounts for 85% of cases; and polycystin-2, which is caused by mutations in the PKD2 gene and accounts for most of the remaining 15% of cases. 4–8 Although the two mutations produce almost identical renal and extrarenal disease, disease progression is typi- cally more rapid in people with the PKD1 gene. Recent research suggests that the products of the polycystin genes are transmembrane proteins found on the primary cilia that line the apical surface of the tubu- lar epithelial cells of the kidney. Because the cilia proj- ect out and above the tubular cell surface like antennas,

they are currently thought to act as sensors of urinary flow and as signal transducers for tubular cell prolifera- tion, differentiation, and apoptosis. 9 The polycystin genes also regulate vascular development in other organs such as the liver, brain, and pancreas, accounting for the extra- renal manifestations that often accompany the disorder. In ADPKD, cysts in the kidney increase in size over time, ultimately destroying normal renal tissue. The kid- neys are usually enlarged and may achieve enormous sizes (Fig. 25-3). The external contours of the kidneys are distorted by numerous cysts, some as large as 5 cm in diameter, filled with straw-colored fluid. 5 Cysts also may be found in the liver and, less commonly, the pan- creas and spleen. Hepatic cysts, which occur in one third of persons with ADPKD, are generally asymptomatic and liver function is normal. 5 Mitral valve prolapse and other valvular abnormalities are found in 20% to 25% of people, but most are asymptomatic. One of the most devastating extrarenal manifestations is a weakness in the walls of the cerebral arteries that can lead to aneu- rysm formation. It has been estimated that persons with ADPKD who have a family member with ADPKD and a history of intracranial aneurysm or cerebral hemor- rhage have a 20% chance of developing an intracranial aneurysm. 6 The manifestations of ADPKD include pain from the enlarging cysts that may reach debilitating levels, episodes of gross hematuria from bleeding into a cyst, infected cysts from ascending UTIs, and hypertension resulting from compression of intrarenal blood vessels with activation of the renin-angiotensin mechanism. 4,5 Renal colic caused by nephrolithiasis, or kidney stones, occurs in about 20% of persons with ADPKD. 6 The progress of the disease is slow, and chronic kidney dis- ease is uncommon before 40 years of age. Ultrasonography usually is the preferred technique for the diagnosis of ADPKD in symptomatic patients and for screening of asymptomatic family members. Computed tomography (CT) may be used for detection of small cysts. Genetic linkage studies are now available

A

B

Cyst formation in autosomal dominant polycystic kidney disease

Cyst formation in autosomal recessive polycystic kidney disease

FIGURE 25-2. Mechanism of cyst formation in polycystic kidney disease. (A) In autosomal dominant polycystic kidney disease, cystic outpouchings arise in every tubule segment and rapidly close off the nephron of origin. (B) In autosomal recessive polycystic kidney disease, cysts are derived from collecting tubules, which remain connected to the nephron of origin. (FromWilson PD. Polycystic kidney disease. N Engl J Med. 2004;350:155. Copyright © 2004. Massachusetts Medical Society.)

FIGURE 25-3. Gross pathology of polycystic kidneys. (From the Centers for Disease Control and Prevention Public Health Images Library. No. 861. Courtesy of Edwin P. Ewing, Jr).