Genetics and Pathogenesis of Polycystic Kidney Disease

Abstract

Polycystic kidney disease (PKD), a common genetic cause of chronic renal failure in children and adults, is characterized by the accumulation of fluid-filled cysts in the kidney and other organs. The renal cysts originate from the epithelia of the nephrons and renal collecting system and are lined by a single layer of cells that have higher rates of cellular proliferation and are less differentiated than normal tubular cells (1). Abnormalities in gene expression, cell polarity, fluid secretion, apoptosis, and extracellular matrix have also been described in PKD, but the mechanism of cyst formation remains incompletely understood (2–6). In recent months, there have been several advances in our understanding of the genetics and pathogenesis of PKD. Genes responsible for autosomal recessive PKD in humans and mice have been cloned, the PKD2 gene product has been identified as an intracellular calcium release channel, the PKD1 gene product has been found to regulate the cell cycle, and a neglected cellular organelle, the primary cilium, has emerged as a potential key player in polycystic disease. In this review, we will discuss how the cloning of the human PKD genes and the characterization of animal models have provided new insights into the pathogenesis of PKD. It is hoped that a more thorough understanding of the genetics and pathogenesis of PKD will lead to improvements in diagnosis and treatment. PKD can be inherited as an autosomal dominant trait (ADPKD) or an autosomal recessive trait (ARPKD) (Table 1). ADPKD is a common disease that occurs in both children and adults, whereas ARPKD is uncommon and occurs primarily in neonates and children. ADPKD is caused by mutations of either the PKD1 gene on chromosome 16 or the PKD2 gene on chromosome 4. The gene responsible for ARPKD (PKHD1) has recently been identified on chromosome 6. Renal cysts can also occur in association with other genetic diseases (e.g., tuberous sclerosis, von Hippel-Lindau disease, Zellweger syndrome, juvenile nephronophthisis), but these entities will not be discussed further here.Table 1: Characteristics of autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD)Autosomal Dominant Polycystic Kidney Disease ADPKD is one of the most common genetic diseases in humans affecting all ethnic groups worldwide with an incidence of 1 in 500 to 1 in 1,000 (7). The clinical manifestations include abdominal mass, chronic flank or back pain, gross hematuria, urinary tract infection, and urolithiasis. Affected individuals typically present in the third and fourth decade, and ESRD usually occurs within 5 to 10 yr after the development of renal insufficiency. However, presentation in infancy or childhood has also been reported (8,9). In addition to causing progressive renal failure, renal cysts can be complicated by hemorrhage, rupture, infection, nephrolithiasis, and intractable pain. Systemic hypertension is also very common, occurring in more than 75% of patients. Increased BP has been attributed to activation of the renin-angiotensin system, but a primary defect in blood vessels may also exist (10,11). Although ADPKD is characterized by kidney cysts and renal failure, it should be regarded as a systemic disease. The genes responsible for ADPKD are widely expressed, and mutations can affect a variety of extrarenal tissues (12). Cysts can arise in other epithelial organs, including the liver (75% of patients), pancreas (rare), ovaries, and choroid plexus. The liver cysts originate from the bile ducts and can become infected or hemorrhage but do not cause liver failure; cystic enlargement of the livers can produce symptoms due to mass effects. Other extrarenal manifestations include cerebral and aortic aneurysms, cerebral dolichoectasis, and colonic diverticuli. Cardiac valvular abnormalities include mitral valve prolapse, mitral regurgitation, aortic insufficiency, and tricuspid regurgitation. Left ventricular hypertrophy is common and has been observed in normotensive individuals. A striking feature of ADPKD is the variability of the phenotype. ADPKD is fully penetrant, meaning that virtually 100% of individuals who inherit a mutated PKD gene will develop renal cysts that can be detected sonographically by age 30 (13). However, the severity of the disease, the age of onset of ESRD, and the spectrum of extrarenal manifestations vary widely between affected individuals, even within the same family (14). Possible explanations for the variable expressivity of the disease are discussed below. Genetics of ADPKD ADPKD is genetically heterogeneous and can arise from mutations in two genes, named PKD1 and PKD2 (15,16). Mutations of PKD1 located on chromosome 16p13.3 are responsible for 85% of cases, whereas mutations of PKD2 on chromosome 4q21–23 are responsible for 15% of cases. In elderly patients, mutations of PKD2 are responsible for a higher percentage of cases. Forty percent of PKD patients presenting