POLYCYSTIC KIDNEY-DISEASE - ETIOLOGY, PATHOGENESIS, AND TREATMENT

Once viewed as hopelessly incurable disorders and the dustbin for careers in academic medicine, the polycystic kidney diseases have emerged as prime targets of pathophysiologic study and palliative and definitive treatment in the era of molecular medicine. Polycystic kidney disease (PKD) may be hereditary or acquired. The major inherited types are autosomal dominant (AD) and autosomal recessive (AR). ADPKD is caused by at least two (and possibly three) genes located on separate chromosomes, while ADPKD-1 is due to a 14 kb transcript in a duplicated region on the short arm of chromosome 16 very near the alpha-globin gene cluster and the gene for one form of tuberous sclerosis. ADPKD-2 has been assigned to the long arm of chromosome 4. ARPKD is due to a mutated gene on both copies of the long arm of chromosome 6. Cysts originate in renal tubules. Proliferation of tubule epithelial cells modulated by endocrine, paracrine, and autocrine factors is a major element in the pathogenesis of renal cystic diseases. In addition, fluid that is abnormally accumulated within the cysts is derived glomerular filtrate and, to a greater extent, by transepithelial fluid secretion. Abnormal synthesis and degradation of matrix components associated with interstitial inflammation are additional features in the pathogenesis of renal cystic diseases. The ADPKD genotypes are characterized by bilateral kidney cysts, hypertension, hematuria, renal infection, stones, and renal insufficiency. ADPKD is a systemic disorder; cysts appear with decreasing frequency in the kidneys, liver, pancreas, brain, spleen, ovaries, and testis. Cardiac valvular disorders, abdominal and inguinal hernias, and aneurysms of cerebral and coronary arteries and aorta are also associated with ADPKD. Treatment is supportive: dietary regulation of salt and protein intake, control of hypertension and renal stones, acid dialysis and transplantation at the end stage. ARPKD is a relatively rare disease that causes clinical symptoms at birth, with significant mortality in the first month of life. The cysts develop primarily in the collecting ducts because of a failure in the maturation process. Early complications include Potter's syndrome; excessive size of the kidneys, causing respiratory dysfunction; hypertension; and renal insufficiency. Hepatic fibrosis is an associated extrarenal problem that results in significant morbidity in young children and adolescents. Treatment includes supportive care, dialysis, and renal transplantation. Acquired cysts (solitary/simple) are commonplace in older persons. Multiple cysts may be seen in association with potassium deficiency, congenital disorders, metabolic diseases, and toxic renal injury, Acquired polycystic disease occurs in the setting of chronic, progressive renal scarring due to diabetes mellitus, chronic glomerulonephritis, or other renal disorders that lead to azotemia. Acquired cystic kidney disease (ACKD) is seen most commonly in patients undergoing dialysis (>75,000 cases) and is discovered incidentally in most instances. The nephrons that survive the underlying renal diseases are stimulated to grow and accumulate abnormal amounts of fluid. The disease is the consequence of the uremic environment, with replacement of renal function with an allograft leading to reversal of the cystic lesions in some cases. In contrast to patients with ADPKD and ARPKD, those with ACKD are more likely to have solitary or multicentric adenocarcinomas. Future therapies of hereditary renal cystic disorders will be directed at diminishing the extent of epithelial cellular proliferation transepithelial fluid secretion, and interstitial fibrosis and at correcting the genetic defects.