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Kidney and Urinary Tract Function

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for diagnosis of ADPKD, but are usually reserved for cases in which radiographic imaging is negative and the need for a definitive diagnosis is essential, such as when screening family members for potential kidney dona- tion. Magnetic resonance angiography is recommended for persons who have a family history of cerebral aneu- rysm or stroke and for those with new-onset or severe headache. The treatment of ADPKD is largely supportive and aimed at delaying progression of the disease. Control of hypertension and prevention of ascending UTIs are important. Pain is a common complaint of persons with ADPKD, and a systematic approach is needed to differ- entiate the etiology of the pain and define an approach for management. Cyclic adenosine monophosphate (cAMP) has been shown to increase proliferation of epithelial cells in cyst walls and the rate of fluid secretion into cysts. One of the prime mediators of cell proliferation, acting through cAMP, is arginine vasopressin (AVP), also known as the antidiuretic hormone . In studies using genetically pro- duced polycystic animals, the use of vasopressin V2 receptor inhibitors reduced cyst growth and preserved renal function. Because an increase in urine osmolality serves to increase vasopressin levels, it is often recom- mended that persons with ADPKD drink approximately 3000 L of water throughout the waking hours to reduce plasma AVP levels. 6,7 Normally cAMP is broken down by phosphodiesterases. Because caffeine raises cAMP levels by interfering with phosphodiesterase activity, it is also recommended that caffeinated beverages be avoided. 6,7 In addition to increasing water intake to decrease vasopressin levels, the angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) may be used to interrupt the renin-angiotensin- aldosterone system as a means of reducing intraglomer- ular pressure and renal vasoconstriction. Although not approved by the Food and Drug Administration (FDA), there has been recent interest in the use of vasopressin receptor antagonists (vaptans) to decrease cyst develop- ment. 9 Dialysis and kidney transplantation are reserved for those who progress to kidney failure. Autosomal Recessive Polycystic Kidney Disease Autosomal recessive (childhood) polycystic kidney disease (ARPKD) is characterized by cystic dilation of the cortical and medullary collecting tubules 3–5 (see Fig. 25-2B). It is rare compared with ADPKD, occurring in 1 to 20,000 live births. Autosomal recessive (childhood) polycystic kidney disease is caused by mutations in the PKHD1 gene. The gene product, fibrocystin, is found in the collecting ducts of the kidney, biliary ducts of the liver, and exocrine ducts of the pancreas, and appears to be involved in the regulation of cell proliferation and adhesion. Perinatal, neonatal, infantile, and juvenile subcategories have been defined, dependent on time of presentation. The perinatal and infantile types are most common. Serious manifes- tations are usually present at birth, with the infant pro- gressing rapidly into renal failure.

The typical infant with ARPKD presents with bilat- eral flank masses, accompanied by severe renal fail- ure, signs of impaired lung development, and variable degrees of liver fibrosis and portal hypertension. Potter facies and other defects associated with oligohydram- nios may be present. Hypertension is usually noted within the first few weeks of life and is often severe. Approximately 75% of infants die during the perinatal period, often of pulmonary hypoplasia. 3 Children and juveniles who survive infancy develop a distinctive type of liver fibrosis. In older children, liver disease is the pre- dominant clinical concern. The treatment of ARPKD is largely supportive. Aggressive ventilatory support is often necessary in the neonatal period because of pulmonary hypoplasia and hypoventilation. Modern neonatal respiratory technol- ogy and renal replacement therapy (e.g., dialysis and kidney transplant) have increased the 10-year survival rate of children surviving beyond the 1st year of life. Morbidity and mortality in the older child is related to complications of kidney failure and liver disease. Nephronophthisis and Medullary Cystic Kidney Disease Nephronophthisis and adult-onset medullary cystic kid- ney disease both produce progressive medullary tubu- lointerstitial cystic disease, but vary in terms of genetic causes and patterns of inheritance. 4,5 Nephronophthisis has an autosomal recessive pattern of inheritance with onset in infancy, childhood, or adolescence. It is caused by mutations in NPHP genes, whose gene products are located on the primary cilia, similar to those of ADPKD and ARPKD. Medullary cystic kidney disease has an autosomal dominant pattern of inheritance, with onset in adolescence and progression to renal failure in adulthood that is caused by a mutation in the MCKD 1 or 2 genes. 4 Common characteristics of the two cystic diseases are small and shrunken kidneys and the presence of a variable number of cysts, usually concentrated at the corticomedullary junction area of the kidney. The ini- tial insult involves the distal tubules, with tubular base- ment membrane disruption followed by chronic and progressive tubular atrophy involving both the medulla and cortex. Although the presence of medullary cysts is important, the cortical tubulointerstitial damage is the eventual cause of chronic kidney disease and failure. 5 Nephronophthisis can present as three clinical vari- ants: infantile, juvenile, or adolescent. 4 The juvenile form is most common and accounts for 5% to 10% of chronic kidney disease in children. Symptoms begin between 4 to 6 years of age, and progress to chronic kidney disease within 10 years. Some juvenile forms of nephronophthisis have extrarenal complications, includ- ing ocular motor abnormalities, retinitis pigmentosa, liver fibrosis, and cerebellar abnormalities. The onset and progression of the adolescent form causes chronic kidney failure at 10 to 20 years of age, and the infantile form before 2 years of age. Children with nephronophthisis and adults with med- ullary cystic kidney disease present first with polyuria,