Polycystic Kidney Disease, Autosomal Recessive

Clinical characteristics Autosomal recessive polycystic kidney disease (ARPKD) belongs to a group of congenital hepatorenal fibrocystic syndromes and is a cause of significant renal and liver-related morbidity and mortality in children. The majority of individuals with ARPKD present in the neonatal period with enlarged echogenic kidneys. Renal disease is characterized by nephromegaly, hypertension, and varying degrees of renal dysfunction. More than 50% of affected individuals with ARPKD progress to end-stage renal disease (ESRD) within the first decade of life; ESRD may require kidney transplantation. Pulmonary hypoplasia resulting from oligohydramnios occurs in a number of affected infants. Approximately 30% of these infants die in the neonatal period or within the first year of life from respiratory insufficiency or superimposed pulmonary infections. With neonatal respiratory support and renal replacement therapies, the long-term survival of these infants has improved to greater than 80%. As advances in renal replacement therapy and kidney transplantation improve long-term survival, it is likely that clinical hepatobiliary disease will become a major feature of the natural history of ARPKD. In addition, a subset of individuals with this disorder are identified with hepatosplenomegaly; the renal disease is often mild and may be discovered incidentally during imaging studies of the abdomen. Approximately 50% of infants will have clinical evidence of liver involvement at diagnosis although histologic hepatic fibrosis is invariably present at birth. This can lead to progressive portal hypertension with resulting esophageal or gastric varices, enlarged hemorrhoids, splenomegaly, hypersplenism, protein-losing enteropathy, and gastrointestinal bleeding. Other hepatic findings include nonobstructed dilatation of the intrahepatic bile ducts (Caroli syndrome) and dilatation of the common bile duct, which may lead to recurrent or persistent bacterial ascending cholangitis due to dilated bile ducts and stagnant bile flow. An increasing number of affected individuals surviving the neonatal period will eventually require portosystemic shunting or liver transplantation for complications of portal hypertension or cholangitis. The classic neonatal presentation of ARPKD notwithstanding, there is significant variability in age and presenting clinical symptoms related to the relative degree of renal and biliary abnormalities. Diagnosis/testing The suspicion of a diagnosis of ARPKD is based on clinical findings in the proband and the absence of renal disease in the proband's biological parents. Identification of biallelic pathogenic variants in PKHD1 in the affected individual establishes the diagnosis ARPKD. A recent study indicates that DZIP1L may be a second gene associated with ARPKD; more evidence will be required for this to be definitively proven. Management Treatment of manifestations: Management of affected neonates centers on stabilization of respiratory function by mechanical ventilation and (rarely) unilateral or bilateral nephrectomy if massive kidney enlargement impairs diaphragmatic excursion. Neonates with oliguria or anuria may require peritoneal dialysis within the first days of life, and early recognition and treatment of dehydration and hypertension is critical. Affected children with significant chronic kidney disease should be treated with all modalities of modern pediatric ESRD therapy. Treatment of biliary dysfunction focuses on (1) malabsorption of nutrients and fat-soluble vitamins and (2) the risk for ascending cholangitis, and includes administration of synthetic bile acids and early recognition and treatment of ascending cholangitis. In those with progressive portal hypertension, endoscopy with sclerotherapy or banding of varices may be required. Portosystemic shunting and/or consideration of liver transplantation may be required. Those with ESRD and severe portal hypertension may be candidates for dual renal/liver transplantation. Prevention of secondary complications: Ursodiol treatment may increase the amount of bile acid and/or reduce the development of gallstones. Immunization against encapsulated bacteria in those with severe portal hypertension and splenic dysfunction is recommended. Palivizumab (Synagis®) for children younger than age 24 months with chronic lung disease and/or prematurity is recommended. Prophylaxis with antibiotics is recommended for those at high risk of developing ascending cholangitis. Surveillance: Regular monitoring of blood pressure, renal function, serum electrolyte concentrations, hydration status, nutritional status, and growth. Hepatobiliary dysfunction leading to portal hypertension is monitored by physical examination evaluating for hepatosplenomagly; regular examination of platelet count, in addition to serum albumin levels, PT/PTT, and 25-OH vitamin D, vitamin E levels, and fat-soluble vitamin levels. Periodic ultrasonography and referral to a hepatologist if hepatomegaly and/or splenomegaly develops; periodic monitoring by esophagogastroduodenoscopy (EGD) to detect esophageal varices. Consideration of MR cholangiography, a more sensitive measurement for biliary ectasia, at baseline and then as indicated. Agents/circumstances to avoid: Sympathomimetic agents in individuals with hypertension; nephrotoxic agents (NSAIDS and aminoglycosides) unless clinically indicated. Potentially hepatotoxic agents (e.g., acetaminophen doses of >30 mg/kg/day, herbal supplements, and alcohol) should be minimized. Preclinical data suggest that caffeine, theophylline-like medications, and calcium channel blockers should be avoided unless clinically necessary. Evaluation of relatives at risk: If the pathogenic variants in the family are not known, high-resolution renal and hepatic ultrasonographic evaluation and monitoring of systemic blood pressure may identify disease in sibs of a proband. Genetic counseling ARPKD is inherited in an autosomal recessive manner. Each sib of a proband has a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of inheriting a pathogenic variant and being a carrier, and a 25% chance of inheriting neither pathogenic variant and not being a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if both pathogenic variants have been identified in the family. No systematic data are available on the sensitivity and specificity of prenatal ultrasound examination in establishing the diagnosis of ARPKD in pregnancies at 25% risk.