ARPKD): Kidney-Related and Non-Kidney-Related Phenotypes

Pediatr Nephrol (2014) 29:1915–1925 DOI 10.1007/s00467-013-2634-1 EDUCATIONAL REVIEW Clinical manifestations of autosomal recessive polycystic kidney disease (ARPKD): kidney-related and non-kidney-related phenotypes Rainer Büscher & Anja K. Büscher & Stefanie Weber & Julia Mohr & Bianca Hegen & Udo Vester & Peter F. Hoyer Received: 26 April 2013 /Revised: 5 September 2013 /Accepted: 6 September 2013 /Published online: 10 October 2013 # IPNA 2013 Abstract Autosomal recessive polycystic kidney disease disease. In this review we focus on common and uncommon (ARPKD), although less frequent than the dominant form, is kidney-related and non-kidney-related phenotypes. Clinical a common, inherited ciliopathy of childhood that is caused by management of ARPKD patients should include consideration mutations in the PKHD1-gene on chromosome 6. The charac- of potential problems related to these manifestations. teristic dilatation of the renal collecting ducts starts in utero and can present at any stage from infancy to adulthood. Renal Keywords ARPKD . Extrarenal manifestation . Children . insufficiency may already begin in utero and may lead to early Hepatic fibrosis . Portal hypertension . Caroli’ssyndrome abortion or oligohydramnios and lung hypoplasia in the new- born. However, there are also affected children who have no evidence of renal dysfunction in utero and who are born with Introduction normal renal function. Up to 30 % of patients die in the perinatal period, and those surviving the neonatal period reach Autosomal recessive polycystic kidney disease (ARPKD) be- end stage renal disease (ESRD) in infancy, early childhood or longs to the family of cilia-related disorders and is an important adolescence. In contrast, some affected patients have been inherited disease with distinct clinical features and genetics. In diagnosed as adults with renal function ranging from normal contrast to the relatively frequent autosomal dominant polycys- to moderate renal insufficiency to ESRD. The clinical spectrum tic kidney disease (ADPKD), ARPKD is much rarer, with an of ARPKD is broader than previously recognized. While bilat- incidence varying from approximately 1/10,000 to 1/40,000 eral renal enlargement with microcystic dilatation is the pre- live births in Caucasians [1–3]. It is generally diagnosed on dominant clinical feature, arterial hypertension, intrahepatic the basis of clinical criteria, especially renal ultrasonography. biliary dysgenesis remain important manifestations that affect The organs that are primarily affected are the kidneys (poly- approximately 45 % of infants. All patients with ARPKD cystic kidneys) and liver (congenital hepatic fibrosis). In addi- develop clinical findings of congenital hepatic fibrosis (CHF); tion, several other extrarenal manifestations occur less frequent- however, non-obstructive dilation of the intrahepatic bile ducts ly but can be observed at any age and disease stage [2, 4, 5]. in the liver (Caroli’s disease) is seen at the histological level in The variability of organ involvement in ARPKD is not comple- only a subset of patients. Cholangitis and variceal bleeding, tely understood [6, 7]; however, different combinations of sequelae of portal hypertension, are life-threatening complica- mutations in the fibrocystin gene PKHD1 and its resulting tions that may occur more often in advanced cases of liver changes in the fibrocystin/polyductin protein structure may at least partially explain the phenotypic variance [7, 8]. It is widely recognized and corroborated by intrafamilial clinical variability * : : : : : R. Büscher ( ) A. K. Büscher S. Weber B. Hegen U. Vester among affected siblings that resulting ARPKD phenotypes P. F. Hoyer Children’s Hospital, Pediatrics II, University of Duisburg-Essen, frequently cannot be simply explained on the basis of the Hufelandstr. 55, 45122 Essen, Germany PKHD1 genotype. Phenotypes may also depend on the back- e-mail: [email protected] ground of other genes, combinations of mutations or disease- modifying genes, epigenetic factors, hormonal effects, and J. Mohr Department of Pediatrics, HELIOS Klinikum Krefeld, environmental influences [6, 7, 9]. However, severe pheno- Lutherplatz 40, 47805 Krefeld, Germany types, such as neonatal demise, are more often associated with 1916 Pediatr Nephrol (2014) 29:1915–1925 chain-terminating, truncating PKHD1 mutations than with risks of acute bleeding, and they are also at risk of developing moderate phenotypes, and the presence of two chain- bacteremic infections from both splenic dysfunction and terminating mutations invariably results in perinatal lethality cholangitis [3, 11, 16]. Patients with severe PH and dependent [8, 10]. In contrast, amino acid substitutions are more common- complications (e.g., gastroesophageal varices) may require ly associated with nonlethal presentation, and the presence of at porto-systemic shunting. Portal decompressive surgical shunts least one amino acid substitution is required for affected indi- are uncommon in pediatric ARPKD patients and are only viduals to survive the perinatal period [8, 10]. implanted at specialized transplant centers [20]. Because nor- Pulmonary hypoplasia, a serious complication that generally mal kidney function plays a pivotal role in ammonia disposal, occurs as the result of oligohydramnios, is due to poor fetal porto-systemic shunting can be especially contraindicated in urine output, leading to respiratory failure and neonatal death patients with impaired kidney function, unless they have [2, 3]. Almost 30 % of affected newborns that present with successfully undergone kidney transplantation [12, 21]. large, echogenic kidneys die within the neonatal period owing In addition, after 40 years of age, adult ARPKD patients are to respiratory insufficiency [2, 3, 9, 11]. Some patients that at increased risk of developing benign and malignant liver survive the neonatal period present with complications primar- tumors, particularly cholangiocarcinoma [16, 20]. Although ily associated with liver disease, such as portal hypertension this is not a significant problem while patients are in pediatric (PH) [3, 4] and esophageal bleeding [9, 12, 13], later in child- care, it may be important to be aware of this possibility when hood and adulthood; others may progress to end-stage renal adolescents are transitioned to internists [20]. disease (ESRD) within the first decades of life [3]. Other Extrarenal cysts are uncommon in pediatric patients and are associated comorbidities, such as systemic hypertension [4], more frequently seen in adults [22]. Liver cysts (Fig. 5)are renal failure [3, 14, 15], or chronic lung disease [11], can also more common in ADPKD patients and occur only rarely in occur when the children get older. As more patients with ARPKD patients, although choledochal cysts have been report- ARPKD survive to adulthood, liver and other complications ed in the latter group [2, 12]. Gunay-Aygun and colleagues [23] are likely to become more prevalent, with hepatosplenomegaly performed ultrasound evaluations in 110 parents from 64 inde- being the predominant clinical finding [3]. pendent ARPKD families and identified multiple liver cysts in The focus of our review is the broadened spectrum of the several parents, suggesting that carrier status of PKHD1 muta- ARPKD phenotype beyond the kidney, with attention given to tions creates a predisposition for liver cysts. Furthermore, they certain kidney-related and non-kidney-related manifestations suggest that ARPKD patients might have liver cysts that are (Fig. 1; Table 1). continuous with the biliary tree, differing from the isolated cysts predominantly observed in ADPKD patients [23]. Hepatobiliary disease Complications of liver disease: portal hypertension, Autosomal recessive polycystic kidney disease is character- esophageal varices, and variceal bleeding ized by dysgenesis of the hepatic portal triad, which is associated with defective remodeling of the ductal plate, hyper- Although PH in ARPKD was not systematically studied in the plastic biliary ducts, and congenital hepatic fibrosis (CHF) past, it starts early in life and progresses over time [12, 13, 17]; (Fig. 2)[13, 16, 17]. Although these pathological changes are 40–50 % of infants surviving the first year of life will develop present at the microscopic level at birth, the significance of evidence of PH over time [9, 11]. While renal disease diag- these findings is variable, and clinical and radiographic com- nosed during the first year of life is most severe in neonates, plications of CHF may become apparent at any time between many of the surviving patients develop sequelae from con- birth and adulthood (Fig. 3)[16–18]. Liver manifestations genital hepatic fibrosis later in life, including hypersplenism, may comprise the major symptomatic disease complications PH, and variceal bleeding [13]. Despite these hepatobiliary in older patients [4, 19]. Fortunately, hepatocellular function is complications, hepatocellular function is usually preserved for usually preserved early in the course of the disease. Subsets of a long time, and patients are more likely to present with patients develop Caroli disease, which is associated with hematemesis or melena resulting from bleeding esophageal recurrent cholangitis and risk of sepsis (Fig. 4). In some varices. PH can only be diagnosed clinically by the presence patients, particularly after the use of dialysis to treat ESRD of splenomegaly, hypersplenism, or esophageal varices, the due to the complete

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