Autosomal recessive polycystic kidney disease: a hepatorenal fibrocystic disorder with pleiotropic effects

Abstract

Autosomal recessive polycystic kidney disease (ARPKD) is an important cause of chronic kidney disease in children. The care of ARPKD patients has traditionally been the realm of pediatric nephrologists; however, the disease has multisystem effects, and a comprehensive care strategy often requires a multidisciplinary team. Most notably, ARPKD patients have congenital hepatic fibrosis, which can lead to portal hypertension, requiring close follow-up by pediatric gastroenterologists. In severely affected infants, the diagnosis is often first suspected by obstetricians detecting enlarged, echogenic kidneys and oligohydramnios on prenatal ultrasounds. Neonatologists are central to the care of these infants, who may have respiratory compromise due to pulmonary hypoplasia and massively enlarged kidneys. Surgical considerations can include the possibility of nephrectomy to relieve mass effect, placement of dialysis access, and kidney and/or liver transplantation. Families of patients with ARPKD also face decisions regarding genetic testing of affected children, testing of asymptomatic siblings, or consideration of preimplantation genetic diagnosis for future pregnancies. They may therefore interface with genetic counselors, geneticists, and reproductive endocrinologists. Children with ARPKD may also be at risk for neurocognitive dysfunction and may require neuropsychological referral. The care of patients and families affected by ARPKD is therefore a multidisciplinary effort, and the general pediatrician can play a central role in this complex web of care. In this review, we outline the spectrum of clinical manifestations of ARPKD and review genetics of the disease, clinical and genetic diagnosis, perinatal management, management of organ-specific complications, and future directions for disease monitoring and potential therapies.

Keywords: congenital hepatic fibrosis; dialysis; genetic testing; kidney transplantation; liver transplantation; polycystic kidney disease; preimplantation genetic diagnosis.

FIGURE 1

The primary cilium and cystoproteins. The cilium concentrates and organizes a number of channels, receptors, and effectors, such as transcription factors and proteolytic fragments of cystoproteins. It therefore plays a critical role in transmitting information regarding the external milieu back into the cell and ultimately in regulating cellular and tubular differentiation and homeostasis. Cyst formation is characterized by deregulation of the balance between cell proliferation and differentiation. Cilia appear to play a role in maintaining this balance through sensing the extracellular milieu, responding to mechanical cues, and modulating different signaling cascades. Ciliary dysfunction contributes to increased intracellular accumulation of cAMP and activation of mammalian target of rapamycin (mTOR), features common to cystic epithelia in human and rodent models of renal cystic disease. Numerous groups have demonstrated that almost all cystoproteins, including polycystins; FPC; the nephrocystins; the Bardet Biedl syndrome (BBS) proteins; oral-facial-digital syndrome, type I (OFD1) protein; and the tuberous sclerosis type I (TSC1) protein Hamartin; all of these localize to the cilia/centrosome complex, providing compelling evidence that this complex is critical in the pathogenesis of renal cystic disease. mTORC1, mammalian target of rapamycin complex 1; V2R, V2 receptor.

FIGURE 2

Radiologic findings and pathologic features associated with ARPKD. A, Neonatal sonography with nephromegaly and increased echogenicity. B, Contrast-enhanced computed tomography in a symptomatic 4-year-old girl reveals a striated nephrogram and prolonged corticomedullary contrast retention. C, Light microscopy: ARPKD kidney from a 1-year-old child reveals discrete medullary cysts and dilated collecting ducts, hematoxylin and eosin (H&E) ×10. D, Light microscopy: later-onset ARPKD kidney with prominent medullary ductal ectasia, H&E ×10. E, Coronal heavily T2-weighted image of the abdomen in an 8-year-old boy reveals marked cystic and fusiform dilatation of the intrahepatic biliary system. F, Light microscopy: congenital hepatic fibrosis with extensive fibrosis of the portal area; ectatic, tortuous bile ducts; and hypoplasia of the portal vein, H&E ×40.