Clinical Description
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 two organ systems primarily affected are kidney and liver; secondary effects are seen in several other organ systems.
Presentation. The majority of affected individuals present in the neonatal period. With modern obstetric ultrasonography, the diagnosis may be suspected when abnormalities are detected by prenatal ultrasound examination. Severely affected fetuses detected during prenatal ultrasound display a "Potter-like" oligohydramnios phenotype with lethal pulmonary hypoplasia and massively enlarged echogenic kidneys, which can compromise normal delivery.
Due to its wide clinical variability, the diagnosis of ARPKD may be made during any stage of childhood; in rare cases it does not present until adolescence or adulthood [Gunay-Aygun et al 2010b]. A minority of affected individuals present as older children or young adults with evidence of hepatic dysfunction as the prominent presenting feature (see Liver).
Kidney. Large bilateral flank masses (nephromegaly) are invariably present on physical examination.
Urine output is usually not diminished; polyuria and polydipsia are consistent with a renal concentrating defect. However, oliguria and overt acute renal failure may be seen in the first week of life.
Hyponatremia is often present in the neonatal period but usually resolves unless renal failure is present.
Renal function (as reflected in serum concentrations of creatinine and blood urea nitrogen [BUN]) is often impaired. Apparent improvement in renal function over time occurs with progression of normal kidney development over the first three years of life.
Hypertension, often severe, is usually noted within the first few weeks of life but may improve over time with developmental maturation.
End-stage renal disease (ESRD). More than 50% of affected individuals progress to ESRD, usually in the first decade of life [Hoyer 2015, Sweeney et al 2016]. ESRD may require kidney transplantation (see Management).
Perinatal presentation and corticomedullary involvement demonstrated by high-resolution ultrasound examination are associated with more rapid progression of renal disease [
Gunay-Aygun et al 2010b].
In a large cohort of neonatal survivors, actuarial kidney survival rates were 86% at age five years, 71% at age ten years, and 42% at age 20 years [
Bergmann et al 2005].
Individuals with
DZIP1L pathogenic variants identified to date did not reach ESRD until the second or third decade of life [
Lu et al 2017]
Liver. 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 [Sweeney & Avner 2011, Sweeney & Avner 2014, Sweeney et al 2016].
Congenital hepatic fibrosis (CHF). The invariant liver lesion of ARPKD caused by pathogenic variants in PKHD1 (also known as CHF) is a developmental abnormality of biliary ductal plate remodeling. The prevalence of CHF in those with ARPKD caused by pathogenic variants in DZIP1L has not yet been adequately determined; among the seven individuals with DZIP1L pathogenic variants identified to date, only one individual was examined for this finding and the CHF was mild [Lu et al 2017].
Individuals with CHF develop progressive portal hypertension with resulting esophageal or gastric varices, enlarged hemorrhoids, splenomegaly, hypersplenism, protein-losing enteropathy, and gastrointestinal bleeding [
Telega et al 2013,
Sweeney et al 2016].
Up to 70% of affected individuals (including long-term survivors with classic presentations and those who present with predominantly hepatobiliary disease) develop portal hypertension due to progressive periportal fibrosis; bleeding from esophageal varices contributes significantly to the morbidity and mortality of the disease [
Gunay-Aygun et al 2013,
Sweeney & Avner 2014,
Sweeney et al 2016].
Although histologic hepatic fibrosis is invariably present at birth, clinical, radiographic, or laboratory evidence of liver disease may be absent in newborns [
Shneider & Magid 2005]. In 115 children with ARPKD with a mean age at diagnosis of 29 days,
Zerres et al [1996] found that 45% had clinical evidence of liver involvement at presentation.
Caroli syndrome. In addition to CHF, nonobstructed dilatation of the intrahepatic bile ducts (Caroli syndrome) and dilatation of the common bile duct occur in more than 60% of individuals with ARPKD.
The resultant abnormal hepatobiliary drainage contributes to a significant risk for recurrent or persistent bacterial ascending cholangitis with sepsis.
Cholestasis may also lead to malabsorption of fat-soluble vitamins (A, D, E, and K).
The overall abnormal proliferation of biliary cells has reportedly led to benign or malignant tumors in older individuals. Cholangiocarcinoma has been reported in individuals with ARPKD in adulthood [
Fonck et al 2001].
Hepatosplenomegaly. A subset of individuals with ARPKD are identified with hepatosplenomegaly [Roy et al 1997]; the renal disease is often mild and may be discovered incidentally during imaging studies of the abdomen.
In a well-studied National Institutes of Health (NIH) cohort of 73 individuals who had confirmed ARPKD, splenomegaly was an early indicator of biliary dysfunction [
Gunay-Aygun et al 2013].
Splenomegaly was found in 60% of the affected children younger than age five years but did not correlate with renal function, the type of
PKHD1 variant, or severity of renal disease [
Gunay-Aygun et al 2013].
In a study that challenged many assumptions about the timing of liver involvement in ARPKD,
Adeva et al [2006] reported that nearly one third of individuals with pathogenic variants in
PKHD1 and hepatic involvement were older than age 20 years at the time of initial presentation.
This wide variability in age of diagnosis was confirmed in a cohort of 78 affected individuals enrolled in an NIH natural history study, in which affected individuals ranged in age from one to 56 years [
Gunay-Aygun et al 2010a,
Gunay-Aygun et al 2010b], demonstrating that the clinical spectrum of ARPKD/CHF is much broader than previously assumed.
Lung. Pulmonary hypoplasia resulting from oligohydramnios occurs to varying degrees in a number of affected infants and is a major cause of morbidity and mortality in the newborn period. Massively enlarged kidneys may also lead to hypoventilation and respiratory distress as a result of limitation of diaphragmatic excursion.
In contrast to neonates with other disorders complicated by oligohydramnios, a small proportion of newborns with ARPKD and oligo- or anhydramnios in the third trimester may have relatively minor lung disease [
Sweeney & Avner 2011]. The reason for this is unclear, but the authors speculate that intrauterine renal overproduction of growth factors critical for lung development (including members of the epidermal growth factor axis) may have an as-yet unexplained positive effect on lung development.
Long-term pulmonary function appears to be good unless individuals with ARPKD require mechanical ventilation in the newborn period [
Jahnukainen et al 2015].
Dysmorphic features. Facial characteristics associated with the oligohydramnios sequence including low-set ears, micrognathia, flattened nose, limb positioning defects, and growth deficiency may be present.
Other
Recent data suggest that with aggressive nutritional support, growth may be normal in a significant number of children [
Sweeney & Avner 2011,
Sweeney et al 2016]. Aggressive nutritional support in the first two years of life has dramatically improved growth rates even in children with significant renal impairment and portal hypertension [
Telega et al 2013].
Feeding difficulties may result from mechanical compression of the stomach by enlarged kidneys, liver, or spleen, the latter a complication of portal hypertension. Alternatively, significant renal impairment may result in feeding difficulties, loss of appetite, and/or impaired gastric motility.
Children with ARPKD appear to have neurocognitive functioning comparable to other children with a similar degree of chronic kidney disease. Neurocognitive functioning includes intellectual functioning, academic achievement, attention regulation, executive functioning, and behavior [
Hartung et al 2014].
Mortality. Although the short- and long-term mortality rates of ARPKD are significant, the survival of children with ARPKD has improved significantly with modern neonatal respiratory support and renal replacement therapies.
Kidney and liver transplantation. For individuals with ARPKD who undergo kidney transplantation, allograft survival rates are comparable to those in individuals without ARPKD [Telega et al 2013]. It is estimated that approximately 10% of affected children surviving the neonatal period will require liver transplantation [Wen 2011].
Of those affected individuals who succumb after kidney transplant, 64%-80% of the time mortality is directly attributable to cholangitis/sepsis, a consequence of hepatobiliary disease [Telega et al 2013].
A significant number of individuals with ARPKD who require a renal transplant also suffer from significant hepatobiliary disease and progressive portal hypertension that will most likely require portosystemic shunting or a liver transplant in the future [
Gunay-Aygun et al 2013].
Risk/benefit analysis suggests that individuals who have severe renal and severe hepatobiliary disease will have less morbidity and mortality if they undergo a liver transplant at the same time as their renal transplant (a dual organ transplant) [
Chandar et al 2015].
An algorithm for management and evaluation of the risk/benefit of dual organ transplant in individuals with ARPKD who have both severe kidney and liver disease has been proposed to assist clinicians in the decision-making process [
Telega et al 2013] (see
Management).
Penetrance
Penetrance for ARPKD is complete for those with PKHD1 pathogenic variants; significant intrafamilial variation in disease severity is observed [Sweeney & Avner 2011, Sweeney & Avner 2014, Sweeney et al 2016].
Penetrance for the renal abnormalities associated with ARPKD (enlarged echogenic kidneys with poor corticomedullary differentiation, systemic hypertension, and varying levels of renal dysfunction) is complete in those reported with DZIP1L pathogenic variants to date. Congenital hepatic fibrosis, an invariant finding in ARPKD associated with PKHD1, was mild in the single affected individual with DZIP1L pathogenic variants in whom this was examined [Lu et al 2017].
Nomenclature
ARPKD has also been referred to as "infantile polycystic kidney disease." In their original description of polycystic kidney disease in childhood, Blyth & Ockenden [1971] used clinical and histologic findings in the kidneys and liver to categorize childhood PKD as perinatal, neonatal, infantile, and juvenile, suggesting four distinct diseases or "stages of disease." Subsequently, families with multiple affected sibs (see, e.g., Kaplan et al [1988], Guay-Woodford & Desmond [2003]) provided evidence that these distinctions were not meaningful.
The most recent trend is to refer to this condition as ARPKD/CHF; at least one patient advocacy group, the ARPKD/CHF Alliance, has adopted this terminology (see Resources).