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.

Suggestive Findings

Autosomal recessive polycystic kidney disease (ARPKD) should be suspected in individuals with bilaterally enlarged, diffusely echogenic kidneys. Diagnosis is typically made based on clinical presentation and radiographic findings [Sweeney & Avner 2011, Telega et al 2013, Hartung & Guay-Woodford 2014, Sweeney & Avner 2014, Hoyer 2015, Sweeney et al 2016]. Specific diagnostic criteria of ARPKD (modified from Zerres et al [1996]):

• Typical findings on renal imaging
  AND
• One or more of the following:
  • Imaging findings consistent with biliary ductal ectasia (see Ultrasonography)
  • Clinical/laboratory signs of congenital hepatic fibrosis (CHF) that leads to portal hypertension and may be indicated by hepatosplenomegaly and/or esophageal varices
  • Hepatobiliary pathology demonstrating a characteristic developmental biliary ductal plate abnormality and resultant CHF (see Childhood and young adulthood)
  • Absence of renal enlargement and/or characteristic imaging findings in both parents, as demonstrated by high-resolution ultrasonography (HRUS) examination
  • Pathologic (biopsy or autopsy) or genetic diagnosis of ARPKD in an affected sib

Establishing the Diagnosis

The diagnosis of ARPKD is established in a proband with renal cystic enlargement, congenital hepatic fibrosis, and biallelic pathogenic variants in PKHD1 identified on molecular genetic testing (see Table 1).

Recently, in the absence of identifiable pathogenic variants in known PKD-associated genes, the discovery of biallelic pathogenic variants in DZIP1L in seven affected individuals from four unrelated consanguineous pedigrees with hallmarks of ARPKD led the authors to suggest that DZIP1L is a second genetic locus for ARPKD [Lu et al 2017]. However, the rare occurrence and the unusual phenotype of the Dzip1l mutant mouse suggest more evidence is required before DZIP1L is definitively proven to be a second locus for ARPKD.

Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

• Single-gene testing. Sequence analysis of PKHD1 is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found. Sequence analysis of DZIP1L may be performed if no pathogenic variant of PKHD1 is identified; note, however, that DZIP1L has not yet been definitively proven to be a second locus for ARPKD.
• A multigene panel that includes PKHD1, DZIP1L, and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes PKHD1 and DZIP1L) fails to confirm a diagnosis in an individual with features of ARPKD. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

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 found to be 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.
• Cerebral aneurysm, a potentially severe complication of autosomal dominant polycystic kidney disease (ADPKD), has been reported in two adults and a child with ARPKD [Chalhoub et al 2013]. Despite the increased incidence of aneurysms in ADPKD and the interactions between ADPKD and ARPKD proteins there is no evidence to date that aneurysms are an extrarenal manifestation of ARPKD [Sweeney & Gunay-Aygun et al 2016].
• 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.

• Approximately 23%-30% of affected infants die in the neonatal period or within the first year of life, primarily of respiratory insufficiency or superimposed pulmonary infections [Hoyer 2015].
• Of those who survive beyond the first year of life (with the use of dialysis and kidney and/or liver transplantation as indicated), one-year survival is approximately 85%-87% [Guay-Woodford & Desmond 2003, Bergmann et al 2005] and ten-year survival is 82% [Hoyer 2015].
• Despite improved survival, morbidity of this dual organ disease is significant due to the following:
  • Renal collecting duct ectatic cysts and marked renal enlargement, leading to systemic hypertension and progressive renal failure
  • Biliary dysgenesis, leading to abnormal bile duct formation with progressive periportal congenital hepatic fibrosis

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).

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been established to date for either PKHD1 or DZIP1L. Most PKHD1 pathogenic variants are "private" or unique to single families [Bergmann et al 2004].

In a study of 73 persons of varying ages with ARPKD caused by PKHD1 pathogenic variants, variant type did not correlate with kidney size or function [Gunay-Aygun et al 2010a]. Frank et al [2014] identified four affected persons who survived the neonatal period despite each carrying a homozygous PKHD1 pathogenic variant expected to lead to premature termination of translation (usually incompatible with life).

Modifying genes, epigenetic changes, and variations in other non-coding regions of the genome are believed to be responsible for the wide interfamilial clinical variability [Sweeney & Avner 2014, Sweeney et al 2016].

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).

Prevalence

The incidence of ARPKD is estimated at 1:10,000 to 1:40,000. The true incidence may be underestimated because of the failure to correctly diagnose persons of all ages, ranging from newborns to young adults [Adeva et al 2006, Gunay-Aygun et al 2010a]. The number of ARPKD cases that may be caused by DZIP1L pathogenic variants is so small that the prevalence of ARPKD would not be affected by any additional cases associated with DZIP1L.

The carrier frequency for a PKHD1 pathogenic variant in the general population has been estimated at 1:70 [Zerres et al 1998].

Renal Manifestations

Disorders with cystic renal disease include the following:

• Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst development and bilaterally enlarged polycystic kidneys. ADPKD is a systemic disease with cysts in other organs (e.g., the liver, seminal vesicles, pancreas, and arachnoid membrane) and non-cystic abnormalities (e.g., intracranial aneurysms and dolichoectasias, dilatation of the aortic root and dissection of the thoracic aorta, mitral valve prolapse, colonic diverticulae, abdominal wall hernias). In approximately 85% of individuals with ADPKD, a pathogenic variant in PKD1 is causative; in approximately 15%, a pathogenic variant in PKD2 is causative.
  Although most ADPKD presents in adulthood, 1%-2% of affected individuals present as newborns, often with signs and symptoms indistinguishable from those of ARPKD [Guay-Woodford et al 1998, Sweeney & Avner 2011, Sweeney & Avner 2014, Sweeney et al 2016]. Renal ultrasonography may distinguish between the two: bilateral macrocysts are typical of ADPKD. Early in the course of ADPKD, especially in younger children, renal involvement may be unilateral. As ADPKD progresses involvement becomes bilateral; cysts can become massive.
  Congenital hepatic fibrosis (CHF), an invariable finding in ARPKD, is rarely observed in ADPKD [O'Brien et al 2012]. (Note: The occurrence of CHF in humans with DZIP1L-related kidney disease has not been adequately addressed.)
  Because ADPKD may not present until the third or fourth decade of life, an asymptomatic parent may not be identified as having ADPKD until after the birth of an affected child [Fick et al 1993]. Renal ultrasound examination of the parents of any individual with atypical ARPKD or suspected ADPKD is needed to evaluate for possible previously undiagnosed ADPKD. Of note:
  • As observed by Pei et al [2009], it may not be possible to exclude the diagnosis of ADPKD in a small subset of persons (i.e., those with PKD2 pathogenic variants) until age 40 years;
  • Approximately 5%-10% of individuals with ADPKD have a de novo pathogenic variant, and thus do not have an affected parent.
• Glomerulocystic kidney disease (GCKD), a disorder that typically presents in the neonatal period with large palpable flank masses, may be clinically indistinguishable from ARPKD. Findings on renal ultrasound examination may also resemble those seen in ARPKD: diffusely enlarged echogenic kidneys and occasional macrocysts. Histologic examination shows dilatation of Bowman's capsule and dysplasia with abnormal medullary differentiation. Ten percent have involvement of the intrahepatic bile ducts, similar to the biliary ductal plate abnormality of ARPKD.
  GCKD can be a subtype of ADPKD; however, in at least one large kindred, linkage to both ADPKD loci was excluded [Sharp et al 1997]. GCKD also occurs as part of genetic disorders including the tuberous sclerosis complex, orofacial digital syndrome type 1, trisomy 13, brachymesomelia-renal syndrome, and short rib-polydactyly syndrome.
• Renal cysts and diabetes syndrome (RCAD) (OMIM 137920). Pathogenic variants in a gene that encodes for the transcription factor hepatocyte nuclear factor 1 beta (HNF1β) represent the most common known monogenetic cause of developmental kidney disease [Clissold et al 2015, Verhave et al 2016]. This disorder is the leading cause of hyperechoic enlarged or normal-sized fetal kidneys, which often lead to a misdiagnosis of ARPKD. Renal cysts are the most frequently detected feature of HNF1β-associated kidney disease, although other renal phenotypes (single kidney, renal hypoplasia/dysplasia) can also occur. Extrarenal phenotypes are common and HNF1β was first identified as a disease gene for diabetes (MODY5). Other phenotypes reported (which serve to differentiate this genetic disorder from ARPKD) include genital malformations, autism, epilepsy, gout, hypomagnesemia, hyperthyroidism, liver and intestinal abnormalities, and a rare form of kidney cancer [Bockenhauer & Jaureguiberry 2016, Limwongse 2016].
• Diffuse cystic dysplasia is characterized by ultrasonographic findings of large echogenic kidneys and histologic findings of disorganized, poorly differentiated nephron segments with primitive elements such as cartilage [Watkins et al 1999]. Diffuse cystic dysplasia can occur sporadically or more commonly as a component of numerous syndromes (e.g., Joubert syndrome, Meckel-Gruber syndrome, Jeune asphyxiating thoracic dystrophy) [Limwongse et al 1999, Limwongse 2016]. In these syndromes, the extrarenal or extrahepatic abnormalities clinically predominate; the diffuse cystic dysplasia remains a more minor feature.
• Other "polycystic kidney" diseases. A number of studies report "polycystic kidneys" as a component of numerous congenital syndromes. In fact, many of these reports may be describing syndromic forms of cystic dysplasia.
  There are a number of diseases where renal cysts are a pathologic finding. These differ from ARPKD in that the renal cysts represent only one component of multiple developmental abnormalities that characterize the syndrome [Limwongse 2016]. A syndrome of neonatal diabetes mellitus, congenital hypothyroidism, hepatic fibrosis, PKD, and congenital glaucoma has been described in two sibs. Liver biopsy confirmed the classic findings of CHF; histologic evaluation of the kidneys was not performed (OMIM 601331).

Other disorders with renal involvement that may mimic ARPKD in the neonatal period include malignancies such as leukemia or Wilms tumor (see Wilms Tumor Overview), bilateral renal vein thrombosis, and radiocontrast nephropathy [Guay-Woodford et al 1998, Sweeney & Avner 2011, Sweeney et al 2016].

Liver Manifestations

Other hepatorenal disorders characterized by renal cystic changes and hepatic fibrosis to consider include a number of disorders already mentioned: juvenile nephronophthisis and multisystem disorders such as Meckel-Gruber syndrome, Bardet-Biedl syndrome, Joubert syndrome, and Jeune asphyxiating thoracic dystrophy [Johnson et al 2003]. In these autosomal recessive disorders the kidneys are usually small or normal in size, in contrast to the enlarged kidneys of ARPKD.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with autosomal recessive polycystic kidney disease (ARPKD), the following evaluations are recommended:

• Respiratory status, including physical examination, pulse oximetry, and chest radiographs (as indicated)
• Tests of renal function, including serum concentrations of BUN, creatinine, and cystatin C, which allows a more accurate estimation of glomerular filtration rate (GFR) [Gunay-Aygun et al 2010a]
• Serum electrolyte concentrations to identify electrolyte abnormalities (e.g., hyponatremia, hyperkalemia)
• Urinalysis to assess for the urinary concentration and proteinuria. Clinical assessment of intravascular volume status for possible volume depletion or overload.
  Note: White blood cells are commonly present in the urine of children with ARPKD and may not represent infection. If there is a clinical suspicion of urinary tract infection, a urine culture should be obtained before initiating treatment.
• Renal ultrasonography (consider high-resolution technology when available)
• Measurement of blood pressure. If elevated, home blood pressure monitoring can be helpful in distinguishing fixed hypertension from "white coat" hypertension (i.e., high blood pressure that occurs during medical examinations).
• Assessment of feeding, weight gain, and linear growth with formal nutrition consultation as appropriate
• Measurement of liver transaminases, serum bile acids, hepatic synthetic function (e.g., by assessing serum albumin concentration, 25-OH vitamin D levels, vitamin E levels and coagulation studies), fat-soluble vitamin levels, complete blood counts, physical examination for hepatomegaly/splenomegaly, and abdominal ultrasonography to assess the clinical extent of liver involvement
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

(See recent comprehensive reviews including Sweeney & Avner [2011], Telega et al [2013], Guay-Woodford et al [2014], Sweeney & Avner [2014], and Sweeney et al [2016] for detailed management strategies.)

Initial management of affected infants centers on stabilization of respiratory function.

Respiratory

• Mechanical ventilation may be necessary to treat pulmonary hypoplasia (characterized by inability to oxygenate despite jet or oscillating ventilation with 100% oxygen) or hypoventilation from massively enlarged kidneys (characterized by increased pCO₂ despite adequate oxygenation). It may also be required in the first 48-72 hours postnatally to determine whether pulmonary hypoplasia or reversible pulmonary disease is present.
• When massively enlarged kidneys prevent diaphragmatic excursion and/or cause severe feeding intolerance, some have advocated unilateral or bilateral nephrectomy [Shukla et al 2004].
  • Experience suggests that unilateral nephrectomy may be of limited value, since the contralateral kidney often shows marked enlargement following unilateral nephrectomy [Author, unpublished observations].
  • Bilateral nephrectomy with placement of a peritoneal dialysis catheter followed by a short period of hemodialysis often allows the peritoneum to heal in preparation for chronic peritoneal dialysis [Sweeney & Avner 2011, Sweeney et al 2016]. The timing of these procedures, as well as potential coordination with a preemptive living donor transplantation, will be dictated by factors such as the age, size, and clinical status of the patient as well as living donor availability.

Renal

• Neonates with oliguria or anuria may require peritoneal dialysis within the first days of life.
• Hyponatremia is common and should be treated depending on the individual's volume status.
• Early recognition and treatment of dehydration is critical. Supplemental feedings or fluid therapy via nasogastric or gastrostomy tubes may be required.
• Hypertension generally responds well to angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor inhibitors (ARBs), which are the treatments of choice. In many cases, hypertension may be severe enough to require multiple antihypertensive medications.
• Affected children with significant chronic kidney disease should be treated with all modalities of modern pediatric end-stage renal disease (ESRD) therapy, including dialysis and kidney transplantation.
• Anemia in children with Stage III or higher chronic kidney disease may require treatment with iron supplementation and erythropoietin-stimulating agents (ESAs).

Liver. Treatment of biliary dysfunction focuses on: (1) malabsorption of nutrients and fat-soluble vitamins; and (2) the risk for ascending cholangitis.

• Administration of synthetic bile acids:
  • The presence of poor serum levels of fat-soluble vitamins (K, D, E, A) or poor weight gain despite adequate caloric supplementation may indicate the need for bile acid supplementation.
  • Clinical suspicion of bile acid deficiency may be verified by measurement of serum bile acids.
  • Administration of synthetic bile acids is indicated if there is evidence of significant intrahepatic ductal dilation (Caroli syndrome), which can be appreciated by magnetic resonance cholangiopancreatography (MRCP).
• Bacterial cholangitis, often an underdiagnosed complication in those with hepatic involvement, may present as recurrent bacteremia