Clinical Diagnosis

Diagnosis is typically made based on clinical presentation and radiographic findings [Sweeney & Avner 2011]. Specific diagnostic criteria of autosomal recessive polycystic kidney disease (ARPKD), modified from Zerres et al [1996]:

• Typical findings on renal imaging
  
  AND
• One or more of the following:
  • Clinical/laboratory signs of hepatic fibrosis that leads to portal hypertension and may be indicated by hepato-splenomegaly and/or esophageal varices
  • Hepatic pathology demonstrating a characteristic developmental ductal plate abnormality
  • Absence of renal enlargement and/or multiple cysts in both parents, as demonstrated by ultrasound examination
  • Pathoanatomic diagnosis of ARPKD in an affected sib
  • Family history consistent with autosomal recessive inheritance

Prenatal. The presence of large echogenic kidneys with poor cortico-medullary differentiation on prenatal ultrasound examination suggests ARPKD, although other diagnoses also need to be considered.

Infancy. The presence of bilateral palpable flank masses in infants with poorly characterized chronic pulmonary disease, a history of oligohydramnios or spontaneous pneumothorax as a newborn, and hypertension are highly suggestive of ARPKD.

Childhood and young adulthood

• The findings on renal imaging are less reliable.
• The hepatic abnormalities are often the prominent presenting features. (See Congenital Hepatic Fibrosis Overview.)

Testing

Liver function tests and transaminases are generally normal.

Molecular Genetic Testing

Gene. PKHD1 is the only gene in which mutations are known to cause the wide clinical spectrum of ARPKD.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Autosomal Recessive Polycystic Kidney Disease

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
PKHD1	Sequence analysis	Sequence variants 2	83% 3, 4, 77% 3, 5, 85% 3, 6, 79% 7	Clinical
	Targeted mutation analysis	Panel of mutations 8	See footnote 8
	Deletion / duplication analysis 9	Partial- and whole-gene deletions	See footnote 10
	Linkage analysis	NA	See footnote 11

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

3. Mutation detection frequency using mutation scanning; mutation detection frequency using sequence analysis is unknown but expected to detect as many as or more mutations than mutation scanning

4. In a study of 75 individuals in 59 unrelated families [Sharp et al 2005]

5. In a study of 164 neonatal survivors from 126 unrelated families [Bergmann et al 2005]

6. In a study of 48 fetuses from 40 unrelated families with at least one child affected by severe ARPKD (defined as perinatal/neonatal mortality) [Bergmann et al 2004b]

7. in 78 individuals from 68 unrelated families in which affected individuals survived beyond age 6 months, traveled to NIH for evaluation, and had clinical confirmation of the diagnosis of arPKD (i.e., typical kidney and liver involvement on imaging and/or biopsy; absence of congenital malformations; autosomal recessive inheritance) [Gunay-Aygun et al 2010a]

8. Mutation panels may vary by laboratory.

9. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

10. In three of 16 persons with ARPKD in whom only one mutation was detected by sequence analysis, three different PKHD1 deletions were identified using MLPA [Zvereff et al 2010].

11. Linkage studies are based on the accurate clinical diagnosis of ARPKD in the affected family member and accurate delineation of the genetic relationships in the family. Linkage analysis is dependent on the availability and willingness of family members to be tested. The markers used for ARPKD linkage are highly informative and tightly linked to the 6p21 locus [Lau et al 2010].

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband

• When clinical diagnostic criteria for ARPKD are met, molecular genetic testing is usually not necessary to confirm the diagnosis.
• When clinical diagnostic criteria for ARPKD are not met, molecular genetic testing can establish the diagnosis in most instances.
  • Some laboratories provide sequence analysis of the entire coding region; others offer sequence analysis of select exons followed by analysis of the remaining exons if two mutations are not identified.
  • If such testing does not identify two mutations, deletion/duplication analysis may be considered.

Note: Although kidney biopsy or liver biopsy can establish the diagnosis in many cases, such invasive tests are not usually necessary when clinical criteria are met.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family or informative linkage studies in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and pre-implantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family or informative linkage studies in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in PKHD1.

Natural History

The two organ systems primarily affected in autosomal recessive polycystic kidney disease (ARPKD) are kidney and liver; however, secondary effects are seen in several other organ systems.

Significant phenotypic variability is seen in ARPKD. Whereas Deget et al [1995] reported little intrafamilial variability in a study of 20 sibships with ARPKD, another study of mutation-confirmed ARPKD in 126 unrelated families found significant intrafamilial variability [Bergmann et al 2005]. Similar findings were reported in 79 individuals from more than 50 families [Gunay-Aygun et al 2010a].

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. A minority of affected individuals present as older children or young adults with evidence of hepatic dysfunction.

Kidney. Large bilateral flank masses are invariably present on physical examination. Urine output is usually not diminished; polyuria and polydipsia are consistent with the 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, generally improves over time, and may be normal in 20%-30% of affected individuals.

Hypertension, often severe, is usually noted within the first few weeks of life.

More than 50% of affected individuals progress to end-stage renal disease (ESRD), usually in the first decade of life [Roy et al 1997, Guay-Woodford & Desmond 2003]. 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].

Liver. The invariant liver lesion of ARPKD (also known as congenital hepatic fibrosis (CHF) or Caroli's disease [Kamath & Piccoli 2003]) is a developmental abnormality of the biliary ductal plate.

Although hepatic fibrosis is histologically 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 of diagnosis of 29 days, Zerres et al [1996] found that 45% had clinical evidence of liver involvement at presentation.

A subset of individuals with ARPKD is 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 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 mutations in PKHD1 and hepatic involvement were older than age 20 years at the time of initial presentation. If these findings are confirmed, the clinical spectrum of ARPKD-CHF is much broader than previously assumed.

The hepatobiliary complications seen in ARPKD include: ascending cholangitis, progressive liver dysfunction, portal hypertension with varices, hypersplenism, and (rarely) overt liver failure with cirrhosis. As advances in renal replacement therapy and kidney transplantation improve long-term survival, it is likely that clinical hepatic disease will become a major feature of the natural history of ARPKD [Dell et al 2009, Sweeney & Avner 2011].

In a cohort of individuals with ARPKD born after 1990, 37% of those who survived the first year of life had evidence of portal hypertension [Guay-Woodford & Desmond 2003]. Bergmann et al [2005] reported age-related clinical evidence of congenital hepatic fibrosis, including portal hypertension, in 44% (72/164) of individuals with confirmed PKHD1 mutations who were diagnosed in the neonatal period and survived beyond the first month of life.

Cholangiocarcinoma has been reported in individuals with ARPKD in adulthood [Fonck et al 2001].

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.

Potter's facies and other components of the oligohydramnios sequence, including low-set ears, micrognathia, flattened nose, limb positioning defects, and growth deficiency, may be present.

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.

Other

• Recent data suggest that with aggressive nutritional support, growth may be normal in a significant number of children [Dell et al 2009, Sweeney & Avner 2011].
• 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 an adult and a child with ARPKD [Neumann et al 1999, Lilova & Petkov 2001].
• Hepatoblastoma has been reported in a child with ARPKD [Kummerfeld et al 2010]. Whether this is a true association or a chance occurrence remains to be determined.

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 [Roy et al 1997, Guay-Woodford & Desmond 2003, Bergmann et al 2005].

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], ten-year survival is 82% [Bergmann et al 2005], and 15-year survival is 67%-79% [Roy et al 1997].

For individuals with ARPKD who undergo kidney transplantation, allograft survival rates are comparable to those in individuals without ARPKD; however, data on patient survival rates are conflicting:

• In a single-center study, mortality following renal transplantation for ARPKD was 36%; four of five deaths were attributed directly to hepatic complications [Khan et al 2002].
• In the North American Pediatric Renal Transplantation Cooperative Study (NAPRTCS), the survival rate at age six years in children with ARPKD was approximately 90% compared to those without PKD [Davis et al 2003]. Sepsis was the cause of death in 64% of those with PKD versus 32% in those with other renal diseases, a difference that the authors speculated was attributable to hepatobiliary disease/cholangitis in those with ARPKD.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been established. Most PKHD1 mutations are unique to single families.

In a recent study of 73 persons with ARPKD of varying ages, mutation type did not correlate with kidney size or function [Gunay-Aygun et al 2010a].

Penetrance

Penetrance is 100%; significant intrafamilial variation in disease severity is observed [Bergmann et al 2005, Dell et al 2009, Sweeney & Avner 2011].

Nomenclature

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.

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 [Dell et al 2009] to young adults [Adeva et al 2006].

The carrier frequency for a PKHD1 mutation in the general population is estimated to be 1:70 [Zerres et al 1998b].

Evaluations Following Initial Diagnosis

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

• Evaluation of respiratory status, including physical examination, pulse oximetry, and chest radiographs (as indicated)
• Serum electrolyte concentrations to identify electrolyte abnormalities (e.g., hyponatremia, hyperkalemia), serum creatinine concentration with calculation of eGFR (modified Schwartz formula) to monitor renal function, 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 and kidney involvement

Treatment of Manifestations

(See recent comprehensive reviews including Dell et al [2009] and Sweeney & Avner [2011] for detailed management strategies.)

Initial management of affected infants is focused on stabilization of respiratory function:

• 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 [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]. 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.

Hyponatremia is common and should be treated depending on the individual's volume status.

Neonates with oliguria or anuria may require peritoneal dialysis within the first days of life.

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

Feeding intolerance and growth failure, even in the absence of renal insufficiency, can be significant, especially in young infants. Aggressive nutritional support, which may include supplemental feedings via nasogastric or gastrostomy tubes, is often required to optimize weight gain and growth [Dell et al 2009, Sweeney & Avner 2011].

Children with growth failure may benefit from treatment with growth hormone [Lilova et al 2003]. The optimal age for starting growth hormone therapy depends on the growth velocity of the child; recent studies suggest that treatment is beneficial in children with chronic kidney disease who are age two years or younger [Seikaly et al 2007].

Anemia in children with stage III or higher chronic kidney disease may require treatment with iron supplementation and erythropoietin-stimulating agents (ESAs).

Bacterial cholangitis, often an underdiagnosed complication in those with hepatic involvement, may present as recurrent bacteremia with enteric pathogens without typical clinical features of cholangitis. Persistent fevers, particularly with right upper-quadrant pain, should be evaluated and treated aggressively.

Esophageal varices should be treated with endoscopic banding or sclerotherapy as indicated. A porto-caval shunt may be necessary to treat progressive portal hypertension; however, Tsimaratos et al [2000] reported recurrent hepatic encephalopathy and death following porto-caval shunting in two individuals with ARPKD who had ESRD. With improved outcomes, liver transplantation may become the preferred therapy in the near future for those who in the past would have been considered for porto-caval shunting.

Successful simultaneous liver-kidney transplantation in individuals with ARPKD has also been reported in a small case series [Harps et al 2011]. At present, only a small percent of individuals with ARPKD, particularly those diagnosed later in life, have required liver transplantation. However, with improved survival and advances in renal replacement therapy, it is likely that the number of individuals with ARPKD requiring liver transplantation may increase.

Prevention of Secondary Complications

With severe portal hypertension and splenic dysfunction, immunization against encapsulated bacteria (pneumococcus; H. influenza type B; meningococcus) is indicated.

Updated guidelines advise that palivizumab (Synagis^®) be administered to at-risk children younger than age 24 months who have chronic lung disease and/or a history of prematurity [Committee on Infectious Diseases 2009].

Although the role of chronic antibiotic prophylaxis in all children with ARPKD remains controversial, prophylaxis with trimethoprim sulfamethoxazole is recommended for persons with ARPKD who have experienced an episode of ascending cholangitis.

Surveillance

The following should be monitored regularly, depending on disease course and complications:

• Blood pressure monitored at periodic physician’s visits as well as home blood pressure monitoring if indicated (See Evaluations Following Initial Diagnosis.)
• Renal function in those with chronic kidney disease stage III or less; close monitoring for the complications of CKD should be undertaken by the treating nephrologist according to standard practices outlined in the KDOQI Guidelines.
• Hydration status
• Nutritional status, with growth plotted on standard growth charts and nutrition consultation as indicated.
• Hepatic involvement, by physical examination and complete blood counts, in addition to serum albumin levels, PT/PTT, and 25-OH vitamin D, vitamin E levels, and fat soluble vitamin levels
• If hepatomegaly is present and/or splenomegaly develops, additional monitoring, including periodic ultrasonography. With hepatosplenomegaly, referral to a pediatric hepatologist is suggested for evaluation and periodic monitoring (including endoscopy if indicated) to detect and treat esophageal varices by banding and/or sclerotherapy.
• Consideration of MR cholangiography, a more sensitive measurement for biliary ectasia, at baseline and then as indicated [Shneider & Magid 2005].

Agents to Avoid

The following should be avoided:

• For affected individuals with hypertension, sympathomimetic agents
• In general, unless the clinical situation warrants their use, known nephrotoxic agents including nonsteroidal anti-inflammatory drugs (NSAIDs) and aminoglycosides.

Work in cell and animal models suggests that caffeine, theophylline-like agents, and calcium channel blockers may exacerbate cyst formation and growth. These experiments suggest that these agents may increase cyclic AMP and intracellular calcium levels in cystic tissue, triggering “cystogenic” pathways and exacerbating cystic kidney disease. However, this has not been rigorously studied in individuals with ARPKD or ADPKD.

Evaluation of Relatives at Risk

Given the possibility of intrafamilial variability, high-resolution renal and hepatic ultrasonographic evaluation of older sibs of an individual with ARPKD may be indicated in some instances to permit early diagnosis and treatment and to allay significant parental anxiety, provided that imaging limitations are understood.

Molecular genetic testing may be possible if the mutations have been identified in an affected family member.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

No specific recommendations exist regarding pregnancy management.

When the pregnancy is complicated by oligohydramnios and/or massively enlarged kidneys, delivery at a tertiary care center is strongly recommended.

Therapies Under Investigation

Novel therapies directed at specific targets in the disease pathogenesis are currently under active investigation. Of note, all studies currently underway or completed have been conducted in adults with ADPKD. Studies in ARPKD are not yet underway but are planned in some instances. For detailed reviews of therapies that have been effective in animal genetic models of ARPKD, see Dell et al [2009], Torres et al [2010], Sweeney & Avner [2011].

Click here for additional therapies under investigation.

Preclinical studies of agents directed against the epidermal growth factor receptor (EGFR)-related growth factor axis demonstrated efficacy in orthologous and non-orthologous ARPKD animal models [Sweeney et al 2000, Dell et al 2001, Sweeney et al 2003, Gunay-Aygun et al 2006, Sweeney & Avner 2006]. Phase II clinical studies with erlotinib, a non-reversible inhibitor of EGFR autophosphorylation, are planned for children with ARPKD in 2012 [Sweeney & Avner 2011].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

Autosomal recessive polycystic kidney disease (ARPKD) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutant allele).
• Heterozygotes are asymptomatic.
• It is important to perform renal ultrasonography on parents of children with suspected ARPKD to exclude the possibility of ADPKD (see Clinical Diagnosis).

Sibs of a proband

• At conception, each sib of a proband has a 25% chance of inheriting both disease-causing alleles and being affected, a 50% chance of inheriting a disease-causing allele and being a carrier, and a 25% risk of inheriting neither disease-causing allele and not being a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband

• The offspring of an individual with ARPKD are obligate heterozygotes (carriers) for a disease-causing mutation in PKHD1.
• The carrier frequency in the general population is estimated to be 1:70 [Zerres et al 1998b]. Therefore, the risk of disease in offspring of a proband is approximately 0.7%.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing is possible once the mutations have been identified in the family.

If the disease-causing mutations in PKHD1 cannot be identified, carrier detection using linkage analysis may be possible in families with at least one affected child and in which informative linked markers have been identified.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

High-risk pregnancies (i.e., those at 25% risk based on family history)

• Prenatal testing for pregnancies at 25% risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified or linkage established in the family before prenatal testing can be performed [Zerres et al 1998a].
• No systematic data are available on the sensitivity and specificity of prenatal ultrasound examination in diagnosis of ARPKD in pregnancies at 25% risk.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Low-risk pregnancies (i.e., those not known to be at increased risk but in which routine prenatal ultrasound examination reveals enlarged cystic kidneys)

• Karyotype or array GH and detailed fetal ultrasonography should be performed to evaluate for the presence of a chromosomal abnormality and/or other congenital anomalies in a fetus not known to be at increased risk for ARPKD.
• Molecular genetic testing of PKHD1 may be appropriate. Failure to detect two mutations, however, does not exclude the diagnosis of ARPKD.
• Renal ultrasound examinations of both parents should be considered in all fetuses with suspected ARPKD to evaluate for the possibility of ADPKD.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified or in which linkage has been established [Lau et al 2010]. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

Notwithstanding the identification of PKHD1 and its protein product, fibrocystin, the pathogenesis of autosomal recessive polycystic kidney disease (ARPKD) remains unclear [Gunay-Aygun et al 2006, Sweeney & Avner 2006, Sweeney & Avner 2011]. Reduced or absent function of fibrocystin is thought to underlie the disease pathogenesis [Hiesberger et al 2004, Zhang et al 2004].

Recent studies suggest that many PKD-related proteins are involved with function of the primary cilia, an organelle located on the apical surface of most epithelial cells including kidney tubule and biliary cells [Lin & Satlin 2004, Pazour 2004]. Abnormal structure and/or function of the primary cilium lead to alterations in its mechano-sensory properties, which may result in activation of downstream second messenger pathways, notably the cyclic AMP system [Nauli et al 2003, Pazour 2004]. These pathways are thought to activate known cystogenic processes such as cell proliferation and fluid secretion. A consistent feature of all proliferative cystic epithelia is the expression of qualitative and quantitative abnormalities of the EFGR axis (reviewed in Sweeney & Avner [2011]). The molecular connection between gene defect, ciliary abnormalities, protein complex formation, and EGFR abnormalities remains highly speculative.

Fibrocystin, along with polycystin-1 and polycystin-2 (involved in Polycystic Kidney Disease, Autosomal Dominant) may exist as multimeric protein complexes in multiple sites in addition to cilia. These polycystin complexes are located on the apical cell surface, the lateral cell surface adjacent to the adherens junction, and the basal cell membrane in association with the focal adhesion kinase [Wilson 2004, Avner & Sweeney 2006]. The integration of signaling downstream from multimeric protein complexes may link the molecular and cellular pathophysiology of ARPKD. Recently, c-Src has been identified as a key intermediate in the abnormal signaling of fibrocystin [Sweeney et al 2008].

Hypertension in ADPKD is believed to be mediated by the renin-angiotensin system (RAS); however, supporting data in ARPKD are limited. Studies in the last decade have highlighted the importance of “local” (e.g., kidney-specific) RAS activation that may not be reflected in systemic measurements. The potential role of local kidney RAS in the pathogenesis of hypertension in ARPKD is supported by a histologic study that demonstrated increased expression of several renin-angiotensin axis components in two kidneys of individuals with ARPKD [Loghman-Adham et al 2005]. More recent data in an ARPKD animal model demonstrated RAS activation in the kidneys of affected animals and also in the liver [Goto et al 2010a, Goto et al 2010b]. This raises the question of whether RAS activation may be a more fundamental feature of ARPKD pathogenesis rather than a nonspecific manifestation of chronic kidney disease.

Normal allelic variants. PKHD1 is an extremely large gene that comprises 86 coding exons [Onuchic et al 2002, Ward et al 2002, Bergmann et al 2004a]. The largest reading frame encompasses 67 exons, but multiple alternatively spliced transcripts have been described [Bergmann et al 2004a].

Pathologic allelic variants. Different types of mutations are distributed across the gene. See LSDB and HGMD Databases in Table A.

Normal gene product. The PKHD1 product is a large protein with receptor-like properties [Onuchic et al 2002, Ward et al 2002]. It is localized to kidney, bile ducts, and pancreas. In addition, fibrocystin has been shown to localize to primary cilia as well as other discrete locations in renal tubular epithelial cells, suggesting a possible link of multiple pathways to ciliary dysfunction in some instances [Ward et al 2003], or multimeric protein complex signaling in cystic epithelium and endothelium. Abnormalities in ciliary structure and function may participate in the pathogenesis of many different types of cystic kidney diseases [Ong & Wheatley 2003] (see Molecular Genetic Pathogenesis).

Abnormal gene product. Reduced or absent function of fibrocystin is thought to underlie the disease pathogenesis [Hiesberger et al 2004, Zhang et al 2004]. See Molecular Genetic Pathogenesis.

Literature Cited

1. Adeva M, El-Youssef M, Rossetti S, Kamath PS, Kubly V, Consugar MB, Milliner DM, King BF, Torres VE, Harris PC. Clinical and molecular characterization defines a broadened spectrum of autosomal recessive polycystic kidney disease (ARPKD). Medicine (Baltimore). 2006;85:1–21. [PubMed: 16523049]
2. Avner ED, Sweeney WE. Renal cystic disease: new insights for the clinician. Pediatr Clin North Am. 2006;53:889–909. [PubMed: 17027616]
3. Avni FE, Guissard G, Hall M, Janssen F, DeMaertelaer V, Rypens F. Hereditary polycystic kidney diseases in children: changing sonographic patterns through childhood. Pediatr Radiol. 2002;32:169–74. [PubMed: 12164348]
4. Bergmann C, Senderek J, Kupper F, Schneider F, Dornia C, Windelen E, Eggermann T, Rudnik-Schoneborn S, Kirfel J, Furu L, Onuchic LF, Rossetti S, Harris PC, Somlo S, Guay-Woodford L, Germino GG, Moser M, Buttner R, Zerres K. PKHD1 mutations in autosomal recessive polycystic kidney disease (ARPKD). Hum Mutat. 2004a;23:453–63. [PubMed: 15108277]
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Suggested Reading

1. Harris PC. 2008 Homer W. Smith Award: insights into the pathogenesis of polycystic kidney disease from gene discovery. J Am Soc Nephrol. 2009;20:1188–98. [PubMed: 19423684]

Author Notes

Rainbow Babies and Children’s Hospital Web site: www.rainbowbabies.org
Children’s Research Institute Web site: www.chw.org/research

Revision History

• 22 September 2011 (me) Comprehensive update posted live
• 14 July 2009 (cd) Revision: deletion/duplication analysis available clincally
• 7 August 2008 (me) Comprehensive update posted live
• 21 March 2006 (me) Comprehensive update posted to live Web site
• 23 October 2003 (me) Comprehensive update posted to live Web site
• 13 January 2003 (kmd) Revision: gene identified
• 19 July 2001 (me) Review posted to live Web site
• April 2001 (kmd) Original submission