DiagnosisClinical DiagnosisDiagnosis 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
ANDOne 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 varicesHepatic pathology demonstrating a characteristic developmental ductal plate abnormalityAbsence of renal enlargement and/or multiple cysts in both parents, as demonstrated by ultrasound examinationPathoanatomic diagnosis of ARPKD in an affected sibFamily 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 adulthoodThe findings on renal imaging are less reliable.The hepatic abnormalities are often the prominent presenting features. (See Congenital Hepatic Fibrosis Overview.)Renal FindingsUltrasonographyInfancy. Fetuses and infants have characteristic large echogenic kidneys with poor corticomedullary differentiation:Macrocysts are usually not present; however, they may be seen, particularly with worsening disease.Stein-Wexler & Jain [2003] proposed that the ultrasonographic findings of "focal rosettes" (corresponding to the macroscopic appearance of radially oriented collecting tubule cysts) are specific for ARPKD; this has not been confirmed.Although the kidneys may be markedly enlarged at birth, over time the majority show stable to decreased renal size relative to body growth [Avni et al 2002]. However, with progressive disease, the ultrasonographic appearance of the kidneys may more closely resemble that seen in autosomal dominant polycystic kidney disease (ADPKD) [Avni et al 2002].Recent studies suggest that high-resolution ultrasonography combined with conventional ultrasound examination may significantly improve the diagnosis of mild disease as well as provide noninvasive, detailed definition of kidney manifestations without extensive use of ionizing radiation or contrast agents [Gunay-Aygun et al 2010b, Turkbey et al 2009]Childhood and young adulthoodKidneys are echogenic and large, but massive enlargement is generally not seen.Macrocysts, more typical of ADPKD, are often seen in older children [Traubici & Daneman 2005].Magnetic resonance imaging (MRI) has been proposed as a noninvasive alternative to renal biopsy for establishing the diagnosis of ARPKD:Findings on MRI include enlarged kidneys with hyperintense T₂-weighted signals.A characteristic hyperintense, linear radial pattern in the cortex and medulla representing microcystic dilatation has been described on RARE-MR urography [Kern et al 2000].Cassart et al [2004] showed that MRI may be a useful additional diagnostic study in the third trimester of pregnancy in fetuses with inconclusive ultrasonography; its accuracy in confirming the diagnosis earlier in pregnancy has not been assessed.Pathology reveals bilateral, symmetric kidney involvement. Microscopically, the kidneys show a pattern of fusiform dilatations ("microcysts" <4 mm in diameter) radiating from the medulla to the cortex [Dell et al 2009]. Tubular localization and microdissection studies have demonstrated that the disease is confined to the collecting tubules in all affected children; a transient proximal tubular cystic phase occurs in fetuses [Nakanishi et al 2000]. Note: Although kidney biopsy may establish the diagnosis in many instances, it is generally not necessary when clinical criteria are met.Hepatic FindingsPrenatal ultrasonography reveals hepatomegaly, mildly increased echogenicity, dilated intrahepatic (and occasionally extrahepatic) biliary ducts, and poorly visualized peripheral portal veins. However, these findings may not be evident at birth.MR cholangiography may delineate hepatobiliary manifestations without invasive biopsy or extensive use of ionizing radiation or contrast agents [Turkbey et al 2009].Pathology. The histologic findings of typical ductal plate abnormalities with bile duct proliferation and ectasia with hepatic fibrosis are present in all individuals with ARPKD [Kamath & Piccoli 2003].TestingLiver function tests and transaminases are generally normal.Molecular Genetic TestingGene. 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 DiseaseView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityPKHD1Sequence analysisSequence variants 283% 3, 4, 77% 3, 5, 85% 3, 6, 79% 7ClinicalTargeted mutation analysisPanel of mutations 8See footnote 8Deletion / duplication analysis 9Partial- and whole-gene deletionsSee footnote 10Linkage analysisNASee footnote 111. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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 scanning4. 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. 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 StrategyTo confirm/establish the diagnosis in a probandWhen 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. Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in PKHD1.}

Natural HistoryThe 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. OtherRecent 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 CorrelationsNo 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].

Differential DiagnosisRenal 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).
Although most ADPKD presents in adulthood, 1%-2% present as newborns, often with signs and symptoms indistinguishable from those of ARPKD [Guay-Woodford et al 1998, Sweeney & Avner 2011]. 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, an invariable finding in ARPKD, is rarely observed in ADPKD [O'Brien et al 2012].
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 suspected ARPKD is needed to evaluate for possible previously undiagnosed ADPKD. Of note, (1) Pei et al [2009] observed that it may not be possible to exclude the diagnosis of ADPKD in a small subset of persons (i.e., those with PKD2 mutations) until age 40 years and (2) approximately 5%-10% of individuals with ADPKD have a de novo mutation, and thus do not have an affected parent.Glomerulocystic kidney disease (GCKD) (OMIM 137920), a rare 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.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]. 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.
Hallermann et al [2000] reported a family with typical features of ARPKD in association with multiple congenital anomalies including brachymelia, vertebral abnormalities, Potter's facies, ocular hypertelorism, and low-set ears. Linkage to the 6p21 locus was excluded. Three families with similar features were also reported by Gillessen-Kaesbach et al [1993].
A syndrome of neonatal diabetes mellitus, congenital hypothyroidism, hepatic fibrosis, PKD, and congenital glaucoma has been described in two siblings. Liver biopsy confirmed the classic findings of congenital hepatic fibrosis; histologic evaluation of the kidneys was not performed [OMIM 601331].Disorders with renal involvement that may mimic ARPKD in the neonatal period include malignancies such as leukemia or Wilms tumor (see Wilms Tumor Overview, OMIM 194070), bilateral renal vein thrombosis, and radiocontrast nephropathy [Guay-Woodford et al 1998, Dell et al 2009, Sweeney & Avner 2011]. 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. (See Hepatic Fibrosis Overview.)Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo 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 appropriateMeasurement 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 involvementTreatment 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 ComplicationsWith 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. SurveillanceThe 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 statusNutritional 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 levelsIf 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 AvoidThe following should be avoided:For affected individuals with hypertension, sympathomimetic agentsIn 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 RiskGiven 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 ManagementNo 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 InvestigationNovel 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.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Polycystic Kidney Disease, Autosomal Recessive: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDPKHD16p12​.3-p12.2FibrocystinAutosomal Recessive Polycystic Kidney Disease Mutation Database
PKHD1 homepage - Mendelian genesPKHD1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Polycystic Kidney Disease, Autosomal Recessive (View All in OMIM) View in own window 263200POLYCYSTIC KIDNEY DISEASE, AUTOSOMAL RECESSIVE; ARPKD 606702PKHD1 GENE; PKHD1Molecular Genetic PathogenesisNotwithstanding 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.