Autosomal recessive polycystic kidney disease in children

INTRODUCTION — Autosomal recessive polycystic kidney disease (ARPKD, MIM #263200), previously called infantile polycystic kidney disease, is a recessively inherited disorder characterized by cystic dilations of the renal collecting ducts and developmental defects of hepatobiliary ductal plate remodeling, which result in varying degrees of congenital hepatic fibrosis.

The clinical features, diagnosis, and management of ARPKD will be reviewed here. ADPKD and other pediatric renal cystic conditions are discussed separately. (See "Autosomal dominant polycystic kidney disease (ADPKD) in children" and "Kidney cystic diseases in children".)

EPIDEMIOLOGY — The estimated incidence of autosomal recessive polycystic kidney disease (ARPKD) is 1:20,000 live births, with a carrier frequency of one in 70 [1-3]. The age of presentation varies with approximately one-third of patients presenting before 1 year of age, one-third between 1 and 20 years of age, and one-third after 20 years of age [4].

PATHOGENESIS

PKHD1 gene variants — Most cases of ARPKD are caused by variants in PKHD1 (polycystic kidney and hepatic disease 1 gene) located on chromosome 6p21, which encodes fibrocystin (also referred to as polyductin), a large integral membrane protein [5,6]. There are more than 750 reported PKHD1 variants [7]. The most common, accounting for 20 percent of cases, is the missense variant in exon 3, c.107C>T. Most patients with ARPKD are compound heterozygotes, who carry two different mutant alleles. A list of reported variants of the PKHD1 gene can be found on the ClinVar Miner website.

Although the function of fibrocystin is unknown, it is found in the cortical and medullary collecting ducts and the thick ascending limb of the kidney, and in the epithelial cells of the hepatic bile duct [8]. It is also expressed in the liver, pancreas, and lungs. It is expressed along with proteins associated with autosomal dominant polycystic kidney disease (ADPKD); however, fibrocystin does not share any homology with these proteins [8,9]. This suggests that defects in fibrocystin disrupt normal functioning of renal cilia, pointing toward a shared pathogenesis of cyst formation in the two disorders (see "Autosomal dominant polycystic kidney disease (ADPKD): Genetics of the disease and mechanisms of cyst growth").

It has been challenging to correlate genotype with phenotype in PKHD1-associated ARPKD given the diversity of variants [10,11]. In an observational study of 304 patients, the 13 individuals with biallelic null variant had the poorest outcome with end-stage kidney disease (ESKD) and hepatic and respiratory disease [11]. Patients with two missense variants or a missense variant and null variant in the region affecting amino acids 709 to 1837 less frequently developed ESKD during the 18 years of observation, whereas missense variants affecting amino acids 2625 to 4074 were associated with a higher risk of substantial hepatic complications. However, this study was limited by a potential bias due to limited data from very severely affected patients who did not survive the neonatal period.

In addition, phenotypic variability has been reported within a family with the same gene defect [12-14]. In one study, different phenotypic expression was seen in 11 of 20 affected families, including variability at the age of diagnosis and degree of liver and kidney involvement [13]. However, a report on the longitudinal clinical courses of 35 sibling pairs who were included in the ARPKD registry study (ARegPKD) and survived the neonatal period revealed comparable clinical courses of kidney and liver diseases in most families, suggesting a strong impact of the underlying genotype [15].

DZIP1L gene variants — The DZIP1L gene is a second locus for ARPKD, although it is much less common than PKHD1. Variants in the DZIP1L gene were reported in seven patients with an atypical form of ARPKD from four unrelated consanguineous families [16]. These patients had enlarged hyperechogenic kidneys and arterial hypertension, and four progressed to end-stage kidney disease (ESKD). They had no clinically apparent liver disease. In animal models, the underlying pathogenesis appears to be due to compromised ciliary membrane translocation of the PKD proteins, polycystin-1 and -2.

PATHOLOGY — The two primary organ systems affected in ARPKD are the kidney and hepatobiliary tract. Other findings, such as those in the lungs and lower extremity deformities, are secondarily involved as a result of kidney and/or liver disease. (See 'Clinical manifestations' below.)

Kidney — The kidneys are increased in size with microcysts (usually less than 2 mm in size), which radiate from the medulla to the cortex, and are visible as pinpoint dots on the capsular surface. Histologic examination reveals bilateral cystic dilatations of the collecting ducts, with flattening of the epithelium (picture 1 and picture 2) [17,18]. Microdissection studies and scanning electron microscopy show that there is no obstruction of the urinary flow in the dilated collecting ducts [18]. The severity of the kidney disease is proportional to the percentage of nephrons affected by cysts. Thus, in patients with milder disease, the ectasia of the collecting tubules is less prominent and irregularly distributed. Over time, larger renal cysts (up to 1 cm) and interstitial fibrosis develop, which contribute to the progressive deterioration of kidney function seen in patients who survive beyond the neonatal period.

Hepatobiliary tract — ARPKD is always associated with biliary dysgenesis due to persistence of embryologic bile duct structures, which can become massively dilated. This leads to varying degrees of dilatation of the intrahepatic bile ducts (Caroli disease) and hepatic fibrosis [19-22]. Histologic examination demonstrates ductal plate disruption with portal fibrosis surrounding increased numbers of hyperplastic, ectatic biliary ducts with normal liver parenchyma. Some patients may have macroscopic dilations of the intrahepatic bile ducts in addition to congenital fibrosis, a combination of findings referred to as Caroli syndrome [23]. The degree of liver involvement varies in ARPKD, but over time, hepatomegaly and portal hypertension develop in most patients. (See "Caroli disease".)

CLINICAL MANIFESTATIONS

Age at presentation — Clinical presentation of ARPKD varies based on the age of onset of symptoms and the predominance of hepatic or kidney involvement [4,24-28]. Patients who presented during infancy were more likely to have severe kidney disease and poor survival rate. Patients diagnosed as adolescents or adults typically present with symptoms related to congenital hepatic fibrosis (hepatomegaly, portal hypertension) [29,30]

Prenatal — ARPKD is often detected by routine antenatal ultrasonography in fetuses after 24 weeks of gestation; however, a normal antenatal ultrasound does not exclude a diagnosis of ARPKD [10]. A presumptive diagnosis is based on the characteristic findings of markedly enlarged echogenic kidneys with poor corticomedullary differentiation [1,31]. In some cases, discrete cysts ranging in size from 5 to 7 mm in diameter may be detected; larger cysts are unusual, especially those >10 mm in diameter, and are more compatible with a diagnosis of multicystic dysplasia. These findings may be accompanied by oligohydramnios and the absence of urine in the fetal bladder.

Other hepatorenal fibrocystic diseases (eg, autosomal dominant polycystic disease [ADPKD] and hepatocyte nuclear factor-1-beta [HNF1B]-related cystic kidney disease) or syndromic ciliopathies such as Bardet-Biedl and Joubert syndromes may have similar ultrasound findings. Exclusion of other system involvement such as polydactyly or cerebellar vermis hypoplasia improves diagnostic accuracy. Ultrasounds of both parents should be performed to see if there is any evidence of ADPKD or HNF1B-related cystic kidney disease, both of which are autosomal dominant disorders. In addition, prenatal genetic testing may be helpful in differentiating ARPKD from other diagnoses. As noted above, it is challenging to correlate phenotype with a specific genotype and caution should be exercised in making any management decision based on prenatal genetic test results. (See 'PKHD1 gene variants' above and 'Differential diagnosis' below.)

Neonatal — Neonatal presentation varies depending on the severity of kidney disease and includes respiratory distress, impaired kidney function, and in the most severe cases, Potter sequence (picture 3).

Respiratory distress — Severely affected neonates generally present with respiratory distress due to pulmonary insufficiency. These patients are often diagnosed prenatally, and oligohydramnios is a common antenatal finding. A subset of patients may also have features consistent with Potter sequence, which is associated with severe oligohydramnios.

Respiratory distress is a common manifestation of ARPKD due to pulmonary insufficiency, which is primarily caused by pulmonary hypoplasia [2,10,32,33]. Other factors that negatively affect pulmonary function include limited diaphragmatic excursion caused by hypoventilation due to the massively enlarged kidneys, and pneumothoraces, a relatively common complication. Large case series report approximately 40 percent of patients were supported by mechanical ventilation, and 30 percent died primarily from insufficient pulmonary function, as the degree of pulmonary involvement was incompatible with life even with mechanical ventilation [32,33].

Kidney manifestations — During the neonatal period, infants can present with the following kidney manifestations, which may or may not be accompanied by respiratory distress.

●Bilateral markedly enlarged kidneys, which may compress the lungs contributing to pulmonary function impairment, or stomach leading to difficulty in feeding.

●Kidney function impairment reflected by increased serum/plasma concentrations of creatinine and blood urea nitrogen (BUN). In the most severe cases, neonates have end-stage kidney disease (ESKD) and require kidney replacement therapy (KRT) for survival.

●Hypertension.

●Hyponatremia during the first few weeks of life due to the inability to dilute the urine maximally [34].

Potter sequence — The most severely affected neonates present with Potter sequence that include the following composite of findings associated with severe oligohydramnios (see "Oligohydramnios: Etiology, diagnosis, and management in singleton gestations" and "Congenital anomalies: Epidemiology, types, and patterns", section on 'Sequence'):

●Positional limb deformities (eg, club feet and hip dislocation)

●Typical facial appearance of pseudoepicanthus, recessed chin, posteriorly rotated, flattened ears, and flattened nose (picture 3)

●Pulmonary hypoplasia

Infancy and childhood — For patients who survive the neonatal period, there is improvement of kidney function due to continued renal maturation. However, over time progressive deterioration of kidney function develops, which may be rapid or slow, and often results in ESKD. Patients also show increasing evidence and progression of hepatobiliary disease [2,10]. A subset of older patients may present with signs and symptoms due to liver disease, with little evidence of kidney involvement [35].

Kidney manifestations — Kidney function initially improves for the first three years of life but is followed by progressive decline of kidney function, which may result in ESKD. Manifestations of kidney dysfunction include [33,34,36-38]:

●Urinary concentrating defect – Symptoms of polyuria and polydipsia due to a reduced concentrating ability is typically the first sign of kidney dysfunction preceding a decline in glomerular filtration (GFR) [39]. In most patients, the maximal urine osmolality is below 500 mosmol/kg.

●Metabolic acidosis – Metabolic acidosis is due to decreased urinary acidification capacity.

●Hypertension – Hypertension develops during the first months of life in approximately two-thirds of children with ARPKD, and is often difficult to control [28,33,34,36,37]. Hypertension generally precedes decrease in kidney function and is observed in patients with normal serum or plasma creatinine levels. The underlying pathogenesis is unknown but may be due to the activation of the local renin-angiotensin system and enhanced sodium retention by the distal collecting ducts [40]. Multiple agents may be required for adequate blood pressure control. Inadequately controlled hypertension may result in cardiac hypertrophy, heart failure, and central nervous system complications [28] and may contribute to kidney function deterioration.

●Recurrent urinary tract infections [33].

●Other urinary abnormalities – Mild proteinuria, and increased urinary excretion of magnesium [28].

●Progressive decline in GFR – Progressive decline in GFR usually occurs after the first three years of life, when kidney function improves with normal kidney development. However, after this "golden period," ongoing cyst formation and development of interstitial fibrosis results in decreased kidney function. Approximately 30 percent of patients with ARPKD require KRT for ESKD by the age of 10 years, and up to 60 percent by the age of 20 years [28,32,41,42].

In general, patients who present in the perinatal period have greater impairment of their kidney function than those who present later in life and are more likely to progress to ESKD at an early age [28,43]. In a study of 385 patients from a multicenter European registry, independent risk factors associated with dialysis within the first year of life after controlling for confounding variables included presence of oligohydramnios or anhydramnios, prenatal kidney enlargement, a low Apgar score, and postnatal respiratory support [43]. These results will be useful to counsel family regarding anticipated outcome and management decisions.

Hepatobilirary manifestations — Hepatobiliary manifestations include:

●Liver – Liver involvement is always present but the clinical manifestations may become apparent at any time between birth and adulthood [33]. It is caused by ductal plate malformation of the developing biliary system that leads to biliary dysgenesis, congenital hepatic fibrosis, and dilatation of the intrahepatic bile ducts (Caroli disease) [19-22]. In some older patients, liver disease may be the predominant clinical feature [35]. In these cases, kidney ultrasonography may be required to detect clinically silent kidney disease. (See "Caroli disease".)

In patients with significant liver involvement, the physical examination may detect an enlarged liver, especially the left lobe under the xiphoid [44]. However, liver function tests usually remain in the normal range. Ultrasonography of the liver reveals hepatomegaly, increased echogenicity, and dilatation of the peripheral intrahepatic ducts and the main bile ducts [45]. Hepatic cysts may be present, and there may also be signs of portal hypertension. Magnetic resonance cholangiography can also visualize nonobstructive dilations of the intrahepatic bile ducts [46].

●Portal hypertension – Portal hypertension develops secondary to congenital hepatic fibrosis and is associated with hypersplenism with thrombocytopenia, ascites, and esophageal variceal hemorrhage [22,29,41,44,47].

●Acute bacterial cholangitis – Acute bacterial cholangitis should be suspected when fever, elevated gamma-glutamyl transpeptidase levels, and elevated inflammatory markers are observed [44]. It is associated with dilatation of the bile ducts, which may occur during the first few months of life [37]. (See "Acute cholangitis: Clinical manifestations, diagnosis, and management", section on 'Clinical manifestations'.)

Portal hypertension and recurrent cholangitis are significant hepatobiliary complications, as a small but significant number of long-term survivors require liver transplantation [33]. Cholangiocarcinoma associated with Caroli disease and congenital hepatic fibrosis has been reported in adult patients [41,48].

Other findings — Other findings described in patients with ARPKD include:

●Feeding difficulties due to fatigue from pulmonary compromise or compression of the stomach by enlarged kidneys, liver, or spleen [49].

●Thrombocytopenia, which is due to splenic sequestration and is suggestive of portal hypertension [28].

●Growth impairment, which may be due to multiple factors including chronic kidney disease and feeding difficulties. (See "Growth failure in children with chronic kidney disease: Risk factors, evaluation, and diagnosis", section on 'Contributing factors'.)

●Risk of neurocognitive dysfunction due to early-onset chronic kidney disease and severe hypertension [50].

●Left ventricular hypertrophy, which is associated with systolic mechanical dysfunction [51].

DIAGNOSIS — Molecular genetic testing is the gold standard for diagnosis and should be performed when available to identify the underlying variants [52].

Molecular genetic testing — Molecular genetic testing is the gold standard for the diagnosis of ARPKD. It allows for the exclusion of other genetic cystic renal diseases that have similar presentations. The advances in next-generation sequencing (NGS) enable simultaneous analysis of a large number of genes at relatively low cost. Therefore, targeted NGS panel testing is the most efficient diagnostic approach [53-55].

Molecular genetic testing is based on the observation that ARPKD is associated with variants of the PKHD1 and rarely the DZIP1L. However, because of the large size of the PKHD1 gene and the large number of variants associated with ARPKD, it is possible that genetic testing could miss the diagnosis, as direct sequencing cannot detect all variants (eg, variants in deep intronic or in promoter or regulatory regions) [10,56]. In two case series of patients with strong clinical evidence of ARPKD, the reported rate of detecting variants was 80 to 85 percent [32,33].

A list of reported variants of the PKHD1 gene can be found on the ClinVar Miner website. The pathogenic impact of many of the variants is not proven because of the inability for genotype and phenotype correlation. (See 'PKHD1 gene variants' above.)

Clinical diagnosis — If genetic testing is unavailable, the clinical diagnosis of ARPKD is typically made by an abdominal ultrasound that demonstrates both the characteristic findings of large echogenic kidneys with poor corticomedullary differentiation, and coexisting liver disease [2]. In cases in which the diagnosis is uncertain, other imaging modalities (eg, magnetic resonance imaging [MRI]) may be useful in making the diagnosis. Kidney biopsy is not needed to make the diagnosis of ARPKD [49].

Imaging

●Ultrasound – The following kidney and hepatic findings are required for the diagnosis of ARPKD.

•Kidney – The ultrasound findings of ARPKD are characterized by bilateral enlarged hyperechogenic kidneys with poor corticomedullary differentiation and multiple tiny cysts [10,49,57]. High-resolution ultrasound may improve diagnostic sensitivity, especially in patients with only medullary involvement in whom standard-resolution ultrasonography may be normal. In this setting, high-resolution ultrasonography is able to detect ductal dilations confined to the medulla [28].

Macrocysts, typically seen in patients with autosomal dominant disease, are not usually present during infancy in patients with ARPKD, but may appear in older children [58]. As a result, in older patients, it may be more challenging to differentiate ARPKD from autosomal dominant polycystic kidney disease (ADPKD) by ultrasound. (See 'Differential diagnosis' below.)

•Hepatic – Ultrasound findings of the liver include hepatomegaly, increased echogenicity, and dilatation of the peripheral intrahepatic ducts and the main bile ducts [22,45]. Hepatic cysts may be present and there may also be signs of portal hypertension. Ultrasound elastography with acoustic radiation force impulse (ARFI) is a noninvasive method to detect hepatic fibrosis, and a preliminary study suggests that it may be useful to detect and quantify liver fibrosis and portal hypertension in children with ARPKD [59]. (See "Portal hypertension in adults", section on 'Ultrasonography' and "Portal hypertension in adults", section on 'Transient elastography'.)

●Other modalities – If ultrasound results are equivocal, other imaging modalities may be useful in the diagnosis of ARPKD.

•MRI shows enlarged kidneys with hyperintense T2 weighted singles. RARE-MRI (rapid acquisition with relaxation enhancement) demonstrates microcystic dilatation characterized by a hyperintense, linear radial pattern in the cortex and medulla [60]. MRI also demonstrates the typical hepatic findings of an enlarged liver with bile duct ectasia and portal fibrosis [45].

•Computed tomography (CT) provides better visualization of the cysts than ultrasound, but should not be used initially because of its associated radiation exposure.

DIFFERENTIAL DIAGNOSIS

Other renal cystic disorders — The differential diagnosis of ARPKD includes other renal cystic disorders. ARPKD is clinically differentiated from the following disorders by its characteristic kidney and hepatic findings, which are typically detected by ultrasonography. In some cases, molecular genetic testing is used to distinguish ARPKD from other renal cystic diseases [61,62].

●Autosomal dominant polycystic kidney disease (ADPKD) generally presents later than ARPKD. It is a systemic disease with cysts not only in the kidney, but in other organs (ie, liver, pancreas, arachnoid membrane, seminal vesicle), and with noncystic abnormalities (ie, intracranial aneurysms, cardiac valve disease, colonic diverticula, abdominal wall and inguinal hernias). However, congenital hepatic fibrosis, a characteristic feature of ARPKD, is rarely observed in ADPKD. Parental renal ultrasound may also show renal cysts. (See "Autosomal dominant polycystic kidney disease (ADPKD): Treatment" and "Autosomal dominant polycystic kidney disease (ADPKD): Extrarenal manifestations" and "Autosomal dominant polycystic kidney disease (ADPKD) in children".)

●Glomerulocystic cortical cysts can be found in patients with congenital genetic disorders such as tuberous sclerosis, orofacial digital syndrome type 1, trisomy 13, brachymesomelia-renal syndrome, and short-rib-polydactyly syndrome [49]. These disorders have other clinical features that distinguish them from ARPKD. (See "Renal manifestations of tuberous sclerosis complex", section on 'Glomerulocystic kidney disease' and "Kidney cystic diseases in children", section on 'Genetic disorders'.)

●Hepatocyte nuclear factor-1-beta (HNF1B)-related cystic disease is an autosomal dominant disorder that is associated with renal cortical cysts and maturity-onset diabetes. Up to 50 percent of patients have de novo variants. The severity of kidney disease is variable, ranging from severe perinatal kidney failure to asymptomatic adults. Antenatal ultrasonography often shows bilateral hyperechogenic kidneys. Patients with HNF1B cystic disease do not have the hepatic findings that are found in patients with ARPKD. (See "Classification of diabetes mellitus and genetic diabetic syndromes", section on 'Hepatocyte nuclear factor-1-alpha'.)

●Nephronophthisis (NPHP) is an autosomal recessive genetically heterogenic disorder with variants in genes that encode proteins involved in the function of primary cilia, basal bodies, and centrosomes. Ultrasound imaging demonstrates increased echogenicity with loss of corticomedullary differentiation but in kidneys of normal or slightly reduced size, in contrast to large kidneys seen in patients with ARPKD. Abnormalities in extrarenal organs including hepatic fibrosis are seen in 10 to 20 percent of patients with NPHP. Hepatic fibrosis is associated some NPHP gene defects. (See "Clinical manifestations, diagnosis, and treatment of nephronophthisis", section on 'Extrarenal manifestations'.)

Other hepatic disorders — Other hepatorenal disorders characterized by renal cystic changes and hepatic fibrosis include a number of multisystem disorders such as Meckel-Gruber syndrome, Bardet-Biedl syndrome, Joubert syndrome, and Jeune asphyxiating thoracic dystrophy [49,61,63]. However, these disorders have typically small or normal-size kidneys, in contrast to the enlarged kidneys of ARPKD, as well as other differentiating clinical manifestations such as neurologic findings. (See "Clinical manifestations, diagnosis, and treatment of nephronophthisis", section on 'Associated syndromes'.)

MANAGEMENT

Overview — The management of ARPKD consists of supportive therapy, as there is no curative intervention. Treatment is provided by a multidisciplinary team consisting of perinatologists, neonatologists, nephrologists, hepatologists, and geneticists that coordinate care from the perinatal period to adulthood [2]. This may include management of neonatal respiratory distress, arterial hypertension, kidney replacement therapy (KRT) in patients who progress to end-stage kidney disease (ESKD), and the care of the complications due to portal hypertension and recurrent cholangitis.

Perinatal management — Once a presumptive prenatal diagnosis of ARPKD is made, ultrasound monitoring every two to three weeks is suggested to monitor kidney size and amniotic fluid volume [2]. However, prenatal ultrasound is not an accurate predictor of subsequent neonatal pulmonary function.

Delivery should be performed at a center that provides neonatal intensive care including mechanical ventilation and KRT. Delivery options should include planning for cesarean delivery, particularly for cases with fetal abdominal dystocia due to markedly enlarged kidneys.

The preferences of the family regarding the degree of intervention during delivery (eg, resuscitation), and the decision to offer or withhold mechanical ventilation or dialysis to the neonate should be determined prior to delivery [2].

Neonatal management — Neonatal management initially focuses on stabilizing the respiratory status of patients with respiratory distress, followed by a clinical assessment confirming the diagnosis and a thorough evaluation of the neonate's kidney status.

●Initial respiratory stabilization – In neonates who present with respiratory distress due to pulmonary hypoplasia, the initial management focuses on supportive respiratory care, which often includes mechanical ventilation [2,28]. In the delivery room, evaluation of the respiratory status includes physical examination and assessment of oxygenation using pulse oximetry and/or blood gas sampling. In one large case series, 40 percent of neonatal patients underwent mechanical ventilation [33]. (See "Neonatal resuscitation in the delivery room" and "Overview of mechanical ventilation in neonates".)

Nephrectomy is reserved for neonates in whom it is deemed absolutely necessary for survival. Although there are reports suggesting that unilateral or bilateral nephrectomy has some benefit in patients with severely enlarged kidneys with compromised lung function and improves feeding difficulties [64], we do not suggest this procedure be performed except in the most compromised patients, as kidney function is preserved for many years even in perinatal-onset ARPKD patients with severe disease [28].

●Assessment – Neonatal assessment should include the following:

•Blood pressure (BP) measurement.

•Kidney function studies – Serum creatinine and blood urea nitrogen (BUN) to detect impaired glomerular filtration rate (GFR). Initial serum creatinine levels reflect maternal values. Kidney function impairment is detected if there is not the usual decline of serum creatinine to normal newborn levels over the first few days of life. (See "Neonatal acute kidney injury: Pathogenesis, etiology, clinical presentation, and diagnosis", section on 'Serum creatinine'.)

•Serum electrolytes – In particular, neonates with ARPKD are at risk for hyponatremia (due to limited ability to maximally dilute urine), and hyperkalemia in patients with limited kidney function (GFR).

•For patients with prenatal diagnosis, abdominal ultrasonography to confirm the diagnosis.

●Ongoing care – Additional management issues include:

•Hypertension – In patients with significant hypertension that requires medical intervention, we begin therapy with either an angiotensin converting enzyme inhibitor (ACE-I) or an angiotensin receptor blocker (ARB). We do not recommend using both an ACE-I and an ARB together. [2,10,49]. (See "Management of hypertension in neonates and infants".)

•Hyponatremia – Hyponatremia is a frequent transient manifestation in neonates with ARPKD [10], which should be managed with fluid restriction. (See "Fluid and electrolyte therapy in newborns", section on 'Hyponatremia'.)

•Feeding difficulties are common in the neonate with ARPKD because of limited fluid intake, and early stopping of feeding from fatigue or satiety due to gastric compression by the enlarged kidneys. Poor feeding contributes to growth impairment. These infants may require supplemental nasogastric feedings to obtain adequate caloric intake for optimal growth [49]. In some cases, the caloric density of the feeds may need to be increased because of fluid restriction. (See "Chronic kidney disease in children: Overview of management", section on 'Growth and nutrition'.)

•Renal management – Patients should have ongoing monitoring of kidney function (serum creatinine), fluid and electrolyte status, and blood pressure.

For neonates with ESKD, dialysis is the only KRT option and needs to be performed in a tertiary center with pediatric expertise in the care of neonates with chronic kidney disease (CKD). Both hemodialysis and peritoneal dialysis have been performed in neonates with ARPKD, and the choice is dependent on the experience and availability at each center. If peritoneal dialysis is performed, unilateral or bilateral nephrectomy may be needed to accommodate the volume of peritoneal dialysate fluid required for dialysis. However, despite the advances in the medical management of infants with ESKD, chronic dialysis started during the first month of life is associated with significant morbidity and mortality [65].

Infancy and childhood management — Management of patients who survive the neonatal period focuses on the care of kidney and hepatic complications, including ongoing surveillance.

Monitoring — Because ARPKD is a progressive disease, the following should be monitored on a regular basis [49]:

●Blood pressure – The frequency of evaluation varies depending upon the degree of kidney impairment and whether the patient is hypertensive. BP should be measured at each clinical visit. If office BP is elevated, home BP monitoring can be helpful in distinguishing fixed hypertension from "white coat" hypertension (ie, high blood pressure that occurs during medical examinations). (See "Definition and diagnosis of hypertension in children and adolescents", section on 'Diagnosis'.)

●Kidney function – Kidney function should be evaluated at a minimum of once a year by monitoring the serum creatinine. The frequency of testing is greater in those with more severe kidney involvement or in those with evidence of deteriorating function.

●Liver status – Yearly evaluation consists of physical examination to detect splenomegaly suggestive of portal hypertension) and laboratory testing including complete blood count and liver function studies (serum transaminases, hepatic synthetic function [coagulation studies and serum albumin]) [2,45,49]. A reduced platelet count has been shown to be a good surrogate marker for the presence and severity of portal hypertension in ARPKD [29].

In children with known ARPKD, annual abdominal ultrasound is suggested to monitor for signs of portal hypertension [53]. Abdominal ultrasonography should be performed whenever there is a clinical suspicion of splenomegaly, and at the latest, at five years of age to determine the degree of liver involvement (status of intra- and extra-bile ducts and evidence of portal hypertension) [2]. In patients with a normal study, subsequent follow-up testing is suggested every two to three years to monitor for liver involvement. (See "Portal hypertension in adults", section on 'Ultrasonography'.)

●Growth and nutrition – Feeding intolerance can be significant and aggressive nutritional support including supplemental feedings may be required to optimize weight gain and growth [49]. Some patients may benefit from treatment with recombinant growth hormone [66].

Renal management — The management of patients with progressive impaired kidney function is similar to that of patients with other forms of chronic kidney disease (CKD). (See "Chronic kidney disease in children: Overview of management".)

●Hypertension – For patients with hypertension that requires medical intervention, we prefer the use of ACE inhibitors or angiotensin II receptor blockers (ARBs) because there are data that suggest that ACE inhibitors or ARBs may slow the progress of CKD for other disorders (eg, autosomal dominant polycystic kidney disease [ADPKD]). (See "Chronic kidney disease in children: Overview of management".)

●Urinary tract infection – Urinary tract infections are common in patients with ARPKD [33,67]. Whenever patients have fever, dysuria, or flank pain, a urine culture should be obtained. Empirical treatment is started and modified based on the results of a urine culture. (See "Urinary tract infections in infants older than one month and children less than two years: Acute management, imaging, and prognosis", section on 'Overview'.)

●End-stage kidney disease (ESKD) – KRT is needed in patients who progress to ESKD. Kidney transplantation is the preferred KRT because there is no disease recurrence, and the outcome is excellent. Nephrectomy may be needed to accommodate the placement of the new graft. In addition, the removal of the native affected kidneys will help in blood pressure control post-transplantation. Other KRT options include hemodialysis and peritoneal dialysis. (See "Overview of kidney replacement therapy for children with chronic kidney disease".)

KRT improves survival for children with ARPKD and ESKD. As the lifespan of these patients is extended, they are more likely to develop complications related to congenital hepatic fibrosis, such as portal hypertension [68]. Although combined liver-kidney transplantation may be an option for children with ARPKD and severe Caroli disease [69-71], a large European observational study reported, combined liver-kidney transplantation in ARPKD was associated with increased mortality compared with kidney transplantation and was not associated with improved five-year kidney transplant survival [72].

Hepatic complications — Patients with ARPKD are at risk for the following complications of the hepatobiliary system [2,10]. (See "Caroli disease", section on 'Management'.)

●Bacterial cholangitis is a complication seen in patients with more hepatic involvement, and should be considered when patients have persistent fever, especially in association with right upper-quadrant pain. If we suspect bacterial cholangitis, we start empiric intravenous antibiotics. Bacterial cholangitis can be the source of recurrent bacteremia with enteric pathogens, however the utility of antibiotic prophylaxis is not clearly established [15]. (See "Caroli disease", section on 'Clinical manifestations' and "Caroli disease", section on 'Management' and "Acute cholangitis: Clinical manifestations, diagnosis, and management", section on 'Management'.)

●The risk of ascending cholangitis is increased in kidney transplant recipients who receive immunosuppressive therapy. This complication is a major cause of death in ARPKD patients, suggesting that pre-emptive liver transplantation should be considered as a therapeutic option in a subgroup of patients with severe liver disease being evaluated for kidney transplantation [69,73,74].

●Progressive portal hypertension, although uncommon, may be life-threatening due to bleeding esophageal varices. A clinical diagnosis for portal hypertension is based on the presence of splenomegaly and thrombocytopenia (suggestive of splenic sequestration). In patients with portal hypertension, esophago-gastroscopy should be performed annually to detect and treat varicose vessels [73]. Esophageal varices may be medically treated with a nonselective beta blocker or treated with endoscopic banding or sclerotherapy. In some patients who still have well-maintained liver function, porto-caval shunting may be indicated. However, porto-caval shunting may be followed by hepatic encephalopathy in patients with ESRD [75]. Liver transplantation is another option for patients being considered for porto-caval shunt. (See "Portal hypertension in adults", section on 'Diagnosis' and "Caroli disease", section on 'Management'.)

●Reduction in levels of 25-hydroxyvitamin D, vitamin E, and other fat-soluble vitamins due to malabsorption. Regular monitoring of vitamin levels and replacement as needed. (See "Overview of vitamin D" and "Overview of vitamin E".)

●Increased risk for infections caused by encapsulated organisms (pneumococcus, H. influenza type B, and meningococcus). Prophylactic immunizations, similar to those provided to asplenic patients, should be administered to patients with severe portal hypertension and splenic dysfunction. (See "Prevention of infection in patients with impaired splenic function", section on 'Vaccinations'.)

Genetic counseling — Parents of a child with ARPKD should be informed that each child or new fetus will have a:

●One in four risk of developing the disease (although the expression of the disease may be different in subsequent offspring).

●One in two risk of being a carrier.

●The risk for ESKD and need for KRT is greatest for those with prenatal and perinatal evidence of disease (oligohydramnios and/or kidney enlargement).

Prenatal genetic screening is possible in families in which a pathologic variant has been identified [76,77]. Some studies have reported prenatal variant detection rates of 70 to 80 percent in families with a range of ARPKD phenotypes [78,79].

If the disease-causing variants 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. Since this technique is an indirect diagnosis, its accuracy depends upon the correct diagnosis in previously affected siblings [77]. Older asymptomatic siblings of affected children should be evaluated for hepatic fibrosis.

Preimplantation genetic testing is possible in families who have had a child with a severe form of ARPKD if the PKHD1 variant of each parent has been identified [80]. (See "Preimplantation genetic testing".)

OUTCOME — The outcome of ARPKD is dependent on the degree of kidney and hepatic involvement, which is most often reflected by the age of presentation [4,32,33]. Severe disease and poor prognosis are associated with the presence of biallelic truncating variants [11,81]. The mortality rate is greatest for patients who present as neonates with severe kidney disease associated with pulmonary insufficiency, with reported rates of 30 percent [32,33]. (See 'Neonatal' above.)

Patients who survive the first month have a greater than 80 percent chance of survival beyond 15 years of age [4,32,33,82,83]. In a longitudinal study of 164 patients with ARPKD who survived the neonatal period, kidney survival was approximately 85 percent at 5 years, 70 percent at 10 years, and 40 percent at 20 years [32]. Approximately three-quarters of the cohort developed systemic hypertension, and 44 percent developed congenital hepatic fibrosis and portal hypertension. Improved management of kidney insufficiency and end-stage kidney disease (ESKD) has resulted in a greater number of patients developing portal hypertension [68].

A small case series of 11 patients (age range 5 to 16 years) reported that pulmonary outcome for childhood survivors was good with no patient requiring oxygen supplementation [84]. Most patients had normal pulmonary function tests, except for those who received mechanical ventilation who had findings suggestive of airway obstruction. One patient had a history of asthma.

SUMMARY AND RECOMMENDATIONS

●Introduction – Autosomal recessive polycystic kidney disease (ARPKD, MIM #263200), previously called infantile polycystic kidney disease, is a recessively inherited disorder characterized by cystic dilations of the renal collecting ducts, and developmental defects of hepatobiliary ductal plate remodeling that result in varying degrees of congenital hepatic fibrosis.

●Epidemiology – The estimated incidence of ARPKD is 1:20,000 live births. (See 'Epidemiology' above.)

●Pathogenesis – ARPKD is primarily caused by variants in the PKHD1 gene that encodes for fibrocystin (also referred to as polyductin), which localizes to the primary cilia in the cortical and medullary collecting ducts and the thick ascending limb of the kidney, and in the epithelial cells of the hepatic bile duct. Variants in the DZIP1L gene have been reported as a rare cause of ARPKD. (See 'Pathogenesis' above.)

●Pathology – The kidney pathologic findings of ARPKD include enlargement of the kidneys by cystic dilatations (microcysts) of the collecting tubules; hepatic findings of ductal plate disruption and portal fibrosis that surround hyperplastic, ectatic biliary ducts; and normal liver parenchyma. (See 'Pathology' above.)

●Clinical manifestations – The clinical manifestations vary with the age of presentation. (See 'Clinical manifestations' above.)

•Prenatal – In severe cases, ARPKD can be detected after 24 weeks of gestation by routine antenatal ultrasonography, which demonstrates the characteristic markedly enlarged echogenic kidneys with poor corticomedullary differentiation. (See 'Prenatal' above.)

•Neonatal – In the neonate, patients present with massively enlarged kidneys. Almost half of the patients diagnosed as neonates will have respiratory distress due to pulmonary hypoplasia. A subset of patients will have clinical features of Potters syndrome (pulmonary hypoplasia, positional limb deformities, and characteristic facial features (picture 3) associated with oligohydramnios). (See 'Neonatal' above.)

•Infancy and childhood – Older patients typically have less severe renal disease and more liver involvement, resulting in portal hypertension and an increased risk of cholangitis. Nevertheless, the majority of patients will have progressive deterioration of kidney function (eg, hypertension, decrease in estimated glomerular filtration rate) and increasing evidence and progression of hepatobiliary disease (eg, portal hypertension). A significant number of patients will proceed to end-stage kidney disease (ESKD) and require kidney replacement therapy (KRT). (See 'Infancy and childhood' above.)

●Diagnosis – Molecular genetic testing is the gold standard for establishing the diagnosis. If unavailable, the clinical diagnosis of ARPKD is typically made by an abdominal ultrasound that demonstrates both the characteristic findings of large echogenic kidneys with poor corticomedullary differentiation, and coexisting liver disease. (See 'Diagnosis' above.)

●Differential diagnosis – The differential diagnosis of ARPKD includes other renal cystic disorders and hepatobiliary diseases. ARPKD is clinically differentiated from these disorders by its characteristic kidney and liver findings on abdominal ultrasonography. (See 'Differential diagnosis' above.)

●Management – There is no known curative intervention for ARPKD. The management of ARPKD consists of supportive therapy including the management of respiratory distress in affected neonates, and KRT for patients who progress to ESKD. Genetic counseling includes prenatal genetic testing for interested family members and for siblings of affected patients who may be carriers of a PKHD1 variant. (See 'Management' above.)

●Outcome – The outcome of ARPKD is dependent on the degree of kidney and hepatic involvement, which is often reflected by the age of presentation. The mortality rate (30 percent) is greatest for patients who present as neonates with severe kidney disease and pulmonary hypoplasia. (See 'Outcome' above.)