Autosomal Recessive Polycystic Kidney Disease (ARPKD)

Autosomal recessive polycystic kidney disease (ARPKD) is a rare genetic disorder characterized by the formation of fluid-filled sacs (cysts) in the kidneys. Most affected infants have enlarged kidneys during the newborn (neonatal) period and some cases may be fatal at this time. ARPKD is not simply a kidney disease and additional organ systems of the body may also be affected, especially the liver. High blood pressure (hypertension), excessive thirst, frequent urination, and feeding difficulties may also occur. Some affected children may also have distinctive facial features and incomplete development of the lungs (pulmonary hypoplasia) causing breathing (respiratory) difficulties. The severity of the disorder and the specific symptoms that occur can vary greatly from one person to another. Some affected children eventually develop end-stage renal disease sometime during the first decade of life. In some patients, symptoms do not develop until adolescence or even adulthood. ARPKD is caused by changes (mutations) in the PKHD1 gene.

Autosomal recessive polycystic kidney disease is an important inherited cause of chronic kidney disease (CKD). The most typical disease expression occurs in neonates and includes a history of oligohydramnios, massively enlarged kidneys, and the “Potter” sequence with pulmonary hypoplasia that leads to respiratory insufficiency and perinatal death in ∼30% of affected newborns

Causes

ARPKD is caused by mutations of the PKHD1 gene and is inherited in an autosomal recessive pattern.

Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier of the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.

PKHD1 is a large gene and many different mutations to this gene cause ARPKD. The PKHD1 gene contains instructions for creating (encoding) a protein known as fibrocystin (or polyductin). If patients have two mutations that result in no protein being generated, the result is usually lethal. However, in the majority of patients, at least one copy of the gene generates some functional protein and these cases are usually viable. The exact role and function of this protein in the body are unknown.

The ARPKD protein may be involved in the proper development or function of cilia, a hair-like structure found on most cells in the body. Cilia are classified as motile or immotile. Motile cilia have specific mechanical functions such as moving or propelling mucus over the cell in the respiratory tract, while immotile (primary) cilia were believed to play a sensory or mechano-sensory role. Immotile cilia are active structures required for normal health and development that are involved in sensing the environment outside of the cell and sending related signals into the cell. The exact relationship between the ARPKD protein and the cilia and their ultimate roles in proper kidney function and health is not fully understood. More research is necessary to determine the complex, underlying mechanisms that ultimately cause ARPKD.

The symptoms of ARPKD result from the development and continued enlargement of cysts in the kidneys and other organ systems of the body. Cysts within the kidneys form within nephrons, which are small tubules that serve as the basic filtering units of the kidneys and help to remove waste from the blood. Cysts form at the tips or ends of the nephrons, a section known as the collecting tubules. Specifically, a cyst is a widened (dilated) collecting tubule that has swollen or ballooned. Because of the numerous cysts that form, the kidneys become enlarged and normal nephrons are destroyed, eventually eliminating kidney function. In a normal kidney, the nephrons and collecting tubules help to regulate the amount of water and acid in the body.

The liver symptoms of ARPKD result from the improper development of the network of bile ducts found within the liver. Bile ducts may be widened (dilated) and duplicated and surrounding tissue may become inflamed, ultimately causing scarring in the affected area. This scarring process is known as congenital hepatic fibrosis. All children with ARPKD have congenital hepatic fibrosis, but not all children develop clinically evident liver disease.

Related Disorders

Symptoms of the following disorders can be similar to those of ARPKD. Comparisons may be useful for a differential diagnosis.

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by the formation of cysts within the kidneys. Since ADPKD is a dominant disease, most affected individuals have a family history of PKD, unlike ARPKD. Symptoms caused by cyst formation in the kidneys include high blood pressure (hypertension), pain on the sides of the body between the last rib and the hip (flank pain), blood in the urine (hematuria), and progressively poor function of the kidneys (kidney insufficiency). In ~50 percent of patients, ADPKD progresses to end-stage renal disease by 60 years of age, requiring renal replacement therapy, either dialysis or renal transplantation. ADPKD is not simply a kidney disorder and other organ systems of the body can potentially be affected (multisystem disorder) by the development of cysts and another disease. The specific symptoms present in each person depending upon the specific organ systems involved. The liver, pancreas, a membrane covering the spinal cord and brain (arachnoid membrane), and the glands of the male reproductive tract that produce fluid that is part of semen (seminal vesicles) may develop cysts. Abnormalities affecting the heart and blood vessels (cardiovascular system) may also occur in individuals with ADPKD. ADPKD usually does not cause renal insufficiency until the fourth or fifth decade and was once known as “adult” polycystic kidney disease. However, it can occur in children and infants. ADPKD is mainly caused by mutations of one of two genes that create certain proteins essential for the proper health of the kidneys and other parts of the body. Rarely, atypical mutation combinations to the ADPKD genes can result in a disease that is similar to ARPKD.

Recently, two diseases similar to ARPKD due to PKHD1 mutations have been described. Two mutations to the DZIP1L gene can result in enlarged hyperechogenic kidneys and a decline in renal function with renal failure in the teens or twenties. Patients do not seem to develop hepatic fibrosis. DZIP1L encodes a cilia-related protein. The second disease, polycystic kidney disease with hyperinsulinemic hypoglycemia (HIPKD) is caused by two mutations in the PMM2 gene including at least one specific promoter mutation. PMM2 encodes a key enzyme in N-glycosylation, and two PMM2 mutations usually result in the congenital disorder of glycosylation type 1a (CDG1A), a multisystem disorder with prominent neurologic involvement, but the promoter mutation results in problems specific to the kidneys and liver. Kidneys are enlarged, and multicystic, and can result in renal failure. Cysts can be present in the liver, and as the name suggests, they often have hyperinsulinemic hypoglycemia.

A variety of other disorders may have cystic kidneys as a feature. These disorders may sometimes be referred to as syndromic forms of polycystic kidney. These disorders usually have additional neurological, digital, eye, and/or other symptoms and physical findings that distinguish them from ARPKD. These disorders include Bardet-Biedl syndrome, Meckel syndrome, Joubert syndrome, Senior-Loken syndrome, nephronophthisis, and oral-facial-digital syndrome.

Symptoms

The severity and progression of ARPKD can vary greatly from one person to another, even among members of the same family. In severe cases, ARPKD can cause life-threatening complications during infancy. In other cases, affected individuals may not develop symptoms until later during childhood or adolescence. Some children may need a kidney (renal) transplant early in childhood; others may not need a transplant until early adulthood, or not at all. In rare cases, individuals may not develop symptoms until young adulthood. Generally, individuals who develop ARPKD later in life have milder kidney disease, but more severe liver disease.

Most of the medical literature on ARPKD, especially those written before the identification of the ARPKD disease gene, disproportionately focused on the most severe cases. Therefore, much of the literature may give the incorrect impression that ARPKD is a uniformly fatal or debilitating disease. Researchers now know that ARPKD can range from mild to severe. Consequently, it is important to note that affected individuals will not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms, and overall prognosis.

The characteristic finding of ARPKD is the development of fluid-filled sacs (cysts) in the kidneys. All affected individuals develop cysts in the kidneys, but the number, size, progression, and severity of cyst development varies greatly from one person to another. In most affected individuals, renal cysts grow and multiply in utero causing abnormal enlargement of the kidneys. Enlarged kidneys may be apparent at birth or during the newborn period. In these infants, the kidneys are firm and can be felt (palpated) on both flanks. Additional symptoms associated with cystic kidneys include high blood pressure (hypertension) and flank pain. High blood pressure is common in children with ARPKD and can be widespread, severe, and difficult to manage.

In severe cases of ARPKD, affected infants may face life-threatening complications shortly after birth, especially breathing (respiratory) insufficiency or failure. Breathing difficulties usually occur due to deficient levels of amniotic fluid (oligohydramnios) during pregnancy. Massively enlarged kidneys, which prevent the proper development of the lungs, may also contribute to respiratory insufficiency or failure. Although some children do not survive the newborn period (approximately 30 percent by most estimates), the majority of children survive.

Children who survive beyond the newborn period usually develop worsening kidney function, although the kidneys may reduce in size. Most children do not develop chronic renal insufficiency until late childhood, adolescence, or young adulthood. Renal insufficiency refers to the impaired ability of the kidneys to perform their basic functions. The kidneys are two bean-shaped organs located under the ribcage. The kidneys have several functions including filtering and excreting waste products from the blood and body, creating certain hormones, and helping maintain the balance of certain chemicals in the body such as potassium, sodium, chloride, calcium, and other electrolytes. Damage to the kidneys in ARPKD may be slowly progressive and can cause a variety of symptoms including weakness and fatigue, changes in appetite, puffiness or swelling, back pain, poor digestion, excessive thirst, and frequent urination. Eventually, many children progress to end-stage renal disease.

In severe cases of ARPKD, affected infants have extremely enlarged kidneys and decreased urine production at birth. Decreased urine production in utero contributes to a deficiency of amniotic fluid (oligohydramnios), the fluid that surrounds a developing fetus. In addition to protecting and cushioning a fetus, the amniotic fluid contains growth factors and other substances that are vital to fetal development. Low amniotic fluid levels can impair lung development and, consequently, some affected infants may have underdeveloped lungs (pulmonary hypoplasia). These infants can experience severe, life-threatening breathing (respiratory) complications during the newborn period. Infants with oligohydramnios may also develop distinctive facial features including deep-set eyes, a flattened nose, a small jaw (micrognathia), and abnormal, low-set ears. The physical findings associated with oligohydramnios are sometimes referred to as Potter’s sequence.

In addition to the kidneys, the liver is also commonly affected in children and adults with ARPKD. The liver performs many functions in the body including converting food into energy and nutrients, storing vitamins, and filtering toxins from the body. Children with ARPKD develop a liver condition known as congenital hepatic fibrosis, in which excess fiber-like connective tissue spreads throughout the liver. Although all children have congenital hepatic fibrosis, not all children develop liver dysfunction. Liver abnormalities that can occur in ARPKD include enlargement of the liver (hepatomegaly), inflammation and infection of the tubes (bile ducts) that carry bile from the liver to the gallbladder and intestines (cholangitis), and high blood pressure of the main vein of the liver (portal hypertension).

Portal hypertension can cause increased pressure and swelling (distention) of veins (varices) of the esophagus, the stomach, and intestines. These veins can rupture and potentially cause life-threatening gastrointestinal bleeding (variceal bleeding). Affected children may experience progressive liver dysfunction and scarring (cirrhosis) and ultimately liver failure.

Children with ARPKD may also experience feeding difficulties due to poor kidney function or from compression of the stomach by enlarged kidneys, liver, and/or spleen. Feeding difficulties and chronic renal failure may contribute to poor growth in affected individuals. Some children may be prone to urinary tract infections and have problems with water and salt balance.

Some children with ARPKD may also experience enlargement of the spleen (splenomegaly). Splenomegaly can potentially result in low levels of red blood cells (anemia), platelets (thrombocytopenia), and white blood cells (leukopenia). Anemia can cause fatigue, pale skin, irregular heartbeat, and shortness of breath. Thrombocytopenia can result in easy bruising, prolonged bleeding from cuts, spontaneous nosebleeds, and superficial bleeding in the skin (petechiae). Leukopenia decreases the body’s ability to fight infection and disease.

Diagnosis

ARPKD may be suspected before birth based on clinical findings (e.g., palpable flank mass, underdeveloped lungs, oligohydramnios, and hypertension).

Suggestive Findings

Autosomal recessive polycystic kidney disease (ARPKD) should be suspected in individuals with bilaterally enlarged, diffusely echogenic kidneys. Diagnosis is typically made based on clinical presentation and radiographic findings [rx]. Specific diagnostic criteria of ARPKD (modified from [rx]:

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

Typical Findings on Imaging

Ultrasonography (US) is the diagnostic method of choice for assessing fetal and pediatric ARPKD because it is cost-effective, painless, widely available, and does not require radiation or sedation. It is predominantly useful in identifying renal abnormalities, but abdominal US may also indicate biliary ductal involvement or splenic enlargement in those with ARPKD. However, the renal US alone is never diagnostic

The renal diagnostic criteria for ARPKD detected by ultrasonography are

Increased renal size (in relation to normative size based on age and size of the affected individual);
Increased echogenicity;
Poor corticomedullary differentiation.

Prenatal

Sonography may demonstrate echogenic, enlarged, reniform kidneys, oligohydramnios, or an empty urinary bladder in severe cases of ARPKD.
Severely affected fetuses with oligohydramnios may have pulmonary hypoplasia and high mortality due to pulmonary insufficiency, or multiple intrauterine compression anomalies of lethal Potter sequence.
The presence of large reniform echogenic kidneys with poor corticomedullary differentiation and oligohydramnios on prenatal ultrasound examination suggests ARPKD, although other diagnoses are possible.

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 but not diagnostic.
Biliary findings as noted above, as well as signs of portal hypertension such as hepatosplenomegaly, make a diagnosis of ARPKD more likely.

Childhood and young adulthood

The findings on renal imaging are noted as above and renal size may actually decrease with age as fibrosis progresses.
The hepatobiliary abnormalities with progressive portal hypertension are often the prominent presenting features.

Microscopic cystic renal lesions may be present in the early stages with later development of macroscopic cysts. Studies suggest that HRUS may significantly improve the diagnosis of mild disease as well as provide a noninvasive, detailed definition of kidney manifestations without extensive use of ionizing radiation or contrast agents [rx].

Pathology (Biopsy or Autopsy)

The histologic findings of developmental ductal plate abnormalities, including bile duct proliferation, biliary ectasia, and periportal fibrosis, are present in all individuals with ARPKD [rx].

The hepatobiliary disease in ARPKD is the result of a developmental defect where a failure of ductal plate remodeling results in the persistence of embryologic bile duct structures; these eventually can become massively dilated.
The dilated bile ducts may evolve into macroscopic cysts that are in connection with the intrahepatic bile ducts and can be detected by imaging modalities, particularly MRCP.
Associated portal veins are often abnormal, demonstrating dilations and an increased number of smaller portal vein branches.
A significant amount of fibrosis may be seen in the portal tract even at birth, and as affected children age, the amount of peri-portal fibrosis increases, resulting in hepatomegaly and progressive portal hypertension.

Interestingly and for unclear reasons, ARPKD-affected livers often demonstrate proportionally larger left lobes compared to the right lobes

A prenatal ultrasound may reveal enlarged kidneys (as early as 18 weeks after conception in some cases). An ultrasound may also reveal innumerable small cysts that are dilated collecting tubules. True renal cysts may also be present. An ultrasound, however, may fail to detect kidney enlargement or oligohydramnios.

Magnetic resonance imaging offers no advantage over HRUS or genetic testing in the diagnosis of ARPKD.

Magnetic resonance cholangiopancreatography (MRCP). Imaging findings consistent with biliary ductal ectasia are based on MRCP, which provides a clear depiction of the biliary duct system. The findings on MRCP are a sensitive measure of biliary ductal anatomy. Combined with the imaging findings of the kidney, the biliary duct abnormalities are diagnostic of ARPKD and have largely replaced the more invasive analysis of ductal anatomy by liver biopsy [rx].

Genetic testing

It is done for mutations in the PKHD1 genes and is available at several different laboratories (see Genetic Testing Registry: https://www.ncbi.nlm.nih.gov/gtr/). Genetic testing may be employed for prenatal or preimplantation genetic diagnostics for some at-risk families who have had at least one pregnancy diagnosed with ARPKD. Molecular genetic testing approaches can include single-gene testing, the use of a multigene panel, and more comprehensive genomic testing.

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

Treatment

The treatment of ARPKD is directed toward the specific symptoms that are apparent in each individual. Specific treatments are aimed at preserving kidney and liver function. In infancy, many children with respiratory difficulties may require mechanical ventilation to assist in breathing. Medications such as nitric oxide can help provide oxygen to (oxygenate) the lungs.

In severe cases, newborns that experience decreased urine production (oliguria) or no passage of urine (anuria) may require peritoneal dialysis during the first few days of life.

Selected patients may receive treatment with a vasopressin receptor antagonist, tolvaptan. Few randomized clinical trials have shown convincing results of tolvaptan in checking the progression of kidney disease in ADPKD.[rx][rx]

Medications can be used to control and manage high blood pressure, specifically angiotensin-converting enzyme (ACE) inhibitors. In some individuals, high blood pressure can be resistant to therapy (refractory) and severe enough to require more than one medication. Antibiotics may be used to treat urinary tract infections or cholangitis.

Some children may require nutritional supplements including vitamin D, iron, bicarbonate, and citrate. Adequate fluid and salt supplementation may also be necessary. Because of feeding difficulties and growth delays, some children may require the insertion of a tube through a small surgical opening in the stomach (gastrostomy) or a tube through the nose, down the esophagus, and into the stomach (nasogastric tube). These tubes are used to directly provide essential nutrients. In severe cases, growth hormone therapy may be necessary.

Individuals with end-stage renal disease, in which the kidneys no longer function, require dialysis or kidney transplant. Dialysis is a procedure in which a machine is used to perform some of the functions of the kidney – filtering waste products from the bloodstream, helping to control blood pressure, and helping to maintain proper levels of essential chemicals such as potassium. End-stage renal disease is not reversible so individuals will require lifelong dialysis treatment or a kidney transplant. The rate of progression of kidney dysfunction to end-stage renal disease can vary greatly from one person to another. Some individuals require a kidney transplant in childhood; others may not require a transplant until adulthood, or not at all.

Targeted therapies for hereditary renal cystic diseases are undergoing extensive clinical studies. Drugs targeting mTOR signaling pathways like rapamycin, by checking cellular proliferation are under their Phase II/III clinical trials. A variety of drugs like methylprednisone, urine alkalinization, lovastatin, epidermal growth factor tyrosine kinase receptor inhibitor, and cyclin-dependent kinase inhibitor are undergoing animal studies to assess utility in this group of patients.[rx][rx][rx]

For example, combined somatostatin and tolvaptan block the effect of cyclic adenosine monophosphate and inhibit fluid secretion and cell proliferation. Triptolide, which affects calcium signaling, also exhibits antiproliferative effects. A number of other agents may prove helpful in halting the progression of autosomal dominant polycystic kidney disease.

Progressive portal hypertension may require treatment with a portacaval shunt, in which a connection is made between the portal vein and the inferior vena cava, the main vein that drains blood from the lower two-thirds of the body. A portacaval shunt is designed to relieve high blood pressure of the portal vein.

Variceal bleeding is a medical emergency and requires immediate treatment. Variceal bleeding may be treated by sclerotherapy, a procedure in which a solution such as sodium chloride is injected into an affected blood vessel. The solution irritates the blood vessel eventually causing it to scar and the blood to clot. A small percentage of individuals with ARPKD may eventually require liver transplantation.

Erythropoietin may be used to stimulate the bone marrow to produce red blood cells in some children with ARPKD who experience anemia. Surgical removal of the spleen (splenectomy) has been used in some cases to treat severe splenomegaly.

Genetic counseling is recommended for affected individuals and their families. Another treatment is symptomatic and supportive.

Autosomal Recessive Polycystic Kidney Disease (ARPKD)

Causes

Diagnosis

Suggestive Findings

Typical Findings on Imaging

Pathology (Biopsy or Autopsy)

Genetic testing

Treatment

Autosomal Recessive Hypophosphatemic Rickets type 2

Axenfeld-Rieger Syndrome (ARS)

4-Layered Lissencephaly

Classic Lissencephaly

Hyperhomocysteinemic Syndrome

Homocystinuria due to Cystathionine Beta-synthase (CBS) Deficiency