Autosomal Recessive Polycystic Kidney Disease

What is Autosomal Recessive Polycystic Kidney Disease?

Autosomal recessive polycystic kidney disease, also known as ARPKD, is a rare genetic disorder that mainly affects your kidneys and liver. Warning signs such as kidneys that are bigger and brighter than normal could be started detecting while the baby is still in the womb or during infancy. ARPKD typically starts because of changes in a specific gene called PKHD1, which leads to kidney cysts and liver fibrosis at an early age. By the time they’re 20, about half of people with ARPKD will require a kidney transplant or dialysis due to end-stage renal failure. It’s also important to monitor liver function as issues such as portal hypertension, enlargement of the spleen and bile duct infection are common, especially in older patients.

There are two main types of polycystic kidney disease (PKD): the more common autosomal dominant type, and the much rarer autosomal recessive type. Both types have unique clinical and genetic characteristics.

Autosomal dominant polycystic kidney disease (ADPKD), also known as adult polycystic kidney disease, typically affects kidneys and progressively leads to fibrosis, hypertension, and chronic kidney failure, with symptoms starting in adulthood, around 30 years old. It’s the most common genetic cause of kidney failure and end-stage kidney disease in adults.

On the other hand, autosomal recessive polycystic kidney disease (ARPKD), earlier known as infantile polycystic kidney disease, could present at any age including newborns, infants, juveniles, or even adults. It mainly involves the kidney and liver, and is marked by kidney cysts, liver bile duct malformation and fibrosis in both the liver and kidney. ARPKD is associated with cysts, largely microcystic in early childhood. These cysts are largely seen in the renal medulla and could develop into calcified renal stones.

The symptoms of ARPKD can vary greatly, with those diagnosed at a young age generally experiencing more severe symptoms than those diagnosed later in life. Additionally, ARPKD is always accompanied by liver bile duct issues. This could range from mild bile blockage to liver fibrosis, portal vein hypertension, esophageal varices, bile duct infection, and cirrhosis.

One important thing to be aware of about ARPKD is that around 30% – 40% of newborns with the disease reportedly die from respiratory complications, mainly due to reduced urine production. However, improved neonatal care has reduced this mortality rate to just about 20%. The survival rates for those who survive the newborn stage are 85% at 1 year and 82% at 10 years. These statistics may stem from older studies, prior to improvements in newborn intensive care which have bought down the death rate to about 20% in the first month of life.

What Causes Autosomal Recessive Polycystic Kidney Disease?

ARPKD, or autosomal recessive polycystic kidney disease, can differ greatly in how it looks and acts in different people. Over 90% of ARPKD cases are caused by changes in a gene called PKHD1, which is found on chromosome 6. The purpose of this gene is to control the production of a protein called fibrocystin. This protein helps cells stick together, helps with the functioning of tiny hair-like structures on cells called cilia, and aids in cell growth in the kidney and liver.

There is also a great deal of alternative slicing of this gene. It plays a key role as it’s in charge of producing a crucial amount of a full-length protein that helps keep the lining of small tube-like structures in the kidney healthy. DZIP1L, a protein interacting with another protein known as DAZ, has also been linked with some cases of ARPKD but it’s extremely rare.

Patients with a condition called tuberous sclerosis have changes in their TSC1 and TSC2 genes. These genes are found on the same chromosome 16 as the PKD1 gene. Patients with tuberous sclerosis often show signs of PKD early on and their symptoms can look a lot like ARPKD.

Risk Factors and Frequency for Autosomal Recessive Polycystic Kidney Disease

ARPKD, which stands for “Autosomal Recessive Polycystic Kidney Disease,” is a common genetic cause of serious kidney problems in infants. But even so, it only occurs in about 1 in every 20,000 to 40,000 newborn babies. This implies that about 1 in 70 people, regardless of age, race, or gender, can potentially carry this disease.

People who carry only one copy of the ARPKD gene may show minor changes in their kidneys or liver that resemble polycystic kidney disease or hepatic cystic disease. It’s also important to note that the number of children diagnosed with ARPKD is about the same as the number diagnosed with early-onset autosomal dominant polycystic kidney disease. This similarity can make it hard to tell them apart in the young age group.

Signs and Symptoms of Autosomal Recessive Polycystic Kidney Disease

ARPKD or the Autosomal Recessive Polycystic Kidney Disease has become easier to detect in patients early, thanks to routine antenatal ultrasound. The scans often reveal very large and bumpy kidneys. Sometimes the kidneys get so big they can block regular vaginal birth.

In the first 30 days post-birth, newborns might suffer serious breathing problems due to underdeveloped lungs. This is mainly because their exceptionally big kidneys compress their thorax which reduces their vital capacity. Within the initial few months, 75% of these infants could develop kidney problems and high blood pressure, which can be severe.

ARPKD can also lead to growth delays due to malnutrition. These could be caused by exceedingly large kidneys, high blood pressure in the portal vein (portal hypertension), kidney problems, and the potential requirement for peritoneal dialysis.

Young children affected by the disease usually present several symptoms including urinary tract infections, blood in urine, and kidney-related bone disease. It is important to note that their cognitive function remains unaffected.

These children often have varying levels of a liver condition called congenital hepatic fibrosis, which causes:

Splenomegaly or enlarged spleen
Thrombocytopenia or low blood platelet count
Esophageal varices that can potentially bleed into the upper gastrointestinal (GI) tract

Children usually come in presenting symptoms of Cholangitis, a form of liver inflammation, such as fever or abdominal pain.

If a newborn is diagnosed with ARPKD, the kidney disease tends to be more severe. However, if diagnosed at a later stage, the kidney impairment might be milder, but liver disease with portal hypertension might be more intense.

Physical examination findings can include:

Potter’s facies (typical facial features due to kidney damage)
Limb deformities
Other signs related to low amniotic fluid (oligohydramnios)
Extremely enlarged kidneys
Splenomegaly (enlarged spleen)

Severe cases can show Potter’s sequence which includes severe oligohydramnios, underdeveloped lungs, limb deformities from compression in the womb like clubfeet or dislocated hips, and Potter’s facies.

Testing for Autosomal Recessive Polycystic Kidney Disease

Autosomal recessive polycystic kidney disease (ARPKD) can sometimes be detected while a baby is still in the womb. This is often identified when doctors observe low amounts of amniotic fluid, or when the baby’s kidneys appear unusually large during a routine ultrasound scan. If there’s a family history of kidney diseases or unexplained infant deaths, the parents’ health status is factored in and genetic testing might be recommended.

Lab tests including kidney and liver function, electrolytes, blood protein levels, blood clotting studies, and a complete blood count could be conducted. A low platelet count could indicate that the spleen is holding onto too many platelets. This often occurs in patients with high blood pressure in the veins that carry blood to the liver.

A baby might show signs of low sodium in their blood for a few weeks after birth because newborns sometimes struggle to produce dilute urine. It’s also important to understand that any serum laboratory tests, like electrolytes and creatine, done on babies will match the mother’s serum values for the first one to two days after birth.

Ultrasounds are typically the primary form of imaging, especially in newborns or during pregnancy. By the 24th week of pregnancy, a diagnosis can often be made, though in some cases it’s been observed as early as the 18th week of pregnancy. Ultrasounds usually show exceedingly large kidneys and an abnormality in the distinction between the outer layer and inner parts of the kidney. In children, larger cysts and higher echoing waves from cysts in the deeper parts of the kidney can be identified. However, the measurement of the whole kidney does not necessarily link to kidney function. Unlike in adults, CT scans should be avoided in children due to the radiation exposure.

Magnetic resonance imaging (MRI) can be another option. It can reveal any lesions in the liver and doesn’t involve any harmful radiation. Unfortunately, MRI scans typically require sedation which carries its own risks.

However, a combination of kidney ultrasound results, clinical observations, and family history absence is usually enough to diagnose ARPKD in most cases. Genetic testing, while reliable and considered the gold standard for diagnosing, it might not always be successful due to the significant number of genetic variants.

Once ARPKD is diagnosed, it is generally assumed that there will be liver involvement, with the initial ultrasound often showing minimal cysts or routine results. However, in the early months of life, liver function generally remains preserved and can be monitored using liver enzymes and other lab tests as well as periodic ultrasounds and MRIs of the liver.

In rare instances, ADPKD, another type of polycystic kidney disorder, can present during childhood or be detected before or shortly after birth. It can be difficult to distinguish between ARPKD and ADPKD due to the overlapping symptoms. But ARPKD is usually more severe, occurs at birth and will always feature a liver disease component. There’s generally no family history of kidney disease or kidney failure and higher mortality rates at birth with kidney failure affecting half of the survivors by the age of 20. On the other hand, ADPKD occurs more slowly and milder, usually surfacing symptoms around the age of 30.

Treatment Options for Autosomal Recessive Polycystic Kidney Disease

Treatment for newborns depends on how severe the illness is and which organs are affected. Doctors will track the baby’s breathing, kidney and liver functions, growth, blood pressure and give treatment to manage symptoms. If the baby was diagnosed before birth with ARPKD (a disease that affects the kidneys and liver), a cesarean section might be the preferred delivery method because of the risks associated with enlarged kidneys.

In severe cases, a surgery to remove the kidneys (nephrectomy) might be required because the kidneys are too large, affecting the baby’s breathing or digestion. This surgery can have significant complications. If the baby’s kidneys have reached the end-stage of the disease, a kidney transplant may be necessary. Removing the non-functioning kidneys can make space for the new one and help control the baby’s blood pressure after the surgery.

The immediate treatment might include help with breathing, managing fluids and electrolytes (for conditions like low sodium levels or high potassium levels), controlling high blood pressure, giving nutritional support, giving bicarbonate or citrate supplements for a condition where the body produces too much acid, giving antibiotics for infections, and possibly using a type of dialysis if needed.

When a baby is born with underdeveloped lungs (a condition known as pulmonary hypoplasia), it can usually be managed by supporting the baby’s breathing, which allows the lungs to continue developing. Pulmonary hypertension can sometimes be treated with nitrous oxide. To prevent infections from the respiratory syncytial virus, the use of palivizumab, a preventive medication, is recommended. Many babies diagnosed with ARPKD before birth will have significant pulmonary hypoplasia. Breathing problems are the main cause of death in newborns with this disease.

Kidney failure can cause high potassium levels, while low sodium levels are often found in newborns with this disease. The low sodium levels are usually short-term and are treated by restricting fluids. Patients with liver disease may need extra bile acids, have a procedure to control varices (abnormally dilated vessels), or might need a surgery to create a new pathway for blood flow in the liver. If the kidneys are no longer working, treatments can include hemodialysis, kidney transplant, or usually a type of dialysis called peritoneal dialysis. A kidney removal surgery may be needed for adequate peritoneal dialysis.

Babies with serious kidney failure may also require iron and a hormone called erythropoietin to manage anemia, calcium and vitamin D for bone health, drugs that bind to phosphate due to high phosphate levels, sodium bicarbonate or potassium citrate for the overproduction of body acids, and a drug that behaves like a hormone in the body to control a gland in the neck called the parathyroid. A hormone used for growth appears to be safe and effective in promoting normal growth, otherwise, the disease and low food intake can suppress growth.

Babies who eventually receive a kidney transplant are at higher risk of bile duct infection and sepsis due to the required immune-suppressing drugs, therefore it is a concern.

High blood pressure is often severe, requiring multiple medications for control. RAAS blockers are usually the first-line treatments. Other treatments can include beta-blockers, calcium channel blockers, dietary salt restriction, and diuretics when necessary to control the blood pressure. Hypertension usually appears before there is any clinical evidence of kidney failure and will affect 80% of children with this disease. It is usually easier to control hypertension after the first year of life.

Nutrition is particularly beneficial during the first two years of life. It is especially important in children with significant portal hypertension and early kidney failure. Poor feeding can be due to the very enlarged kidneys putting pressure on the stomach and digestion. A growth hormone has been considered to promote growth and appears safe and effective.

Liver disease requires fast treatment of an infection ascending the bile duct and may benefit from bile acid supplements. It helps increase the natural liver bile secretions and minimizes gallstone development. A treatment to block off varices might be needed in patients with progressive portal hypertension. In severe cases, a procedure to create a new pathway for blood to flow from the liver or a liver transplant may need to be considered. Preventive antibiotics are recommended by some experts.

In some cases, depending on the severity of portal hypertension and end-stage kidney disease, transplants of both liver and kidney have shown promising results.

Currently, a drug called tolvaptan is the only FDA-approved treatment for ADPKD, a similar disease, and it has proven effective in preserving kidney function. Clinical trials are being conducted to see if tolvaptan could be a potential treatment for ARPKD. Other possible treatments are being researched.

When a doctor is trying to diagnose Autosomal Recessive Polycystic Kidney Disease (ARPKD), they must also consider and rule out many other conditions that can present in a similar way. These include:

Autosomal Dominant Polycystic Kidney Disease (ADPKD)
CMV infections (cytomegalovirus) in the womb, which can disrupt the baby’s kidney development and can be detected through an amniotic fluid test
Medullary Cystic Kidney Disease, a condition causing damage and scarring in the innermost part of the kidney, it usually starts showing symptoms later in life
Other syndromes like Bardet–Biedl, Joubert, and Meckel syndromes, which, like ARPKD, are caused by problems with the cilia (tiny hair-like structures that cover our cells)
Conditions like Hereditary Renal Agenesis or Dysplasia, where kidneys are either entirely missing at birth or don’t develop properly
Mutations in a gene called HNF1β, which produces a protein that helps to regulate PKHD1 – the key gene involved in ARPKD. Those mutations can also lead to renal cysts resembling ARPKD
Nephronophthisis – a kidney disorder characterized by small, scarred kidneys with cysts. It often progresses to kidney failure in teens and young adults
Von Hippel–Lindau syndrome – a genetic condition causing tumors and cysts to grow in many parts of the body, including kidneys
Other rare genetic conditions, including:
- Brachymesomelia-renal syndrome
- Senior-Løken syndrome
- Smith-Lemli-Opitz syndrome
- Short-rib-polydactyly syndrome
- Trisomy 13
Tuberous Sclerosis – a genetic disorder that causes non-cancerous tumors to grow in many parts of the body

In all these cases, the symptoms can be similar to those of ARPKD, so thorough tests are necessary to ensure a correct diagnosis.

What to expect with Autosomal Recessive Polycystic Kidney Disease

The outcome of patients with complications like lung, liver, and kidney disease depends on the seriousness of these conditions. Newborns with severe kidney disease might not survive due to lung underdevelopment and failure, which can happen in up to 40% of such cases.

Despite advancements in newborn care leading to better survival rates, neonatal mortality still lies around 20%. Those who do survive the early days of life generally have a ten-year survival rate of approximately 82%. However, these individuals often experience worsening kidney failure, high blood pressure, liver scarring, portal hypertension, and end-stage kidney disease. Some reports indicate that over 90% of those who survive the neonatal period live until at least their 20th birthday.

At first, liver disease in ARPKD—a genetic kidney disease—is usually mild in newborns and young children. However, the severity of liver dysfunction tends to increase with age. These children often show signs of portal hypertension, which is high blood pressure in the liver’s veins, due to ongoing liver scarring. But, with proper management, situations like portal hypertension and bleeding from enlarged veins aren’t usually life-threatening, so many of these patients can live until middle age. After 40, individuals with ARPKD face a small increase in their risk of developing liver tumors, especially a type called cholangiocarcinoma.

Possible Complications When Diagnosed with Autosomal Recessive Polycystic Kidney Disease

ARPKD, or Autosomal Recessive Polycystic Kidney Disease, can come with a long list of potential complications including:

Azotemia – a medical condition related to kidney disease
Cholangitis – inflammation in a duct that carries bile
Congenital hepatic fibrosis – a condition that affects the liver from birth
Gastrointestinal bleeding – internal bleeding in the digestive organs
Severe hypertension – very high blood pressure
Increased risk for ascending cholangitis – a risk of infection in the bile duct
Large masses on either side of the lower back
Liver failure and cirrhosis – serious liver conditions
Malabsorption of fat-soluble vitamins – difficulty absorbing certain vitamins from food
Poor growth, feeding, and nutrition
Progressive portal hypertension – a gradual increase in blood pressure in the veins leading to the liver, causing additional complications like esophageal and gastric varices, splenomegaly (enlarged spleen), and gastrointestinal bleeds
Progressive renal failure – gradual loss of kidney function
Renal osteopathy – bone disease due to kidney failure
Respiratory distress due to underdeveloped lungs and limited diaphragm movement because of the enlarged kidneys
Splenomegaly – enlarged spleen (found in about 60% of patients)
Thrombocytopenia – low platelet count in the blood, which can lead to excessive bleeding

Preventing Autosomal Recessive Polycystic Kidney Disease

For parents who have already had one child with ARPKD, there is a 25% chance that any future children they have will also develop this disorder due to how it is inherited. This type of inheritance is called autosomal recessive. The estimated risks for ARPKD are as follows:

If a family member is diagnosed with ARPKD, it’s important for their immediate relatives, particularly brothers and sisters, to be tested as well. Even if they seem to be healthy, siblings have a 66% chance of carrying the ARPKD gene. The family should be informed about the risk of ARPKD in any future children. Amniocentesis, a medical test done during pregnancy, can be performed if anyone wants further information.

Patients and their families need to be educated about the nature of ARPKD, how it might develop over time, possible complications, and treatment options. They should also be informed about available genetic tests and given advice about what the results could mean. For those with ARPKD, it’s best to avoid contact sports. It’s also crucial to ensure that patients and families have the emotional and social support they need during treatment and management of the condition.

Frequently asked questions

Autosomal recessive polycystic kidney disease (ARPKD) is a rare genetic disorder that primarily affects the kidneys and liver. It is characterized by kidney cysts and liver fibrosis, and can be detected in the womb or during infancy. About half of people with ARPKD will require a kidney transplant or dialysis by the age of 20 due to end-stage renal failure.

Autosomal Recessive Polycystic Kidney Disease occurs in about 1 in every 20,000 to 40,000 newborn babies.

The signs and symptoms of Autosomal Recessive Polycystic Kidney Disease (ARPKD) include: - Very large and bumpy kidneys, which can be detected through routine antenatal ultrasound. - Breathing problems in newborns within the first 30 days post-birth due to underdeveloped lungs, caused by the compression of the thorax by the enlarged kidneys. - Kidney problems and high blood pressure in 75% of infants within the initial few months, which can be severe. - Growth delays due to malnutrition, caused by factors such as large kidneys, high blood pressure in the portal vein, kidney problems, and the potential need for peritoneal dialysis. - Urinary tract infections, blood in urine, and kidney-related bone disease in young children affected by the disease. It is important to note that their cognitive function remains unaffected. - Varying levels of a liver condition called congenital hepatic fibrosis, which can cause symptoms such as an enlarged spleen (splenomegaly), low blood platelet count (thrombocytopenia), and potentially bleeding esophageal varices in the upper gastrointestinal tract. - Symptoms of liver inflammation, such as fever or abdominal pain, known as Cholangitis. - Physical examination findings can include Potter's facies (typical facial features due to kidney damage), limb deformities, signs related to low amniotic fluid (oligohydramnios), extremely enlarged kidneys, and splenomegaly (enlarged spleen). - Severe cases of ARPKD can show Potter's sequence, which includes severe oligohydramnios, underdeveloped lungs, limb deformities (such as clubfeet or dislocated hips) due to compression in the womb, and Potter's facies.

Over 90% of ARPKD cases are caused by changes in a gene called PKHD1, which is found on chromosome 6.

The doctor needs to rule out the following conditions when diagnosing Autosomal Recessive Polycystic Kidney Disease: - Autosomal Dominant Polycystic Kidney Disease (ADPKD) - CMV infections (cytomegalovirus) in the womb - Medullary Cystic Kidney Disease - Bardet–Biedl, Joubert, and Meckel syndromes - Hereditary Renal Agenesis or Dysplasia - Mutations in the HNF1β gene - Nephronophthisis - Von Hippel–Lindau syndrome - Brachymesomelia-renal syndrome - Senior-Løken syndrome - Smith-Lemli-Opitz syndrome - Short-rib-polydactyly syndrome - Trisomy 13 - Tuberous Sclerosis

The types of tests that are needed for Autosomal Recessive Polycystic Kidney Disease (ARPKD) include: 1. Lab tests: These include kidney and liver function tests, electrolyte tests, blood protein level tests, blood clotting studies, and a complete blood count. 2. Ultrasounds: Ultrasounds are typically the primary form of imaging used to diagnose ARPKD. They can show enlarged kidneys and abnormalities in the structure of the kidneys. 3. Magnetic Resonance Imaging (MRI): MRI scans can be used to reveal any lesions in the liver without exposing the patient to harmful radiation. However, sedation is often required for MRI scans, which carries its own risks. 4. Genetic testing: Genetic testing is considered the gold standard for diagnosing ARPKD. However, it may not always be successful due to the significant number of genetic variants associated with the condition. 5. Other tests: Additional tests may be conducted to monitor liver function, such as liver enzyme tests and periodic ultrasounds and MRIs of the liver.

Treatment for Autosomal Recessive Polycystic Kidney Disease (ARPKD) depends on the severity of the illness and which organs are affected. Doctors will monitor the baby's vital functions and provide treatment to manage symptoms. In some cases, a cesarean section might be recommended for delivery. Surgery to remove the kidneys (nephrectomy) may be necessary if the kidneys are too large and affecting breathing or digestion. Kidney transplant may be required if the disease has reached end-stage. Immediate treatment may include respiratory support, fluid and electrolyte management, blood pressure control, nutritional support, medication for acid production, antibiotics for infections, and dialysis if needed. Other treatments may be needed to manage complications such as liver disease, pulmonary hypoplasia, and high blood pressure. Clinical trials are also being conducted to explore potential treatments for ARPKD.

The side effects when treating Autosomal Recessive Polycystic Kidney Disease (ARPKD) can include: - Azotemia (related to kidney disease) - Cholangitis (inflammation in a bile duct) - Congenital hepatic fibrosis (affects the liver from birth) - Gastrointestinal bleeding (internal bleeding in the digestive organs) - Severe hypertension (very high blood pressure) - Increased risk for ascending cholangitis (infection in the bile duct) - Large masses on either side of the lower back - Liver failure and cirrhosis (serious liver conditions) - Malabsorption of fat-soluble vitamins (difficulty absorbing certain vitamins from food) - Poor growth, feeding, and nutrition - Progressive portal hypertension (gradual increase in blood pressure in veins leading to the liver, causing complications like esophageal and gastric varices, splenomegaly, and gastrointestinal bleeds) - Progressive renal failure (gradual loss of kidney function) - Renal osteopathy (bone disease due to kidney failure) - Respiratory distress due to underdeveloped lungs and limited diaphragm movement because of enlarged kidneys - Splenomegaly (enlarged spleen) - Thrombocytopenia (low platelet count in the blood, leading to excessive bleeding)

The prognosis for Autosomal Recessive Polycystic Kidney Disease (ARPKD) can vary depending on the severity of the condition and the presence of complications. However, improved neonatal care has reduced the mortality rate for newborns with ARPKD to about 20%. The survival rates for those who survive the newborn stage are 85% at 1 year and 82% at 10 years.

A nephrologist or a pediatric nephrologist.

Genetic Disorders Kidney Disease Liver Disease Urine