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What is ARPKD?
Autosomal recessive polycystic kidney disease, ARPKD, is a rare genetic disorder, occurring in approximately 1 in 20,000 individuals. It affects boys and girls equally and can cause death in the first month of life. If the child survives the newborn period, the chances of survival are good. For these children, approximately one-third will need dialysis or transplantation by the age of 10.
What is the overall outlook for those with ARPKD?
Previously thought to be a fatal condition, the prognosis for children with ARPKD has improved dramatically. Twenty years ago, only half of the children born with the disease survived to their 10th birthday, but now that percentage has increased to 85 percent.
A more positive prognosis may be attributed to prenatal sonogram technology continuing to improve and becoming more routine, allowing doctors to diagnose many cases of ARPKD prior to birth. Accordingly, the birth of an affected child is better planned so the necessary specialists can be alerted. Importantly, the doctors are able to discuss with the parents what they should expect once the baby is born, advising them that the infant may need a breathing tube, may require dialysis, may have severe liver disease, and will require multiple evaluations and treatments to deal with associated complications.
What causes ARPKD?
In recessive disorders such as ARPKD, the child must inherit a copy of the disease gene from each parent in order to be affected. Since the parents each have only one copy of the disease gene, they do not have the disease and are referred to as "carriers." Parents carrying the ARPKD gene have a 25 percent chance that each child will have ARPKD. There is also a 50 percent chance the child will not have ARPKD but will be a carrier of the disease.
What is the kidney problem in ARPKD?
In ARPKD patients, small cysts form in the last section of the nephron called the collecting tubule. A cyst is a balloon-like widening of the tubule. In ARPKD, the abnormality always involves both kidneys. Due to the numerous nephrons with small balloon-like dilatations, the kidneys can become quite enlarged. In addition, the normal function of the collecting tubule is disrupted. In the normal kidney, the collecting tubule fine-tunes the amount of water and acid in the tubular fluid so that the body retains an appropriate amount of water and eliminates excess amounts of acid. In ARPKD patients, the cystic collecting ducts cannot retrieve water efficiently, causing much more urine production than in children with normal kidneys.
For reasons that are not completely understood, the majority of ARPKD patients have a progressive loss of kidney function. However, the age at which kidney failure develops varies greatly among patients, and, for reasons still unknown, the size of the kidneys does not necessarily correlate with the severity of the disease.
Are only the kidneys affected in ARPKD?
ARPKD affects both kidneys and the liver. Affected children may have significant kidney involvement at the time of birth, meaning very enlarged kidneys and decreased urine production. In utero, urine production is a critical factor in maintaining normal amniotic fluid levels. When amniotic fluid levels are very low, lung development can be impaired. In some newborns with low levels of amniotic fluid, impaired lung development can result in serious breathing difficulties that require ventilation upon birth and sometimes can cause death.
Children with ARPKD often produce very large volumes of urine and must urinate much more frequently than children with normal kidneys. Given the kidney abnormality, urine production in ARPKD children does not slow down at night or even when liquid intake is limited.
About one-third of children with ARPKD who live beyond the newborn period will require dialysis and kidney transplantation by 10 years of age.
High blood pressure is very common in children with ARPKD, and current information indicates that untreated high blood pressure can lead to kidney failure more quickly than if the blood pressure is kept within the normal range with medications.
Children with ARPKD also have the liver abnormality called congenital hepatic fibrosis (CHF) that may lead eventually to enlargement of the liver and spleen. In the liver, the abnormality can impede the return of blood from the intestine to the liver. This condition, called portal hypertension, can lead to distention (varices) and increased pressure in the veins around the esophagus, the stomach, and the intestine. These varices can rupture, leading sometimes to life-threatening gastro-intestinal bleeding. In addition, portal hypertension can cause splenic enlargement and hypersplenism, with resulting low red blood cell, white blood cell and platelet counts.
How is ARPKD diagnosed in affected fetuses?
Typically in ARPKD, the kidneys appear to be larger than normal. In some babies, prenatal ultrasound can detect the enlarged kidneys as early as 18 weeks after conception. Some families may also hear the kidneys look "echogenic" (emitting echo signals) during an ultrasound, which can be an indicator of kidney problems such as ARPKD.
Prenatal genetic testing is possible using samples from either chorionic villus sampling or amniocentesis. These genetic tests can either involve a direct search of the gene for mutations or an indirect association using linkage analysis. For linkage analysis, DNA samples are required from the fetus, a previously affected child, and the parents.
Another option for pre-natal diagnosis is a recently developed procedure called pre-implantation genetic diagnosis, or PGD. This is an early form of genetic diagnosis that involves the detection of specific genetic abnormalities in single cells taken from fertilized human embryos. The PGD procedure involves in vitro fertilization whereby eggs harvested from a mother are fertilized in a laboratory with the father’s sperm. Then, the fertilized embryos are tested for a specific genetic disorder (such as ARPKD) by removing one or two cells for genetic analysis. Embryos that are diagnosed as free of the disorder are then placed in the uterus with the intent to initiate a pregnancy; embryos that test positive for the disorder are destroyed. (Is this possible without a previously diagnosed child in the family, without having the specific defective genes determined?)
How many children with ARPKD die in the first month of life? If they survive the first month, what is their life expectancy?
Approximately 70 percent of newborns diagnosed with ARPKD survive the first month of life. Those who do not survive are typically the patients who are born with extremely underdeveloped lungs (pulmonary hypoplasia) that result from the presence of massively enlarged kidneys and/or low amniotic fluid. The largest study available which has evaluated the long-term course of patients with ARPKD who survived the neonatal (first month) period, found that patient survival was 82% at 10 years.
What is the biggest health concern early on?
The immediate life-threatening issue for infants with ARPKD is the severity of lung immaturity. Lung immaturity is caused in part by insufficient amniotic fluid, which is produced by the kidneys, due to the poor prenatal renal function. The severely enlarged kidneys also further limit pulmonary function by impairing diaphragmatic excursion and preventing adequate lung expansion. Mortality in the neonatal period can be as high as 30-50%. If an infant with ARPKD survives this critical period, kidney failure becomes the next most prominent life threatening issue. When the newborn’s life isn’t at risk, the biggest health concerns are often regulating hypertension and the chemical balance of blood.
Can children also have ADPKD?
It was once thought that people who inherited the gene for ADPKD (autosomal dominant polycystic disease) did not form cysts or have symptoms until well into adult life. We now know that ADPKD can be diagnosed at a very young age and even before birth. Any diagnostic tests done during pregnancy should be done in conjunction with medical counseling so the results of the test can be completely understood. For example, knowing a fetus carries the ADPKD gene does not predict the course of the disease. The fetus could go on to show symptoms of ADPKD in childhood or never have a symptom until much later in life.
There seems to be two different groups of children with ADPKD – those who are diagnosed before birth or in the first year of life with large kidneys and/or cysts, and those who are diagnosed after the age of 1.
Children who are diagnosed in the first year of life have some special characteristics:
- Most often, the parent with ADPKD is the mother.
- Most of these children have brothers and/or sisters who are also diagnosed in the first year of life.
- Most are diagnosed before birth with large kidneys, but often they do not have actual cysts.
- Most develop high blood pressure in childhood, so this should be watched for and treated.
Children who are diagnosed after 1 year of age are:
- Just as likely to have an affected father as an affected mother.
- Likely to have cysts, even though their kidneys are not necessarily enlarged.
- Affected with only one cyst (in half the children), or just a few cysts. Whereas, in an adult one cyst alone is not enough to diagnose ADPKD because, as a natural part of aging, people often develop a few kidney cysts without having ADPKD. But in children who are part of an ADPKD family, even one cyst means they are more likely to have the disease.
The number of cysts a child has affects his/her signs and symptoms. Just as in adults, children with many cysts are more likely to have back, side or stomach pain and are also more likely to have high blood pressure than children with only a few cysts.
Almost all children who are diagnosed after the first year of life have perfectly normal kidney function that seems to stay normal throughout childhood. Most children will maintain normal kidney function at least until they are into their mid-20s.