Introduction to Polycystic Kidney Disease

Causes of Polycystic Kidney Disease

There are several factors that contribute to the development of polycystic kidney disease (PKD). Although the exact process has not yet been determined, indications point to at least three factors that are involved with PKD:

• Genetic factors
• Cellular factors
• Hormonal factors

Genetic Factors and Polycystic Kidney Disease

If one or both parents pass down an abnormal gene to a child at conception, a genetically transmitted disease can occur. If receiving the abnormal gene from one parent is enough to produce the disease in the child, it is defined as a dominant gene. In these cases, one of the parents also has the disease. If both parents must have the abnormal gene in order for the child to develop the disease, it is defined as recessive. In these cases, the parents do not have the disease themselves but both carry the abnormal gene. The chances of inheriting a dominant gene are much higher than a recessive one. If a child receives one abnormal gene for a recessive disease, he/she will not develop the disease but may pass that recessive abnormal gene down to his/her children.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited form of polycystic kidney disease. If one parent has the disease, there is a 50% chance of passing the disease to each child. If both parents have the disease, there is a 75% chance that each child will have the disease. Transmission is not sex-linked (not associated with the gender of the effected parent). It is believed that in about 10-25% of cases, a new mutation of the gene spontaneously occurs in a fetus which results in ADPKD.

Autosomal recessive PKD is inherited from a recessive gene which means that both parents have to have the abnormal gene even though neither one of them may have clinical evidence of the disease. Each child that is born to two such parents has a 25% chance of having the disease.

Scientists have recently began to identify the process that triggers the formation of cysts. They have located 2 genes related to ADPKD which are mutated: one gene (PKD1) on chromosome 16 and another gene (PKD2) on chromosome 4. They have also identified the proteins that each of these gene produces: polycystin 1 produced by PKD1 and polycystin 2 produced by PKD2.

When both of these genes are normal, they foster normal kidney growth and development and inhibit formation of cysts, however, if either gene is mutated, it can lead to cyst formation. It is thought that cyst formation may be related to inadequate levels of polycystin. It appears that other factors besides the mutation alone may influence the development of PKD.

Since the first gene related to PKD (PKD1) was identified in 1994, researchers have discovered that there are several types of genetic mutations associated with different forms of polycystic kidney disease.

• A gene called PKD1 on chromosome 16 accounts for Type I ADPKD which is abnormal (mutated) in approximately 85-90% of people with ADPKD.
• A second gene called PKD2, on chromosome 4, was identified and mutations in this gene are responsible for causing Type II ADPKD in 10-15% of ADPKD patients.
• In 2002, the gene responsible for ARPKD on chromosome 6, called PKHD1 was discovered.
• Familial nephronophthisis is caused by a mutation of NPH1, NPH2, NPH3, NPH4, and NPH5 genes.
• Medullary cystic kidney disease is caused by a mutation in either the MCKD1 or MCKD2 gene.

Cellular Factors and Polycystic Kidney Disease

In every cell in the body there is a balance between cellular reproduction and proliferation and cellular death (apoptosis). It is thought that part of the progressive destruction of normal kidney tissue in ADPKD and ARPKD is due to abnormally persistent apoptosis (cell death) that may allow the cystic process to continue unchecked.

Hormonal Factors and Polycystic Kidney Disease

A hormone called epidermal growth factor (EGF) appears to be involved with cyst formation in PKD. Certain cells lining the cysts appear to be very sensitive to being stimulated by EGF. There is a high concentration of EGF in cystic fluid which may be a source of stimulation for the proliferation of cystic cells.