Polycystic kidney disease

Polycystic kidney disease (PKD or PCKD, also known as polycystic kidney syndrome) is a cystic genetic disorder of the kidneys.^[1] There are two types of PKD: autosomal dominant polycystic kidney disease (ADPKD) and the less-common autosomal recessive polycystic kidney disease (ARPKD).

It occurs in humans and some other animals. PKD is characterized by the presence of multiple cysts (hence, "polycystic") typically in both kidneys; however 17% of cases initially present with observable disease in one kidney, with most cases progressing to bilateral disease in adulthood.^[2] The cysts are numerous and are fluid-filled, resulting in massive enlargement of the kidneys. The disease can also damage the liver, pancreas and, in some rare cases, the heart and brain. The two major forms of polycystic kidney disease are distinguished by their patterns of inheritance.

Polycystic kidney disease is one of the most common life-threatening genetic diseases, affecting an estimated 12.5 million people worldwide. In half of the people with Polycystic kidney disease, there is no family history of the disease. In these cases, the gene coding for the disease occurs out of a spontaneous genetic mutation without either parent being a carrier of the gene.

Types

Autosomal dominant

ADPKD is the most common of all the hereditary cystic kidney diseases ^[2][3][4] with an incidence of 1 to 2:1,000 live births.^[2][4] Studies show that 10% of end-stage renal disease (ESRD) patients being treated with hemodialysis in Europe and the U.S. were initially diagnosed and treated for ADPKD.^[2] ADPKD does not appear to demonstrate a preference for any particular ethnicity.

ADPKD is characterized by progressive cyst development and bilaterally enlarged kidneys with multiple cysts. There are three genetic mutations in the PKD-1, PKD-2, and PKD3 gene with similar phenotypical presentations. Gene PKD-1 is located on chromosome 16 and codes for a protein involved in regulation of cell cycle and intracellular calcium transport in epithelial cells, and is responsible for 85% of the cases of ADPKD. A group of voltage-linked calcium channels are coded for by PKD-2 on chromosome 4. PKD3 recently appeared in research papers as a postulated 3rd gene. At this time, PKD3 has not been proven.^[2][3] Fewer than 10% of cases of ADPKD appear in non-ADPKD families.

Cyst formation begins in utero from any point along the nephron, although fewer than 5% of nephrons are thought to be involved. As the cysts accumulate fluid, they enlarge, separate entirely from the nephron, compress the neighboring renal parenchyma, and progressively compromise renal function.

Under the function of gene defect, epithelial cells of renal tubule turn into epithelial cells of cyst wall after phenotype change, and begin to have the function of secreting cyst fluid, which leads to continuous cysts enlargement.^[5]

Autosomal Recessive

Studies show that the incidence of ARPKD (OMIM #263200) is 1:20,000 live births and is typically identified in the first few weeks after birth. Unfortunately, resulting hypoplasia results in a 30% death rate in neonates with ARPKD.^[2] In ARPKD kidneys retain their shape but are larger than the normal anatomical range with dilated collecting ducts from the medulla to the cortex.

Extrarenal manifestations

The major extrarenal complications of ADPKD include cerebral aneurysms, hepatic cysts, pancreatic cysts, cardiac valve disease, colonic diverticula, and aortic root dilatation.

Clinical trials and possible future treatments

It is known that a certain molecule known as cAMP is involved in the enlargement of kidney cysts in PKD kidneys.^[6] Various studies on rodents have shown that a molecule, called vasopressin, increases levels of cAMP in the body. When mice with PKD were given a chemical that blocks vasopressin, there was an impressive decrease in kidney size and some preservation of kidney function. Similarly, when studied mice consumed excessive amounts of water, (which decreases levels of vasopressin) a similar result was seen. It has therefore been suggested that consuming large amounts of water may possibly assist in the treatment of early stage PKD. ^{[7] [8]}

As humans do not always mimic rodents in clinical trials, it is currently not yet certain whether vasopressin inhibitors, such as water, will have corresponding results in humans, or what negative effects excessive water intake may have on the kidneys of individuals with PKD. Clinical trials are currently underway in this field. ^[9]

It has also been suggested that treatment with medications inhibiting vasopressin may assist in the management of PKD and reduce the speed at which kidney cysts form and grow, delaying the onset of end stage renal failure. Clinical trials are currently underway in the testing of Tolvaptan, an FDA approved medication which has not yet been approved for use in the treatment of PKD.^[10]

References

External links