Inherited diseases that cause the kidneys to develop fluid-filled cavities (cysts) are major causes of kidney failure in children and in adults. The most common and important diseases in this category are autosomal dominant polycystic kidney disease (ADPKD) in adults, and autosomal recessive polycystic kidney disease (ARPKD) and nephronophthisis in children. Currently, there are no effective treatments for these disorders.
Previous studies conducted at the University of Kansas and other polycystic kidney disease research centers showed that a chemical compound known as cyclic AMP is largely responsible for the cell proliferation and fluid secretion that are central to the development of kidney cysts.
The drug studied by Mayo Clinic and Indiana University researchers inhibits the production of cyclic AMP by blocking a specific receptor found almost exclusively on the cells from which the cysts develop. In healthy kidneys, cyclic AMP stimulates the reabsorption of water by these cells, which normally do not proliferate and form cysts.
"The fact that these drugs selectively target specific receptors on these kidney cells and bypass other organs makes them relatively nontoxic and adds to their value as a potential treatment for polycystic kidney disease," says Vicente Torres, M.D., Ph.D., a Mayo Clinic nephrologist and one of the study's two primary investigators.
OPC31260 and related drugs are currently being tested as possible treatments for conditions that cause water retention, such as heart or liver failure, demonstrating the drug's safety.
"Because the animals we studied had mutations in the very same genes known to cause ARPKD and nephronophthisis in humans, our findings are likely to pave the way for clinical trials of this drug in people with these diseases," says Vincent Gattone II, Ph.D., an Indiana University School of Medicine researcher who is the study's other primary investigator. "We hope this treatment will also be effective for treating ADPKD."
ADPKD affects 600,000 persons in the United States and 12.5 million people worldwide. It is the third-most common single cause of kidney failure in this country. Many people with this disease develop high blood pressure before age 30, and many die from cardiovascular complications such as heart attacks and strokes.
ARPKD and nephronophthisis are leading causes of kidney failure in childhood. ARPKD affects one in 20,000 Americans. Roughly 30 percent of those children with ARPKD die during infancy; about 50 percent of those who survive develop kidney failure in the first decade of life. Nephronophthisis accounts for up to 5 to 10 percent of kidney failure in childhood.
This research was funded by the National Institutes of Health and by the Polycystic Kidney Disease Foundation.