Mouse model reveals potential way to reduce cardiac deaths in kidney patients

03/29/05

St. Louis, March 29, 2005 -- Scientists have identified an important link between kidney damage and cardiac problems, creating new possibilities for treating the primary cause of death in kidney disease patients.

Researchers tracked a chain reaction that leads from kidney damage to weakening of the skeleton to increased phosphorous in the blood. They showed that higher phosphorous levels were directly linked to vascular calcification, a stiffening of the smooth muscle cells that line blood vessels. Vascular calcification leads to enlargement of one of the heart's four chambers, increased risk of congestive heart failure, heart attack and several other cardiac problems.

Mice treated with an experimental medication that alleviates the skeletal weakening brought on by kidney damage had normal phosphorous levels and decreased signs of vascular calcification.

"We already have treatments available that can control phosphorous levels in the blood, and those should be very helpful for kidney patients," says senior investigator Keith A. Hruska, M.D., the Ira M. Lang Professor of Nephrology and professor of pediatrics and of cell biology and physiology at Washington University School of Medicine in St. Louis. "The drug we used in the mice and other similar agents can treat both the phosphorous levels and skeletal weakening, and those drugs are just entering initial clinical trials."

The study will appear in the April issue of the Journal of the American Society of Nephrology.

Hruska, who is director of nephrology at St. Louis Children's Hospital, has long been interested in the connections between kidney damage and bone weakening. He and other researchers have uncovered a complex network of links between the skeleton and the kidney. Hormones made in the kidney regulate activity in the skeleton and vice-versa.

Last year, Hruska showed that injections of bone morphogenetic protein-7 (BMP-7) could prevent bone weakening in mice whose kidneys had been damaged or removed.

For the new study, researchers worked with a mouse model of metabolic syndrome, a condition common among patients with chronic kidney disease that includes symptoms such as obesity, high blood pressure and insulin resistance. The condition, which is rapidly increasing in both adults and children, is also associated with higher risks of diabetes and heart disease.

The mice develop metabolic syndrome as a result of both a genetic modification and a high-fat, high-cholesterol diet. To simulate chronic kidney disease, scientists damaged or removed part of the kidney. This led to a shutdown of cells that regularly dismantle and rebuild bones, causing vascular calcification.

The body normally takes minerals like calcium and phosphorous circulating in the bloodstream and deposits them in the bones during bone reconstruction. With those processes shut down, scientists theorized, the bloodstream levels of minerals increase, raising pressure to deposit them elsewhere.

Hruska and his colleagues first showed that injection of BMP-7, previously shown to stop the bone disorder, also stopped vascular calcification. In another group of experimental mice, injections of a substance that binds to compounds with phosphorous but has no effect on the skeleton also stopped vascular calcification, proving that phosphorous was the key link.

"Serum phosphorous is a direct stimulus to the smooth muscle cells that line blood vessels, causing them to take on characteristics very similar to osteoblasts, the cells that form bone," Hruska explains.

The changed smooth muscle cells can deposit minerals outside their membranes, dramatically decreasing the flexibility of blood vessels and increasing the work the heart has to do to create a pulse.

"Vascular stiffness happens to patients with end-stage kidney failure when they go on dialysis, and it leads to many dangerous cardiovascular complications," Hruska says. "This study shows us that by treating the skeleton or otherwise decreasing phosphorous levels, we have the potential to produce a decrease in vascular calcification and marked improvements in cardiovascular outcome."

To follow up, Hruska plans a more direct study of the effects of BMP-7 on vascular calcification and further investigation of the skeleton-kidney links that lead to bone weakening in patients with kidney damage.

Source: Eurekalert & others

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