Kidney Injury's Harmful Effects On Bones Blocked In Mice

"We still have some mechanical and structural testing to do to prove that the skeletons of these mice are normal, but if this works out and we're able to apply it in humans, we could be on our way to producing a major improvement in the well-being of patients with chronic kidney disease," says 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.

Hruska was principal investigator for the study, which appears in the February issue of the Journal of the American Society for Nephrology. Scientists gave injections of bone morphogenetic protein-7 (BMP-7), a protein involved in both bone and kidney growth, to mice with damaged and removed kidneys. The injections prevented a condition known as adynamic bone disorder (ABD) that leads to weakening and distortion of bone.

"Adynamic bone disorder means that the cells that remodel bones are markedly diminished in number and activity," Hruska explains. "In the past, the skeleton has been viewed as a mostly dead structure, but that's not the case at all. The adult skeleton is a very active tissue that is continually remodeling."

ABD is the second type of bone weakening related to kidney problems that scientists have identified. In the first, secondary hyperparathyroidism, patients have weakened bones like in ABD, but also have abnormal blood levels of the hormone produced by the parathyroid gland and several other important chemicals.

Hruska suspects secondary hyperparathyroidism may be a failed attempt to compensate for ABD, which first emerged about 15 years ago when scientists began using drugs to suppress parathyroid hormone levels in kidney patients.

Secondary hyperparathyroidism and ABD occur both in patients who lose their kidneys to disease and in those who suffer a sufficiently damaging kidney injury. Studies of both conditions in human patients and animal models recently have uncovered a complex network of links between the skeleton and the kidney.

"We're learning that hormones made in the kidney regulate the skeleton, and hormones made in the skeleton regulate the kidney," Hruska explains.

Assuming that kidney damage produces ABD first, Hruska reasoned that the damage either suppresses a factor that stimulates production of renewed bone or increases production of a factor that inhibits bone renewal. The uniqueness of BMP-7, a protein whose gene scientists have identified in both mice and humans, moved it to the top of his list of suspects.

"Among the factors involved in the development of the skeleton and the kidney, BMP-7 stands out because it continues to be produced even after development is complete," Hruska explains.

For the experiment, Hruska and colleagues damaged one kidney in mice and removed the other. They divided the mice into several groups. In three of the groups, they prevented secondary hyperparathyroidism with dietary changes and a nutritional supplement.

Researchers evaluated bone health through microscopic examination of bone cell numbers, structures, and types, and found that mice given the special diet and supplement developed symptoms similar to adynamic bone disorder. But mice treated with the special diet, the supplement and injections of BMP-7 had normal bone cell counts and structures.

Hruska plans further tests of the experimental mice skeletons. He also hopes to look into BMP-7's effects on an even more harmful side effect of kidney injury: heart disease.

"Kidney damage decreases mineral storage in the bones, and minerals not stored in the bones are stored elsewhere," he explains. "This extraskeletal storage of minerals can take the form of vascular calcification, and that's very bad. That can be a huge contributor to heart attack and heart failure, and those are what kill patients suffering from kidney failure."

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Lund RJ, Davies MR, Brown AJ, Hruska KA. Successful treatment of an adynamic bone disorder with bone morphogenetic protein-7 in a renal ablation model. Journal of the American Society of Nephrology, February 2004.

Funding from the National Institutes of Health supported this research.

The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.