These findings, which are reported in the July 2003 issue of Nature Medicine, could help lead to the development of a therapeutic alternative for the nearly 300,000 kidney disease patients who are currently undergoing dialysis.
"Dialysis is not really a treatment, it's just a means of survival until an opportunity for a transplant opens up," notes the study's senior author Raghu Kalluri, Ph.D., director of the Center for Matrix Biology at BIDMC and Associate Professor of Medicine at Harvard Medical School. "This is a very tedious way of living life," he adds, explaining that the process of mechanically filtering blood through a machine to remove waste products must be performed several times a week for a period of three to four hours per visit, posing risks of infection and other side effects. Furthermore, the procedure is extremely costly.
The kidneys function as a filtration system, keeping the body's blood supply healthy by removing excess fluids and wastes, as well as by producing hormones. When kidneys "fail" - as can result from complications associated with diabetes, lupus or several other diseases - harmful wastes accumulate in the bloodstream, excess fluids build up in the body, and red blood cell production is impeded. Once chronic kidney disease develops, it cannot be reversed or repaired; when the organs cease to function, patients have no alternative but to undergo dialysis while awaiting a kidney transplant.
This new study looked at the role of a molecule called bone morphogenic protein (BMP)- 7 which, in its recombinant form, has been approved by the U.S. Food and Drug Administration for the treatment of bone fractures. Earlier studies had revealed that BMP-7 is highly expressed in the kidneys of healthy individuals. "We wanted to learn if this protein was somehow offering protection against kidney injury," explains Kalluri.
The investigators used mouse models of chronic renal injury, characterized by the presence of scar tissue known as renal fibrosis; once kidney disease was well-established in the animals, they administered human recombinant BMP-7.
"We found that in the kidneys, BMP-7 reverses a process known as epithelial-to-mesenchymal transition, which generates scar-causing cells known as fibroblasts," says Kalluri, explaining that BMP-7 first reduces the number of the fibroblast cells, and then replaces the damaged areas of the kidney tubules with healthy epithelial cells. "In effect," he adds, "BMP-7 is decreasing the bad cells [in this context, fibroblasts] and converting them into good cells [in this context, epithelial cells]."
Although therapies exist to slow progression of kidney disease, once it has developed it becomes intractable, eventually leaving patients no alternative but to undergo dialysis. "The possibility of creating a cost-effective drug that would actually reverse renal injury could significantly reduce the need for dialysis and significantly improve the quality of life for these patients," says Kalluri.
Study co-authors include BIDMC investigators Michael Zeisberg, M.D., Jun-ichi Hanai, M.D., Hikaru Sugimoto, M.D., Ph.D., Tadanori Mammoto, Ph.D., David Charytan, M.D., and Frank Strutz, M.D.
This study was funded by grants from the National Institutes of Health, Deutsche Forschungsgemeinschaft, and support from the Center for Matrix Biology, BIDMC. Ortho Biotech Products, L.P., is the exclusive licensee of BMP-7.
Beth Israel Deaconess Medical Center is a major patient care, teaching and research affiliate of Harvard Medical School, and ranks third in National Institutes of Health funding among independent hospitals nationwide. BIDMC is clinically affiliated with the Joslin Diabetes Center and is a founding member of the Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox.