MEDICINE KIDNEY DISEASE : Discovery of Hormone Holds Promise
California and Utah researchers have succeeded in preventing one form of kidney disease in rats, potentially opening the door to prevention of kidney failure in humans.
The disease, called glomerulonephritis, is one of the most common causes of chronic kidney failure, afflicting as many as 100,000 Americans each year. Once the kidney fails, the patients must either receive a transplant or remain on dialysis for the rest of their lives.
Researchers from the University of Utah and the La Jolla Cancer Research Foundation report today in the British journal Nature that glomerulonephritis in the rats is caused by excess concentrations of a hormone called transforming growth factor-beta (TGF-B).
They found that specialized antibodies can be used to remove the hormone from the blood of the animals and thereby prevent the onset of the disease.
But Utah nephrologist Wayne Border cautioned that it could be many years before the proposed therapy could be used in humans. For one thing, the recently discovered TGF-B has not yet been linked to kidney disease in humans--although, he said, “it would be incredible if it weren’t also playing an important role in man.”
Researchers have not shown in animal experiments that the therapy can halt the disease process once it has begun, he added, but test-tube experiments indicate that it can.
“This important observation opens the door” to the treatment of humans, said Dr. Saulo Klahr of the Washington University School of Medicine, president of the National Kidney Foundation.
Healthy kidneys act as filters that remove both excess water and cellular wastes from blood. When the kidneys fail, an individual will die of poisoning within days unless those wastes are removed artificially by dialysis. More than 130,000 Americans undergo dialysis routinely to maintain their health.
The filtering is carried out within the kidney by small units called glomeruli. Kidney disease occurs when the glomeruli become clogged by abnormally large amounts of a material called “extracellular matrix,” a fibrous meshwork of proteins and other materials.
This scarring and clogging can be produced by diabetes, high blood pressure and glomerulonephritis, in which the immune system attacks the glomeruli, often as the aftereffect of an infection. Physicians do not know the precise mechanism by which the damage occurs, and no effective therapy exists to prevent or halt the scarring.
Scientists study glomerulonephritis in rats by injecting a protein that attacks cells in the glomeruli, damaging them and inducing the formation of extracellular matrix. Studying this phenomenon, Border and cellular biologist Erkki Ruoslahti of the La Jolla foundation discovered that the formation of the matrix was triggered by TGF-B, which was released when the kidney cells were damaged.
The researchers then prepared antibodies to the hormone and injected them into 15 rats at the same time they injected the protein that produces the disease. The rats also received daily injections of the the anti-TGF-B antibody on each of the next six days.
After seven days, the researchers examined the rats that received the anti-TGF-B antibody and found that their glomeruli were normal, Border said, indicating that disease had been prevented. In contrast, the glomeruli of 15 control animals who were given only the disease-producing protein showed marked scarring and inflammation.
So far, there is no evidence that TGF-B plays a similar role in glomerulonephritis in humans. “But our paper is the first to describe a link to TGF-B in kidney disease,” Border said, “so no one has looked for it before.”
They are now collecting human blood samples to look for the hormone, he said, and they are also conducting studies to determine if the anti-TGF-B antibodies can halt the disease process once it has been initiated.
Meanwhile, Ruoslahti and his colleagues in La Jolla have discovered a naturally occurring protein, called decorin, that in the test tube binds to TGF-B and neutralizes its activity in much the same way that the antibody does. Researchers at Telios Pharmaceuticals of La Jolla are developing techniques to produce large quantities of decorin in order to study its potential therapeutic use.
The research may have other applications as well, Ruoslahti said. TGF-B may be involved in other diseases where excess scarring occurs, such as lung disease, and it may play a role in the process by which cancer cells from a tumor metastasize, invading other parts of the body. Developing the ability to interfere with TGF-B, he said, might thus have therapeutic potential in those disorders as well.
Maugh reported from Los Angeles and Monroe reported from San Diego.
BACKGROUND
Kidney disease, caused by diabetes, high blood pressure and glomerulonephritis, affects as many as 100,000 Americans a year. The only treatments are dialysis and kidney transplants. The number of Americans on dialysis has been growing about 10% a year, reaching 130,000 in 1989 and costing the federal government about $2.5 billion a year.
