Find Could Be Key to Fighting Kidney Disease : Medicine: San Diego and Utah researchers say their discovery using rats could someday mean help for the thousands who suffer from glomerulonephritis.
San Diego 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 at an estimated annual cost of $2.5 billion to the federal government.
Researchers from the La Jolla Cancer Research Foundation and the University of Utah 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 can 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.”
Cellular biologist Erkki Ruoslahti, president of the La Jolla Foundation and principal investigator there in the kidney experiments, agreed that TGF-B looks like the culprit.
“There are other growth factor (chemicals) that people have felt might be involved, but we tested them in our cell cultures, and found that they didn’t really have this property,” Ruoslahti said.
Researchers have not shown in animal experiments that the therapy can halt the disease once it has begun, Border 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 a filter that remove both excess water and cellular wastes from blood. When the kidneys fail, a patient 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 Ruoslahti 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, unfortunately, 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 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 in which 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.
Other San Diego researchers involved in the project include Lucia R. Languino and Michael B. Sporn.
The collaboration between Border and the private La Jolla Cancer Research Foundation was based in work the foundation has been doing to understand the connective proteins that form the body’s microscopic framework.
Called the extracellular matrix, these proteins provide a scaffolding to which the body’s cells attach. Scientists have found that TGF-B is the chemical messenger that turns on the cells’ matrix production.
If there is too much TGF-B, there may be a damaging accumulation of connective proteins, such as is seen in scarring from kidney inflammation, Ruoslahti said. If there is too little, cells may migrate where they aren’t supposed to--as do cancer cells.
In turn, the matrix sends signals to the cells.
“It interacts with the cells, telling them how they should be oriented in the body, fixing them into that position, even telling them when to grow and not to grow, when to differentiate and when not to,” Ruoslahti explained.
Ruoslahti is among researchers who believe that it is defects in this matrix-cell communication system that are behind various diseases, including the internal scarring from kidney inflammation.
The La Jolla-Utah kidney results reported in Nature provide a strong link in the chain of evidence being built for this hypothesis, Ruoslahti said.
Ruoslahti’s research in La Jolla continues to look at the role of TGF in other diseases in which the intracellular matrix is involved, including cancer.
Work done at the La Jolla center and elsewhere also indicates that defects in this back-and-forth communication between the matrix and cells allow cancer cells to migrate around the body rather than stay in one place. Recent genetic work there succeeded in making tumor cells non-tumorigenic, simply by increasing their ability to stick to the matrix.
Maugh reported from Los Angeles and Monroe reported from San Diego.
