Kidney tissues trap toxins from drug candidates. Credit: S. GSCHMEISSNER / SCIENCE PHOTO LIBRARY

Drug-makers have come up with a new set of tools to determine if a promising therapy might damage the kidneys.

In the latest issue of Nature Biotechnology, researchers describe the validation of seven specific biomarkers for kidney damage that are found in urine1,2,3,4. It is hoped that these will accelerate drug development from animal safety studies to human clinical trials. The biomarkers are the first major results of a collaboration between pharmaceutical companies, regulatory agencies and academic scientists that was formed in response to a worrying lack of promising drugs in the development pipeline.

"In drug development, what one wants to do is fail early on so you can put your resources into drugs that are more likely to succeed," says Carl Peck, former head of the Center for Drug Evaluation and Research at the Food and Drug Administration (FDA) in Silver Spring, Maryland, who is now at the Center for Drug Development Science, run by the University of California, San Francisco. Peck, who was not involved in the research, estimates that the biomarkers could speed drug development by one to three years.

Because the kidney filters some 150 litres of blood plasma each day, it can easily be damaged by a build-up of toxic substances. It's a major stumbling block in testing the safety of wide variety of drugs, including drugs for cancer and heart disease. For many years, the gold standard for assessing kidney injury has been to examine tissue samples under the microscope, which is practical only in animal studies.

In drug development, what one wants to do is fail early on. ,

A drug that causes kidney damage in rats or primates might not have the same effect in humans, although such findings often lead to promising drug candidates being abandoned before human clinical trials can begin. Levels of serum creatinine and blood urea nitrogen have traditionally been used to assess kidney damage, but these two existing biomarkers tend to spike after serious damage has already occurred and are relatively insensitive and non-specific.

Vishal Vaidya, a molecular toxicologist at the Brigham and Women's Hospital in Boston, Massachusetts, who was involved in validating one of the seven new biomarkers, explains that the research has been a decade in the making and will be a boon to drug-makers. He studies kidney injury molecule-1 (KIM-1), which was first discovered in 1998 after scanning thousands of genes that were activated following kidney damage.

In 2003, he and his colleagues began developing an assay to find a way to measure KIM-1 in urine. In their paper2, Vaidya and his team show that the biomarker spikes nearly 50-fold after kidney damage from known nephrotoxins, and that it is more specific and sensitive than existing biomarkers. The other new biomarkers proved to be sensitive to damage in different regions of the kidney, and so could provide complementary ways of assessing toxicity.

Strange bedfellows

The four papers are the first results of the Predictive Safety Testing Consortium, which was formed in response to the FDA's 2004 Critical Path Initiative, set up to address the decline in the number of newly approved drugs. The consortium is made up of academic researchers; regulatory agencies in the United States and Europe; and 17 drug companies, including Merck and Novartis. As well as focusing on markers for kidney damage, working groups within the consortium are evaluating preclinical biomarkers for liver and muscle toxicity, vascular tissue damage and carcinogenicity.

"It is a true collaboration among fiercely competitive companies and the FDA, with whom [the companies] normally have an adverse relationship," Peck says. To avoid any potential conflicts of interest, candidate biomarkers are evaluated by regulators who are not involved in the collaboration.

In May 2008, the FDA and the European Medicines Agency in London approved KIM-1 and the six other biomarkers for preclinical safety studies. In addition to providing better screens for kidney damage in animals, these biomarkers may prove useful in monitoring humans during clinical trials. That effort is being led by the Biomarkers Consortium, a public–private research partnership that was also founded in response to the Critical Path Initiative, and which is managed by the Foundation for the National Institutes of Health in Bethesda, Maryland.

The kidney-damage biomarkers could also benefit patients who have acute kidney failure, as there are currently no drugs that can treat the condition. Glenn Chertow, a nephrologist at Stanford University in Palo Alto, California, says that he hopes drug-makers will now invest in treatments for kidney injury. "It's a very common condition and it is associated with high mortality," he says.