Stanford, Packard transplantation research findings may pave way to better anti-rejection treatment

STANFORD, Calif. ­ A simple test may pinpoint children at high risk of rejecting newly transplanted kidneys, said researchers at Lucile Packard Children's Hospital and the Stanford School of Medicine. The research, which also identifies more than one type of acute rejection, may increase the long-term survival of transplant patients and reduce the severe side effects caused by common anti-rejection drugs.

Acute rejection affects 15 to 40 percent of kidney transplant recipients nationwide and is a leading cause of re-transplantation or death in these patients. Although the tissue inflammation and cell damage that spell trouble for a transplanted organ are easily diagnosed with a light microscope, this technique can't identify the molecular rabble-rousers at the root of the problem. As a result, physicians have wondered whether patients experience more than one type of acute rejection.

In the new study published in the July 10 issue of the New England Journal of Medicine, Packard Children's Hospital pediatric nephrologist and molecular immunologist Minnie Sarwal, MD, PhD, used microarray technology to peek behind the scenes in more than 60 pediatric kidney transplant patients. The technique, which simultaneously examines more than 12,000 unique human genes, allowed lead author Sarwal and her colleagues to divvy up episodes of acute rejection into at least three distinct subgroups based on their global gene-expression profiles.

Surprisingly, one of the three subgroups associated with particularly poor outcomes expressed many genes specific to B cells - a type of immune cell previously cleared of significant wrongdoing in transplant rejection. Further research pinpointed clumps of B cells within slices of the transplant tissue. The presence of the cells suggested a way for physicians to better employ their arsenal of anti-rejection drugs.

'Although physicians realize that clinical responses to treatment for acute rejection range from complete response to no response, we currently have very few clues to target the high-risk patient group or to individualize treatment,' said Sarwal, who is also an assistant professor of pediatrics at the Stanford School of Medicine. 'If we can now figure out which of the more serious rejections are due to these B cells we can treat them completely differently, perhaps by using antibodies to specifically wipe out B cells in these patients.'

T cells, which function as the immune system's foot soldiers, traditionally have been pegged as primary troublemakers for transplant recipients. While anti-rejection drugs such as steroids do a good job mollifying agitated T cells marshalling for an attack, B cells have mostly been ignored because they make up a relatively small proportion of host cells in the transplanted tissue. The researchers found, however, that when kidneys became peppered with B cells after transplantation, steroid treatment was less successful in treating the rejection.

'What's happened is we've failed to realize that the immune system is very clever and redundant,' said Sarwal. 'It may have developed a mechanism to assist the T cells to attack the transplanted kidney by recruiting the B cells, which rev up the T cells and increase their efficiency.'

Although a simple laboratory test can identify congregations of the offending B cells, most episodes of acute rejection are currently treated in a hit-or-miss fashion.

'We may waste two to three days giving high doses of steroids only to find the rejection episode is steroid-resistant,' said Sarwal. 'Even when we then try antibody therapy, many of these patients will fail to get all their kidney function back and are more likely to lose their kidney over time.' Indiscriminate use of anti-rejection drugs can also cause other problems including growth inhibition and an increased risk of infection and cancer.

The researchers are now experimenting with ways to allow noninvasive monitoring of transplant function from blood or urine samples, eliminating the need for a biopsy. Eventually, they hope physicians will be able to identify possible rejection episodes early by monitoring the expression of a few key genes.

'We need to begin using drugs in a more educated manner,' said Sarwal. 'Ideally, we will be able to avoid over-immunosuppressing our patients with drugs that are clearly not working and that increase their risk of cancer and infection and inhibit growth in children.'

Sarwal's colleagues include co-author Oscar Salvatierra, MD, professor of pediatrics and of surgery and director of the pediatric kidney transplantation program, and Patrick Brown, MD, PhD, professor of biochemistry at the Stanford School of Medicine and a Howard Hughes Medical Institute investigator.