The analysis of three different biomarkers in the urine of kidney plant recipients can diagnose and predict rejection of the transplant, according to a recent clinical trial sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). The biomarker test provides an accurate and noninvasive alternative to standard kidney biopsy. The standard kidney biopsy involves the removal of a small piece of tissue to look for rejection associated damage. The clinical trial findings were published in the July 4 issue of the New England Journal of Medicine.

NIAID director, Dr. Anthony S. Fauci says, “The development of a noninvasive test to monitor kidney plant rejection status is an important advance that will allow doctors to intervene early to prevent rejection and the kidney injury it causes, which should improve long term outcomes for transplant recipients.”

After a kidney transplant, patients receive therapy to prevent immune system rejection of the new organ. Even with immunosuppresive therapy, about 10 to 15 percent of kidney recipients experience rejection within one year of transplantation.

A biopsy is usually performed once a transplant recipient begins to show signs of kidney injury. Although the procedure rarely causes complications, it does carry the risk of bleeding and pain. Sometimes, biopsy samples do not provide an accurate representation of the overall state of the kidney because the samples are small and many not contain any of the damaged tissue.

“Potentially, a noninvasive test for rejection would allow physicians to more accurately and routinely monitor kidney transplant recipients,” says NISAID director of the Division of Allergy, Immunology and Transplantation. “By tracking a transplant recipient’s rejection status over time, doctors may be able to modulate doses of immunosuppressive drugs to extend the survival of the transplanted kidney.”

The study was part of the NIH funded Clinical Trials in Organ Transplantation (CTOT). Investigators at five different clinical sites collected urine samples from 485 kidney transplant recipients ranging from three days to one year after transplantation. Urine cell levels of several different biomarkers, that have been previously associated with rejection, were assessed by researchers led by Dr. Manikkam Suthantthiran of Weill Cornell Medical College in New York and Dr. Abraham Shaked from the University of Pennsylvania School of Medicine in Philadelphia.

Statistical analysis showed that a group of three different biomarkers formed a diagnostic signature that could distinguish kidney recipients with biopsy confirmed rejection from those that showed no signs of rejection or did not have a biopsy performed. Those biomarkers included two messenger RNA molecules that encode immune system proteins, which have been implicated in transplant rejection, and one noncoding RNA molecule that is involved in protein production. Researchers used the signature to designate values for each urine sample and identify a threshold value indicative of rejection.

The test showed a high level of accuracy in identifying transplant rejection. Investigators also found similar results when they tested urine samples collected in a separate clinical trial involved in the Clinical Trials of Organ Transplantation. This validated the diagnostic signature.

To determine if the urine analysis could predict future rejection, scientists analyzed trends in the diagnostic signature of urine samples that were taken weeks prior to rejection episodes. Values of patients experiencing rejection slowly and steadily increased leading up to the event. The results showed a sharp rise occurring about 20 days before a biopsy confirmed rejection had taken place. Values for patients who showed no signs of rejection remained consistent and fell below the rejection threshold. The findings suggest it could be possible to treat impending rejection before a substantial amount of kidney damage has occurred.

The CTOT cooperative research consortium provided the infrastructure and collaborative environment required for conducting such a large and rigorous study involving multiple centers, according to NISAID Transplantation Branch Chief, Dr. Nancy Bridges.

She says, “The test described in this study may lead to better, more personalized care for kidney transplant recipients by reducing the need for biopsies and enabling physicians to tailor immunosuppressive therapy to individual patients.” Dr. Bridges co-authored the paper.