Urine test diagnoses kidney rejection before biopsies

A study has found that the analysis of biomarkers in the urine samples of kidney transplant recipients can diagnose transplant rejection, even before it occurs.

Following a kidney transplant, patients receive therapy to prevent their immune systems from rejecting the organ. But even with this immunosuppressive therapy, approximately 10 to 15% of kidney recipients experience rejection within one year after transplantation.

Typically, if a transplant recipient is showing signs of kidney injury, doctors will perform a biopsy, removing a small piece of kidney tissue to look for rejection-associated damage. Although the procedure seldom causes serious complications, it carries risks such as bleeding and pain. In addition, the biopsy samples are so small that they may not contain any injured tissue, so doctors don’t get an accurate impression of the overall state of the kidney.

In light of this, the National Institute of Allergy and Infectious Diseases (NIAID), part of the US National Institutes of Health, sponsored a clinical trial for a non-invasive biomarker test for kidney rejection. The findings have been published in the New England Journal of Medicine.

“Potentially, a non-invasive test for rejection would allow physicians to more accurately and routinely monitor kidney transplant recipients,” said Dr Daniel Rotrosen, the director of NIAID’s 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.”

As part of the NIH-funded Clinical Trials in Organ Transplantation (CTOT) project, investigators at five clinical sites “collected 4300 urine specimens from 485 kidney-graft recipients from day three through month 12 after transplantation”, the paper explains. Researchers led by Dr Manikkam Suthanthiran of Weill Cornell Medical College and Dr Abraham Shaked of the University of Pennsylvania School of Medicine assessed the urinary cell levels of several biomarkers that previously have been associated with rejection.

Statistical analysis revealed that a group of three urinary biomarkers formed a diagnostic signature that could distinguish kidney recipients with biopsy-confirmed rejection from those whose biopsies did not show signs of rejection or who did not undergo a biopsy. The biomarkers include two messenger RNA (mRNA) molecules that encode immune system proteins implicated in transplant rejection and one non-coding RNA molecule that participates in protein production.

The researchers used the signature to assign values to each urine sample and identify a threshold value indicative of rejection. With this test, they could detect transplant rejection with a high level of accuracy. The investigators obtained similar results when they tested a set of urine samples collected in a separate CTOT clinical trial, thereby validating the diagnostic signature.

To determine whether the urine test also could predict future rejection, the scientists analysed trends in the diagnostic signature in urine samples taken in the weeks before an episode of rejection.

“The average trajectory of the signature in repeated urine samples remained below the diagnostic threshold for acute cellular rejection in the group of patients with no rejection,” said the researchers, “but in the group with rejection, there was a sharp rise during the weeks before the biopsy showing rejection.”

According to NIAID Transplantation Branch Chief Dr Nancy Bridges, a co-author of the paper, the test “may lead to better, more personalised care for kidney transplant recipients by reducing the need for biopsies and enabling physicians to tailor immunosuppressive therapy to individual patients”.

NIAID Director Dr Anthony S Fauci added that doctors will be able to “intervene early to prevent rejection and the kidney injury it causes, which should improve long-term outcomes for transplant recipients”.