A Discrete Gene Signature Is a Diagnostic and Predictive Biomarker for Kidney Transplant Rejection

A genetic signature comprising two messenger RNA molecules that encode immune system proteins and one noncoding RNA molecule that participates in protein production has been shown to be diagnostic and prognostic of acute cellular rejection in kidney transplants.

The standard test for the diagnosis of acute rejection in kidney transplants is the renal biopsy. However, biopsy samples, in addition to being invasive with risk of infection, may not give the physician an accurate impression of the overall state of the kidney, since biopsy specimens are small and may not contain any injured tissue.

Investigators at the [US] National Institutes of Health (Bethesda, MD, USA) and colleagues at Weill Cornell Medical College (New York, NY, USA) and the University of Pennsylvania (Philadelphia, USA) sought a noninvasive test that would accurately detect or predict kidney transplant rejection.

To this end, they collected 4,300 urine specimens from 485 kidney-graft recipients from day three through month 12 after transplantation. Messenger RNA (mRNA) levels were measured in urinary cells taken from the samples and correlated with allograft-rejection status with the use of logistic regression.

The investigators found that a three-gene signature representing 18S ribosomal RNA (rRNA), CD3epsilon mRNA, and interferon-inducible protein 10 (IP-10) mRNA discriminated between biopsy specimens showing acute cellular rejection and those not showing rejection. The signature distinguished acute cellular rejection from acute antibody-mediated rejection and borderline rejection. It also distinguished patients who received anti-interleukin-2 receptor antibodies from those who received T-cell-depleting antibodies and was diagnostic of acute cellular rejection in both groups. Urinary tract infection did not affect the signature.

Levels of the signature RNAs in repeated urine samples remained below the diagnostic threshold for acute cellular rejection in the group of patients with no rejection, but in the group with rejection, there was a sharp rise during the weeks before a biopsy revealed signs of rejection.

"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," said contributing author Dr. Nancy Bridges, transplantation branch chief at the [US] National Institutes of Health. "The National Institutes of Health-funded Clinical Trials in Organ Transplantation (CTOT) cooperative research consortium provided the infrastructure and collaborative environment needed to conduct the large, rigorous, multicenter study that established the efficacy of this biomarker-based test."

The study was published in the July 4, 2013, issue of the New England Journal of Medicine.

Related Links:
National Institutes of Health
Weill Cornell Medical College
University of Pennsylvania