Urine biomarker test can diagnose as well as predict rejection of transplanted kidneys

A breakthrough non-invasive test can detect whether transplanted kidneys are in the process of being rejected, as well as identify patients at risk for rejection weeks to months before they show symptoms, according to a study.
By measuring just three genetic molecules in a urine sample, the test accurately diagnoses acute rejection of kidney transplants, the most frequent and serious complication of kidney transplants, says the study’s lead author, Dr. Manikkam Suthanthiran, the Stanton Griffis Distinguished Professor of Medicine at Weill Cornell Medical College and chief of transplantation medicine, nephrology and hypertension at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.
‘It looks to us that we can actually anticipate rejection of a kidney several weeks before rejection begins to damage the transplant,’ Dr. Suthanthiran says.
The test may also help physicians fine-tune the amount of powerful immunosuppressive drugs that organ transplant patients must take for the rest of their lives, says Dr. Suthanthiran, whose laboratory developed what he calls the ‘three-gene signature’ of the health of transplanted kidney organs.
‘We have, for the first time, the opportunity to manage transplant patients in a more precise, individualised fashion. This is good news since it moves us from the current one-size-fits-all treatment model to a much more personalised plan,’ he says, noting that too little immunosuppression leads to organ rejection and too much can lead to infection or even cancer.
Such a test is sorely needed to help improve the longevity of kidney transplants and the lives of patients who receive these organs, says study co-author Dr. Darshana Dadhania, associate professor of medicine and medicine in surgery at Weill Cornell Medical College and associate attending physician at NewYork-Presbyterian Hospital.
Dr. Dadhania says that the primary blood test now used to help identify rejection — creatinine, which measures kidney function — is much less specific than the three-gene signature.
‘Creatinine can go up for many reasons, including simple dehydration in a patient, and when this happens we then need to do a highly invasive needle-stick biopsy to look at the kidney and determine the cause. Our goal is to provide the most effective care possible for our transplant patients, and that means individualizing their post transplant care,’ she says. ‘Using an innovative biomarker test like this will eliminate unnecessary biopsies and provide a yardstick to measure adequate immunosuppression to keep organs — and our patients — healthy.’
Although a number of researchers have tried to develop blood or urine-based tests to measure genes or proteins that signify kidney organ rejection, Dr. Suthanthiran and his research team were the first to create a gene expression profile urine test — an advance that was reported in NEJM in 2001 and, with an update also in NEJM, in 2005.
The research team measured the levels of messenger RNA (mRNA) molecules produced as genes are being expressed, or activated, to make proteins. To do this, they developed a number of sophisticated tools to measure this genetic material. ‘We were told we would never be able to isolate good quality mRNA from urine,’ he says. ‘Never say never.’
He and his colleagues found that increased expression of three mRNAs can determine if an organ will be, or is being, rejected. The mRNAs (18S ribosomal (rRNA)–normalized CD3ε mRNA, 18S rRNA–
The signature test consists of adding levels of the three mRNAs in urine into a composite score. Tracked over time, a rising score can indicate heightened immune system activity against a transplanted kidney, Dr. Suthanthiran says. A score that stays the same suggests that the patient is not at risk for rejection.
‘We were always looking for the most parsimonious model for an organ rejection biomarker test,’ Dr. Suthanthiran says. ‘Minimising the number of genes that we test for is just more practical and helps to give us a clearer path towards diagnosis and use in the clinic.’

Physicians can tailor a patient’s use of multiple immunosuppressive drugs by lowering the doses steadily, and monitoring the patient’s composite score over time. Any increase would suggest a somewhat higher dose of therapy is needed to keep the organ safe. EurekAlert normalised interferon-inducible protein 10 (IP-10) mRNA, and 18S rRNA) indicate that killer T immune cells are being recruited to the kidney in order to destroy what the body has come to recognise as alien tissue.