A urine test can determine whether a transplanted kidney recipient is in the process of rejecting the donated organ, as well as identifying who is at risk of rejection several weeks and even months before symptoms appear, researchers from Weill Cornell Medical College reported in NEJM (New England Journal of Medicine).
The test measures three genetic molecules in a urine sample to diagnose acute rejection of kidney transplant, a common and serious complication of kidney transplants.
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, said “It looks to us that we can actually anticipate rejection of a kidney several weeks before rejection begins to damage the transplant.”
The test could be a useful for doctors in deciding the right dosage of immunosuppressive drugs that organ transplant recipients need to receive for the rest of their lives. Scientists from Stanford University School of Medicine reported in NEJM (October 2011 issue) that one day kidney transplant recipients may one day not require daily drugs.
Dr. Suthanthiran said:
“We have, for the first time, the opportunity to manage transplant patients in a more precise, individualized fashion. This is good news since it moves us from the current one-size-fits-all treatment model to a much more personalized plan.”
When the immunosuppressive drug dosage is too low the risk of rejection is greater. However, if patients are given too much their immune systems go right down and they have a much higher risk of infection, and even cancer.
Suthanthiran and team conducted a multicenter clinical trial involving 485 kidney transplant recipients at five medical centers. The detailed results of the trial are published in the July 4th Issue of NEJM.
Co-author, Dr. Darshana Dadhania, explained that this biomarker urine test is “sorely needed” to help improve the lives of transplant recipients as well as the longevity of donor organs. This three-gene signature in the new urine test is much more specific than the current primary blood test that measures creatinine levels to determine kidney rejection.
Dr. Dadhania said “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. 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.”
The scientists measured levels of mRNA (messenger RNA) molecules produced as genes are being expressed, or activated to make proteins. They developed some sophisticated tools to measure this genetic material.
They found that an organ will be (or is being) rejected when the expression of three mRNAs increases. “The mRNAs (18S ribosomal (rRNA)-normalized CD3ε mRNA, 18S rRNA-normalized 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 recognize as alien tissue.”
The three mRNA levels in urine are added into a composite score and tracked over time. A rising score indicates that the immune system is very active and working against the transplanted kidney (rejecting the kidney). If the score remains the same, this suggests that the patient is not at risk of rejection.
Dr. Suthanthiran said “We were always looking for the most parsimonious model for an organ rejection biomarker test. Minimizing 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.”
Doctors can administer each patient’s specific multiple immunosuppressive drug dosage by monitoring their composite scores over time and adjusting accordingly. Any increase in composite scores would mean than a higher dose of therapy is needed to prevent rejection.
Dr. Suthanthiran explained “This is akin to monitoring blood glucose in a patient with diabetes. Because different people have different sensitivity to the two-to-four immunosuppressive drugs they have to take, this test offers us a very personalized approach to managing transplantations.”
The human study started in 2006 and was conducted at five medical centers. 4,300 urine samples were collected during the first 12 months of transplantation, starting at day three after the procedure. They were tested at Weill Cornell Medical College, where analysis revealed that the three gene-based biomarkers signature could distinguish organ recipients with biopsy-confirmed rejection from those whose biopsies showed no signs of rejection or who had no biopsy because no clinical sign of rejection was present.
The scientists used the signature to derive a composite score and set a threshold value which suggested rejection. This score detected transplant rejection accurately and had a low occurrence of false-positive and false-negative results.
Dr. Suthanthiran said “It is about 85 percent accurate, which is much higher than the creatinine test used today.”
The team said they are soon conducting another trial to determine whether the signature test can be utilized to personalize individual immunosuppressive therapy.
A single dose of special immune cells to prevent kidney transplant rejection shows promise, researchers from the University of Pittsburgh School of Medicine reported in the American Journal of Transplantation (July 2013 issue).
Written by Christian Nordqvist