Urine Test Predicts Transplanted Kidney Rejection

20.09.2013 14:28

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.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
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
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."
Rejection can be predicted weeks in
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).