NIH-funded study describes noninvasive alternative
to kidney biopsy. Analysis of three biomarkers in
the urine of kidney transplant recipients can
diagnose — and even predict — transplant rejection,
according to results from a clinical trial sponsored
by the National Institute of Allergy and Infectious
Diseases (NIAID), part of the National Institutes of
Health. The findings appear in the July 4 issue of
the New England Journal of Medicine.
“The development of a noninvasive test to monitor
kidney transplant rejection status is an important
advance that will allow doctors to intervene early
to prevent rejection and the kidney injury it causes,
which should improve long-term outcomes for
transplant recipients,” said NIAID Director Anthony
S. Fauci, M.D.
Following a kidney transplant, patients receive
therapy to prevent their immune systems from
rejecting the organ. Even with this
immunosuppressive therapy, approximately 10 to 15
percent of kidney recipients experience rejection
within one year after transplantation.
Typically, a biopsy is performed only after a
transplant recipient shows signs of kidney injury.
Although the procedure seldom causes serious
complications, it carries some risks, such as
bleeding and pain. In addition, biopsy samples
sometimes do not give doctors an accurate impression
of the overall state of the kidney because the
samples are small and may not contain any injured
tissue.
“Potentially, a noninvasive test for rejection would
allow physicians to more accurately and routinely
monitor kidney transplant recipients,” said Daniel
Rotrosen, M.D., 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.”
In the study, part of the NIH-funded Clinical Trials
in Organ Transplantation External Web Site Policy (CTOT),
investigators at five clinical sites collected urine
samples from 485 kidney transplant recipients from
three days to approximately one year after
transplantation. Researchers led by Manikkam
Suthanthiran, M.D., of Weill Cornell Medical College
in New York and Abraham Shaked, M.D., Ph.D., of the
University of Pennsylvania School of Medicine,
Philadelphia, 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 molecules that encode immune system
proteins implicated in transplant rejection and one
noncoding 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 analyzed
trends in the diagnostic signature in urine samples
taken in the weeks before an episode of rejection.
The values for patients who experienced rejection
increased slowly but steadily leading up to the
event, with a characteristic sharp rise occurring
approximately 20 days before biopsy-confirmed
rejection had occurred. In contrast, the values for
patients who did not show any clinical signs of
rejection remained relatively constant and under the
threshold for rejection. These findings suggest that
it might be possible to treat impending rejection
before substantial kidney damage occurs.
“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 NIAID
Transplantation Branch Chief Nancy Bridges, M.D., a
co-author of the paper. The 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, Dr.
Bridges noted.
For more information
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