Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05084768 |
| Other study ID # |
5210340 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
December 7, 2020 |
| Est. completion date |
October 1, 2026 |
Study information
| Verified date |
July 2023 |
| Source |
Loma Linda University |
| Contact |
Ryan Evans, CCRP |
| Phone |
9095583870 |
| Email |
rlevans[@]llu.edu |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Acute rejection after kidney transplantation should ideally be diagnosed prior to immunologic
injury in a non-invasive fashion in order to improve long-term graft function. Donor-derived
cell-free DNA (ddcfDNA) is a promising method to do so as it is elevated prior to acute
rejection and has good predictive performance especially for antibody-mediated and high
severity T-cell mediated rejection. Its ability to predict low severity T-cell mediated
rejection and future graft function remains equivocal. Regulatory T cells (Tregs) are
essential in transplant tolerance by suppressing effector immune responses. Circulating
post-transplant highly suppressive HLA-DR+ Tregs were reduced in recipients who developed
acute rejection. Preliminary results in a cohort including predominantly low severity T-cell
mediated rejection also showed that pre-transplant circulating highly suppressive TNFR2+
Tregs were reduced in and could predict acute rejection. Integrating dd-cfDNA with
HLA-DR+TNFR2+ Treg could improve the predictive performance for acute rejection especially of
low severity and potentially predict graft function. Plasma dd-cfDNA and HLA-DR+TNFR2+ Tregs
will be measured in 150 kidney transplant recipients at scheduled intervals during the first
6 months post-transplant. Predictive accuracy of a model integrating ddcfDNA and
HLA-DR+TNFR2+ Treg for acute rejection will be tested using ROC curve analysis and
multivariate logistic regression. Predictive accuracy for 1-year graft function will be
tested using multivariate linear regression. High predictive performance for acute rejection
and graft function using a model integrating dd-cfDNA and HLA-DR+TNFR2+ Treg would help
identify kidney transplant recipients at immunologic risk early on and allow personalization
of immunosuppression accordingly.
Description:
Background
Despite advances in immunosuppression, 10-year graft survival after kidney transplantation
has remained stagnant at around 50%. Timely diagnosis of acute rejection in kidney transplant
recipients is essential for improving long-term graft survival. Clinical suspicion for acute
rejection currently relies on monitoring elevation in serum creatinine and diagnostic
confirmation with a kidney allograft biopsy. Serum creatinine elevation, however, is
non-specific for acute rejection and is detected after significant immunological damage to
the allograft already happens. Confirmation with a biopsy is invasive, associated with a 1%
major complication rate, and subjected to inadequate sampling as well as expert reader
variance. Novel ways to monitor and diagnose acute rejection prior to immunological injury in
a non-invasive fashion are needed in an effort to improve long-term graft survival after
kidney transplantation. Cell-free DNA is normally released into the bloodstream when cells
undergo apoptosis or necrosis. In the context of kidney transplantation and the presence of
an allograft, donor-derived cell-free DNA (dd-cfDNA) is continuously shed into the
bloodstream of the recipient as a result of allograft cell turnover and represents a small
fraction of total cell-free DNA (donor- plus recipient-derived). Dd-cfDNA fraction is
initially high from ischemia-reperfusion injury and usually decreases to a baseline level 10
to 14 days after kidney transplantation. Subsequently, episodes of allograft injury such as
acute rejection leads to an increase in dd-cfDNA fraction into the recipient's bloodstream.
Using single-nucleotide polymorphisms-based multiplexed polymerase chain reaction technology
and advanced bioinformatics, plasma dd-cfDNA fraction can now be measured in a kidney
transplant recipient without the need for prior genotyping of the donor or the recipient.
Recent studies have demonstrated that plasma dd-cfDNA is a promising novel method to detect
acute rejection prior to immunological injury in a non-invasive fashion as it is elevated in
advance and at the time of biopsy-proven acute rejection. A cutoff dd-cfDNA fraction greater
or equal to 1% was able to predict acute rejection with moderate to good performance in those
studies with area under the curves (AUCs) varying from 0.59 - 0.97 on receiver operating
characteristic (ROC) curve analyses. When examining acute rejection by mechanism, dd-cfDNA
fraction appears to have better predictive performance for antibody-mediated rejection
(ABMR), while its utility to predict T cell-mediated rejection (TCMR) remains equivocal
especially when of lower severity (less than Banff 1B). Nevertheless, in lower severity TCMR
(Banff 1A or subclinical), a dd-cfDNA fraction greater or equal to 0.5% was shown to
potentially identify kidney transplant recipients at risk for a steeper estimated glomerular
filtration rate (eGFR) decline, developing de-novo donor specific antibody, and future
rejection episodes. Despite being approved for clinical use by Medicare, several limitations
remain with dd-cfDNA in the prediction of acute rejection. First, elevation in dd-cfDNA is
not rejection-specific as other medical complications such as urinary tract infections,
systemic infections, and BK virus nephropathy can also increase dd-cfDNA. Secondly,
predictive performance of dd-cfDNA for TCMR, especially of lower severity, remains equivocal.
Finally, it is unclear whether early dd-cfDNA fraction after kidney transplantation can
predict future immunologic graft injuries and function. Novel ways to make dd-cfDNA more
specific for acute rejection, improve its predictive performance for TCMR, and correlate it
with future graft function would further improve its clinical utility. Regulatory T cells
(Tregs) are essential in the induction and maintenance of tolerance in various kidney
transplant animal models by suppressing effector immune responses. Tregs constitute 5 - 10%
of CD4+ T cells and are traditionally identified as a homogeneous population with high
expression of CD25, low expression of CD127, and expression of the master transcription
factor FoxP3. Recent data, however, indicate that Tregs are more heterogeneous and that
expression of additional molecules than the traditional CD25, CD127, and FoxP3 influence
their suppressive functional activity. In human kidney transplantation, posttransplant
circulating CD4+CD25hiCD127lo/- Tregs were similar between recipients who suffered from acute
rejection and those that did not. However, high expression of HLA-DR on post-transplant
circulating Tregs, which identified a population with maximally suppressive functional
activity, was lower in recipients who suffered from acute rejection. Another molecule
identifying a Treg population with maximally suppressive functional activity is TNFR2. TNFR2
mediates the biological function of the pro-inflammatory cytokine TNF-a, which is involved in
the recruitment and activation of effector T cells during allograft rejection. Interestingly,
TNFR2 was shown to be preferentially expressed on Tregs as opposed to effector T cells. In
both murine and human studies, TNF-α signaling via TNFR2+ Tregs increased their survival,
proliferation, and suppressive functional activity.
Preliminary results The investigators previously studied TNFR2+ Tregs in the specific context
of kidney transplantation. The investigators confirmed in a cohort of kidney transplant
candidates that expression of TNFR2 on Tregs correlated with suppressive function measured
via a traditional co-culture assay of Tregs with stimulated effector T cells (r=0.63,
p<0.01). In a cohort of 76 deceased donor kidney transplant recipients, the investigators
published on the role of pre-transplant circulating recipient TNFR2+ Tregs in the prediction
of delayed and slow graft function after kidney transplantation. Since delayed and slow graft
function are known risk factors for the development of acute rejection after kidney
transplantation, the investigators then examined the role of pre-transplant circulating
recipient TNFR2+ Tregs in the prediction of acute rejection in the same cohort of recipients
in which 75 had available acute rejection data with promising results especially with low
severity TCMR.
Hypotheses
Since previous studies and the investigators' preliminary results in a cohort predominantly
including low severity TCMR suggest a role for HLA-DR+TNFR2+ Tregs in the prediction of acute
rejection, the investigators hypothesize that integrating it with dd-cfDNA fraction could
improve specificity and predictive performance for acute rejection, especially TCMR. The
investigators also hypothesize that measurement of early dd-cfDNA fraction and pretransplant
HLA-DR+TNFR2+ Tregs could predict future outcomes after kidney transplantation including
acute rejection and graft function measured by eGFR.
Objectives
1. Test whether integrating dd-cfDNA fraction with HLA-DR+TNFR2+ Tregs in advance or at the
time of allograft injury can improve the predictive performance for acute rejection
after kidney transplantation.
2. Test whether integrating dd-cfDNA fraction at 2 weeks post-transplant with
pre-transplant HLADR+TNFR2+ Tregs can predict future acute rejection episodes and 1-year
graft function.
The investigators will recruit 150 adult kidney transplant recipients with insurance coverage
for dd-cfDNA fraction measurement.
