Assessment of Biomarker Guided CNI Substitution in Kidney Transplantation - Current standard of care for kidney transplant (KTx) recipients has only modestly improved long-term
aggregate graft and/or patient survival, identifying a crucial unmet medical need. As the at-risk KTx population
is heterogeneous, the currently employed and relatively homogeneous therapeutic approach to
immunosuppression in KTx in the US and Canada is suboptimal, and results in a significant proportion of over-
immunosuppressed recipients, many with tacrolimus-related toxicities. In this U01 application, Co-PIs Heeger
and Nickerson will build upon their past, productive collaborative efforts, their established multicenter trial
consortium and infrastructure, as well as their expertise in biomarkers and mechanistic studies to address this
unmet need. The overarching goal of the proposed work is to determine the utility of the HLA-DR/DQ
molecular mismatch (mMM) score, as a risk stratifying biomarker in KTx. While retrospective studies showed
strong correlations between the HLA-DR/DQ mMM score and the risk of developing biopsy proven acute
rejection (BPAR) and/or donor specific antibodies (DSA), no prospective studies have tested the HLA mMM
score as a risk stratifying biomarker for immunological KTx injury. Nor have any studies attempted to test
whether and how the HLA-DR/DQ mMM score performs as a predictor of outcome following a change in
transplant immunosuppression. Herein, we propose a multicenter observational study with a nested
randomized controlled (RCT) trial to address these deficiencies. We will prospectively test the utility of the
HLA-DR/DQ mMM score as a prognostic biomarker of primary alloimmunity [T cell mediated rejection (TCMR),
DSA, and antibody mediated rejection (ABMR)] in KTx (Aim 1, observational study of 800 KTx). We will also
test the hypothesis that the HLA-DR/DQ mMM score is a predictive biomarker that identifies KTx recipients
who will tolerate substituting the calcineurin inhibitor with self-administered, subcutaneous abatacept
(costimulatory blockade), without an unacceptable increased risk of BPAR, while reducing the morbidity of CNI
off-target effects (300 KTx, Nested RCT with a non-inferiority endpoint, Aim 2). Accompanying mechanistic
studies (Aim 3) will provide novel immunological and molecular insights that will also aid in interpreting graft
and recipient outcomes of the trial. If successful, the work will provide crucial information capable of positively,
and directly affecting clinical care. The results from the proposed work also have the potential to influence
positively the design of future RCTs by providing an HLA-DR/DQ mMM score-based stratification or
enrichment strategy for enrolling subjects into trials most likely to be informative for the proposed study agent--
thereby increasing likelihood of trial success in the shortest possible time.
