Proteogenomic Monitoring and Assessment of Liver Transplant Recipients

With the advent of more sensitive molecular techniques, biomarkers of kidney transplant
rejection have been proposed that are potentially much more sensitive, specific and rapidly
testable than conventional predictors of graft function such as GFR or tissue biopsies. Some
of the early biomarkers during this evolution were the Cytotoxic T-cell (CTL) transcripts
like perforin, granzyme B and fas ligand 11-13 for acute rejection. In the case of CAN/IFTA
and CKD the molecular mechanisms and testable biomarkers also remain unclear. A few studies
have reported the involvement of TGF-beta, extracellular matrix proteins like fibronectin and
thrombopondin and tissue inhibitors of metalloproteins (TIMPs) as being upregulated in
patients with Chronic Allograft Nephropathy (CAN/IFTA). Most of these studies were done in
kidney transplant biopsies and the challenge of testing their expression and correlation in
PBL as a minimally invasive tool was only addressed in a few studies. Another limitation of
these first studies was the lack of the power to profile genes globally. To this end the
advent of DNA microarrays has brought about a quantum leap in the ability to profile
thousands of genes simultaneously. Thus far, microarray analysis has been reported in kidney
transplant studies implicating gene signatures for acute rejection in transplant biopsies as
well as for the first time by us in peripheral blood. To our knowledge only two studies have
tried to profile CAN/IFTA in peripheral blood. A recent study attempted to validate three
genes that were derived from a microarray analysis of kidney biopsies using RT-qPCR. All
three genes were significantly differentially expressed in urine but not in PBL. Another
study using microarrays showed that among a panel of 49 peripheral blood genes that were
purported to distinguish "operational tolerance" in kidney rejection, 33 genes could also
distinguish "chronic rejection" with 86% specificity.

Most of the studies in the literature, including our own, as well as our more recent
unpublished peripheral blood gene expression studies of AR and CAN/IFTA reveal clear
molecular signatures for both these forms of transplant outcomes. In sum, these data
establish a first proof of concept that peripheral blood gene expression profiling can be
used to develop markers of kidney allograft rejection and chronic kidney injury.

Inclusion Criteria:

1. Male and female recipients of all races, ≥18 years of age.

2. Patients undergoing primary or subsequent living or deceased donor liver
transplantation.

3. Subject and/or guardian must be able to provide informed consent.

4. Subject and/or guardian must be able to comply with the study protocol.

Exclusion Criteria:

1. Need for combined organ transplantation.

2. Recipients of previous solid organ and/or islet cell transplant.

3. Infection with human immunodeficiency virus (HIV).

4. Inability or unwillingness of a participant and/or guardian to provide informed
consent.