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 Most of the studies in the literature, including our own, as well as our more recent unpublished peripheral blood gene expression studies of AR and CAN/IFTA reveal clear molecular signatures for both these forms of transplant outcomes.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.