MicroRNA Regulation of Cellular Bio-age Provides a Novel Pre-Transplant Prognostic and Predictive Assessment of Post Transplant Allograft Function

Background: Pre-transplant prediction of post-transplant renal function and outcome is extremely challenging, particularly when applied to older and marginal donor organs. We and others have demonstrated previously that allograft bio-age, as determined by CDKN2A expression level, is a superior prognostic and predictive marker for post transplant function. The CDKN2 locus is complex, comprising a series of developmentally and epigenetically regulated transcript isoforms. Transcriptional regulation of these isoforms incorporates a broad range of MicroRNAs (miRNA), non-coding, single-stranded RNA molecules that are involved in the regulation of a variety of biological processes, including embryogenesis, differentiation, and senescence. We have sought to investigate whether CDKN2 associated miRNAs expression profile in „zero hour‟ pre-transplant renal allograft biopsies are linked to clinico-pathological and functional characteristics post-transplant. Methods: MicroRNA profiles were determined in „zero hour‟ allograft biopsies using microfluidic TaqMan® MicroRNA arrays (Applied Biosystem) and were analysed in relation to clinical data including serum creatinine (SC), cold ischaemia time (CIT), donor age and acute rejection. Data were analysed using StatMiner® (Integromics). Furthermore, MicroRNA data were validated using individual assays. Results: 19miRNAs showed pre transplant expression levels that correlated with levels of SC at 6 months post-transplantation and CIT. Significantly, linear regression analyses in the cohort (n=43) revealed that pre-transplant expression of five miRNAs (hsa-miR-125b, hsa-miR-505, hsa-miR-125a-5p, hsa-miR-96 and hsa-miR-1275) were associated with acute rejection episodes (p<0.01).With the exception of hsa-miR-505, these miRNAs also demonstrated an association with CIT. Conclusions: This data indicates that miRNA profiling has clear potential to be used for pre transplant assessment of post transplant allograft function. It offers the potential for prediction of rejection episodes or other complications. Furthermore, there are also clear links with donor bio-age, which may further enhance the diagnostic possibilities