Identification of molecular markers of delayed graft function based on the regulation of biological ageing

Introduction: Delayed graft function is a prevalent clinical problem in renal transplantation for which there is no objective system to predict occurrence in advance. It can result in a significant increase in the necessity for hospitalisation post-transplant and is a significant risk factor for other post-transplant complications. Methodology: The importance of microRNAs (miRNAs), a specific subclass of small RNA, have been clearly demonstrated to influence many pathways in health and disease. To investigate the influence of miRNAs on renal allograft performance post-transplant, the expression of a panel of miRNAs in pre-transplant renal biopsies was measured using qPCR. Expression was then related to clinical parameters and outcomes in two independent renal transplant cohorts. Results: Here we demonstrate, in two independent cohorts of pre-implantation human renal allograft biopsies, that a novel pre-transplant renal performance scoring system (GRPSS), can determine the occurrence of DGF with a high sensitivity (>90%) and specificity (>60%) for donor allografts pre-transplant, using just three senescence associated microRNAs combined with donor age and type of organ donation. Conclusion: These results demonstrate a relationship between pre-transplant microRNA expression levels, cellular biological ageing pathways and clinical outcomes for renal transplantation. They provide for a simple, rapid quantitative molecular pre-transplant assay to determine post-transplant allograft function and scope for future intervention. Furthermore, these results demonstrate the involvement of senescence pathways in ischaemic injury during the organ transplantation process and an indication of accelerated bio-ageing as a consequence of both warm and cold ischaemia

Cr t1/2 calculation and post-transplant organ recovery.

<p>A) Cr t1/2 for immediately functioning grafts, B) Cr t1/2 for DGF requiring haemodialysis.</p

Delayed graft function is related to donor age, CDKN2A/p16 and the expression of hsa-miR-217 and hsa-miR-125b.

<p>Gene and MicroRNA expression was assayed using individual TaqMan®assays and normalised against the following endogenous controls: RNU44, RNU48 and U6snoRNA (for microRNA) and HPRT1 for CDKN2A. Data presented as mean with 95%CI.</p