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.

The use of tunneled central venous catheters: inevitable or system failure?

PURPOSE: To evaluate reasons for tunneled central venous catheter (TCVC) usage in our prevalent hemodialysis population and assess the impact of a surgically aggressive approach to definitive access creation. METHODS: Clinical review of all patients in the West of Scotland dialyzing via a TCVC in November 2010 was performed. Reasons for TCVC usage and TCVC complications were evaluated. Over the subsequent year, aggressive intervention was undertaken to achieve definitive access in all suitable patients and outcomes re-evaluated a year later (November 2011). RESULTS: There was no significant difference in the proportion of patients dialyzing via a TCVC in 2010 compared to 2011 (30.3% (n=193) vs. 31.7% (n=201), respectively; p=0.56). All patients now have a "vascular access plan." Of patients dialyzing via a TCVC in 2010, 37% had died by 2011, 22% remained on long-term line, 20% had successful arteriovenous fistula (AVF) creation, 1% had an arteriovenous graft and 2% were transplanted; 10.4% developed complications of vascular access and required ligation of a functioning AVF. A further 6.5% died within 28 days of surgery. The incidence of culture-positive Staphylococcus aureus bacteremia was 1.6 per 1,000 catheter days. CONCLUSIONS: Aggressive strategies of AVF creation resulted in one-fifth of patients on a long-term TCVC having successful creation of an AVF. This was offset against high failure and significant complication rate from AVF creation in this population. One-third of patients dialyzing via a TCVC died in the subsequent year. Correct patient selection for AVF creation is essential and predialysis care must be optimized to avoid the need for TCVCs entirely.

Pre-transplant CDKN2A expression in kidney biopsies predicts renal function and is a future component of donor scoring criteria.

CDKN2A is a proven and validated biomarker of ageing which acts as an off switch for cell proliferation. We have demonstrated previously that CDKN2A is the most robust and the strongest pre-transplant predictor of post-transplant serum creatinine when compared to "Gold Standard" clinical factors, such as cold ischaemic time and donor chronological age. This report shows that CDKN2A is better than telomere length, the most celebrated biomarker of ageing, as a predictor of post-transplant renal function. It also shows that CDKN2A is as strong a determinant of post-transplant organ function when compared to extended criteria (ECD) kidneys. A multivariate analysis model was able to predict up to 27.1% of eGFR at one year post-transplant (p = 0.008). Significantly, CDKN2A was also able to strongly predict delayed graft function. A pre-transplant donor risk classification system based on CDKN2A and ECD criteria is shown to be feasible and commendable for implementation in the near future.