Telomere Biology and AKI in Cardiac Surgery

Patients with pre-operative renal dysfunction are at increased risk of developing cardiac surgery associated acute kidney injury (AKI) but a proportion of patients with normal kidney function will also be affected. Studies show that patients developing AKI post cardiac surgery have a poorer long term prognosis, even if their kidney function subsequently returns to normal However, the cause for this is not currently understood. We postulate that a unifying mechanism makes such patients more susceptible to developing post-operative AKI and of having an overall worse long term prognosis. We suggest that this mechanism is reduced regenerative capacity of tissues. To test this hypothesis we will measure several markers of cell senescence and aging including telomere length, telomerase activity, and DNA methylation status.

Previous animal studies have shown that reduced telomere length and telomerase activity in mice increases their susceptibility to ischaemia induced renal injury. The current study will look at whether a similar association is seen in humans, using cardiopulmonary bypass as a mechanism for studying ischaemia/inflammatory induced kidney injury. It aims to answer the primary research question: Are telomere length and telomerase activity related to the development of acute kidney injury following cardiac surgery? The presence of such an association would provide new avenues in the development of biomarkers to predict outcomes following cardiac surgery. In addition to scoring tools currently in clinical practice, such biomarkers might allow better risk stratification of patients undergoing cardiac surgery.

Patient Registry and sample storage: Tissue samples and patient data collected in these patients will also form part of the Barts Cardiovascular Registry (BAR). This is a Biobank facility run by Barts Heart Centre in collaboration with United Kingdom (UK) Biobank. All aspects of patient recruitment, data collection, data storage, and data analysis will be covered by Standard Operating Procedures to ensure data quality of the registry.

Quality assurance: The management team for the BAR will be responsible for auditing the completeness and validity of the data.

Sample size: As we have no preceding data on a possible association with telomere biology and AKI post-cardiac surgery we have been unable to perform a power calculation for sample size. In effect, the present study will be a large pilot study looking at this association. Previously reported studies give an incidence of AKI following cardiac surgery of between 15 and 25%. In order to have approximately 200 AKI patients to study, we will aim to recruit 1000 patients. This is realistic given that the Barts Heart Centre should be performing approximately 50 cardiac operations per week. Once recruitment is established, an interim analysis will be performed to allow a more accurate estimation of sample size.

Statistical analysis: All relevant clinical parameters will be analysed by frequencies, tabulations, correlations, distributions of normality and comparisons accordingly. An array of statistical methods will be employed for parametric and non-parametric data including Multivariate of all factors associated with the development of acute kidney injury following cardiac surgery. Receiver operator characteristic (ROC) curve analysis will be used to investigate clinical outcomes and the new markers of cell senescence (telomere length, telomerase activity, and DNA methylation status). Missing data values will be rectified where possible by review of the primary medical records. Missing data values due to incomplete sample collection will be dealt with by statistical modelling.