Cellular Senescence and Cardiac Surgery Associated – Acute Kidney Injury.

Abstract

Introduction: Cardiac-surgery associated-acute kidney injury (CSA-AKI) is associated with increased morbidity and mortality. Furthermore, patients who develop CSA-AKI have higher incidences of progression to chronic renal impairment and reduced long-term mortality. The mechanism for this association is not fully understood. We hypothesized that increased cellular senescence and biological age might be linked to both the development of CSA-AKI and future reduced mortality. Objectives: To investigate the relationship between markers of cellular senescence and aging and the development of CSA-AKI. Methods: DNA was extracted from peripheral leukocytes pre-operatively. Telomere length was measured with quantitative polymerase chain reaction (qPCR) and DNA methylation-based models of biological age and senescence were developed using targeted sequencing. Results: Between January 2016 and April 2017, 254 patients were recruited. Of these 54 (21.3%) developed AKI. No association was found between mean Telomere length (mTL) and CSA-AKI on univariate analysis (p=0.304), or on propensity matching (p=0.833). However, a subgroup analysis of South Asian patients showed a significant association between reduced mTL and CSA-AKI on both univariate (p =0.025) and multivariate analysis (p = 0.036). Predicted methylation age (pMA) was significantly associated with CSA-AKI (p=0.013) whereas chronological age was not (p=.0.106). ROC curve analysis also demonstrated that pMA was a better predictor of CSA-AKI than chronological age (p=0.012 vs p=0.047). In subgroup analysis, South Asian patients again demonstrated a stronger association with CSA-AKI than other 5 ethnicities. On propensity matched analysis of the total population, the difference between chronological age and pMA (Delta age) was reduced in the AKI cohort, although this failed to reach statistical significance (p=0.07). Conclusion: pMA was significantly associated with CSA-AKI with a predictive ability superior to that of chronological age. mTL was found to be significantly associated with CSA-AKI in the South Asian population but not in the study population as a whole.