A Signature of Pre-Operative Biomarkers of Cellular Senescence to Predict Risk of Cardiac and Kidney Adverse Events after Cardiac Surgery

Author(s): Amy Entwistle, Susan Walker, Anne Knecht, Susan L Strum, Asad A Shah, Aliaksei Pustavoitau, Natalia Mitin, Judson B Williams

Importance: Improved pre-operative risk stratification methods are needed for targeted risk mitigation and optimization of care pathways for cardiac patients. This is the first report demonstrating pre-operative, agingrelated biomarkers of cellular senescence and immune system function can predict risk of common and serious cardiac surgery-related adverse events.

Design: Multi-center 331-patient cohort study that enrolled patients undergoing coronary artery bypass grafing (CABG) surgery with 30-day follow-up. Included a quaternary care center and two communitybased hospitals. Primary outcome was KDIGO-defined acute kidney injury (AKI). Secondary outcomes: decline in eGFR ≥25% at 30d and a composite of major adverse cardiac and kidney events at 30d (MACKE30). Biomarkers were assessed in blood samples collected prior to surgery.

Results: A multivariate regression model of six senescence biomarkers (p16, p14, LAG3, CD244, CD28 and suPAR) identified patients at risk for AKI (NPV 86.6%, accuracy 78.6%), decline in eGFR (NPV 93.5%, accuracy 85.2%), and MACKE30 (NPV 91.4%, accuracy 79.9%). Patients in the top risk tertile had 7.8 (3.3-18.4) higher odds of developing AKI, 4.5 (1.6-12.6) higher odds of developing renal decline at 30d follow-up, and 5.7 (2.1-15.6) higher odds of developing MACKE30 versus patients in the bottom tertile. All models remained significant when adjusted for clinical variables.

Conclusions: A network of senescence biomarkers, a fundamental mechanism of aging, can identify patients at risk for adverse kidney and cardiac events when measured pre-operatively. These findings lay the foundation to improve pre-surgical risk assessment with measures that capture heterogeneity of aging, thereby improving clinical outcomes and resource utilization in cardiac surgery.