A signature of pre-operative biomarkers of cellular senescence to predict risk of cardiac and kidney adverse events after cardiac surgery

Abstract

Objective: Measures that capture aging-related decline can identify patients at risk for cardiac surgery-associated adverse events to guide perioperative care and improve patient outcomes. We determined if a panel of biomarkers of cellular senescence, a fundamental aging mechanism, can predict risk of adverse kidney and cardiac events in patients undergoing CABG surgery. Methods: Patients to undergo CABG with or without valve repair or replacement were recruited into a pilot cohort of 66 patients and a development cohort of 331 patients. Blood samples were collected prior to surgery for assessment of expression of preselected biomarkers of senescence. Patients were followed through hospital stay and up to a 30d post-surgery. Daily post-op serum creatinine (sCR) was used to identify incidence of acute kidney injury (AKI) and sCr measures at 30 days were used to identify patients whose eGFR decreased 25% or more as compared to baseline (development cohort only). A composite of major adverse cardiac and kidney events (MACKE30) was used as another endpoint in development cohort only. Results: AKI occurred in 30.0% of patients in pilot study and 19.9% of development cohort. Persistent decline in kidney function at 30d occurred in 11.0%, and MACKE30 in 13.4% of patients. A panel of six biomarkers of senescence (p16, p14, LAG3, CD244, Cd28 and suPAR) were able to identify patients at risk for AKI (AUC 0.76), kidney decline at 30d (AUC 0.73), and MACKE30 (AUC 0.71). When compared between top and bottom tertiles of senescence-based risk models, patients in the top tertile had 7.8 (3.3-8.4) higher odds of developing AKI, 4.5 (1.6-12.6) higher odds of developing renal decline at 30d, and 5.7 (2.1-15.6) higher odds of developing MACKE30. All models remained significant when adjusted for clinical variables Surprisingly, patients with kidney function decline and AKI were largely non-overlapping, and potentially of different etiology. Typical clinical factors that predispose to AKI (e.g., age, CKD, surgery type) associated with AKI but not the 30d decline endpoint. Instead, a new-onset atrial fibrillation associated with 30d kidney decline and not AKI. Conclusions: A 6-member panel of biomarkers of senescence, a fundamental mechanism of aging, can identify patients for risk of adverse kidney and cardiac events when measured pre-operatively.

Profiling an integrated network of cellular senescence and immune resilience measures in natural aging: a prospective multi-cohort study

“…We have previously identified a network of biomarkers that link cellular senescence, immune system function, predisposition to surgery-related adverse events 12 . This network included gene expression of p16, p14, LAG3, CD28, and CD244 measured in peripheral blood T lymphocytes.…”

“…Biomarkers in the SapereX network were selected based on previous studies (ref 12 , Justice et al, in print; Sapere Bio, unpublished). Selection criteria included an independent association with p16 and each marker's capacity to capture distinct as well as potentially overlapping biological functions of the adaptive immune system.…”

“…While SapereX immune markers were independently associated with p16, their relationship is likely to be highly interconnected. For example, in patients with cardiovascular disease, a second-degree interaction between p16 and CD244 was required to predict surgery-associated adverse events 12 . Our study design does not allow us to infer directionality in the relationship between cellular senescence and immune function.…”

“…Previous studies showed little association between cellular senescence and traditional measures of immunosenescence 1,11 . We took a different approach, interrogating a curated list of biomarkers known to reflect adaptive immune function and compared them to the expression of p16, the most uniquely associated biomarker of cellular senescence, as well as longitudinal changes in p16 (ref 12 , Justice et al, in print; Sapere Bio, unpublished). Biomarkers that correlated with p16 individually were retained for further analysis as potential biomarkers of immunosurveillance of senescent cells.…”

“…Biomarkers that correlated with p16 individually were retained for further analysis as potential biomarkers of immunosurveillance of senescent cells. In the first evidence of clinical relevance, the resulting network of biomarkers was used to identify patients at risk for adverse events associated with cardiac surgery 12 . Here, we continue to interrogate and characterize this set of biomarkers to establish a broader relationship between cellular senescence and adaptive immune system function.…”