P008 - CLONAL HEMATOPOIESIS OF INDETERMINATE POTENTIAL AND POST-CARDIAC SURGERY ADVERSE OUTCOMES INCLUDING ACUTE KIDNEY INJURY

Background: Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related growth of somatically mutated hematopoietic stem cells that exhibit dysregulated inflammation. Present in 15-30% of all adults over 65, CHIP has been associated with death, incident hematological cancer, cardiovascular events, incident acute kidney injury (AKI), and progression of chronic kidney disease (CKD). DNMT3A is the most commonly altered gene in CHIP, but somatic variants in other driver genes (e.g. TET2, JAK2) have demonstrated greater pathogenicity for CKD and AKI. Higher variant allele fractions (VAFs), representing a greater proportion of cells carrying the variant, also correlate with worse outcomes. The Steroids in Cardiac Surgery (SIRS) trial found no impact of intraoperative steroids on AKI in cardiac surgery. Given the reported association of non-DNMT3A CHIP with incident AKI in the general population, we hypothesize that non-DNMT3A CHIP would be associated with post-cardiac surgery AKI and other adverse outcomes.

METHODS AND RESULTS: Targeted sequencing for CHIP was performed in 453 SIRS participants. 6 samples were then excluded from the study due to baseline renal failure and 1 for missingness. Mean age was 73 years (SD = 9.5), and 148 patients (33%) were female. Using pre-established criteria, non-DNMT3A CHIP was present in 62 (14%) participants. All CHIP was identified in 98 (22%) patients and large clone CHIP (VAF ≥ 10%) was present in 44 (10%) patients. Baseline eGFR of evaluated patients was 69 ml/min per 1.73 meters-squared. Stage 2 or worse AKI occurred in 32 (7%) participants. A composite of major adverse post-surgical events including myocardial infarction, stroke, respiratory or renal failure, or death in 6-month follow-up occurred in 111 (25%) participants.
Adjusted for age, sex, baseline eGFR, diabetes, hypertension, and smoking, non-DNMT3A CHIP was associated with a more than doubling of risk for stage 2 AKI (OR = 2.8, 95% CI = 1.2 – 6.6, P = 0.02). Large clone CHIP was not associated with stage 2 AKI but was associated with the post-surgical adverse events composite (OR = 2.3, 95% CI =1.2 - 4.4, P = 0.02).

Conclusion: In keeping with prior observations of association between non-DNMT3A CHIP and incident AKI and progressive CKD in the general population, we observed more than double the risk of post-cardiac surgery stage 2 or worse AKI with non-DNMT3A CHIP. Further examination of the impact of CHIP on post-cardiac surgery adverse events including AKI is needed. Non-DNMT3A CHIP could inform risk stratification and potentially be a therapeutic target.