Genetic predisposition may not improve prediction of cardiac surgery-associated acute kidney injury

Front Genet. 2023 Apr 13;14:1094908. doi: 10.3389/fgene.2023.1094908. eCollection 2023.


Background: The recent integration of genomic data with electronic health records has enabled large scale genomic studies on a variety of perioperative complications, yet genome-wide association studies on acute kidney injury have been limited in size or confounded by composite outcomes. Genome-wide association studies can be leveraged to create a polygenic risk score which can then be integrated with traditional clinical risk factors to better predict postoperative complications, like acute kidney injury. Methods: Using integrated genetic data from two academic biorepositories, we conduct a genome-wide association study on cardiac surgery-associated acute kidney injury. Next, we develop a polygenic risk score and test the predictive utility within regressions controlling for age, gender, principal components, preoperative serum creatinine, and a range of patient, clinical, and procedural risk factors. Finally, we estimate additive variant heritability using genetic mixed models. Results: Among 1,014 qualifying procedures at Vanderbilt University Medical Center and 478 at Michigan Medicine, 348 (34.3%) and 121 (25.3%) developed AKI, respectively. No variants exceeded genome-wide significance (p < 5 × 10-8) threshold, however, six previously unreported variants exceeded the suggestive threshold (p < 1 × 10-6). Notable variants detected include: 1) rs74637005, located in the exonic region of NFU1 and 2) rs17438465, located between EVX1 and HIBADH. We failed to replicate variants from prior unbiased studies of post-surgical acute kidney injury. Polygenic risk was not significantly associated with post-surgical acute kidney injury in any of the models, however, case duration (aOR = 1.002, 95% CI 1.000-1.003, p = 0.013), diabetes mellitus (aOR = 2.025, 95% CI 1.320-3.103, p = 0.001), and valvular disease (aOR = 0.558, 95% CI 0.372-0.835, p = 0.005) were significant in the full model. Conclusion: Polygenic risk score was not significantly associated with cardiac surgery-associated acute kidney injury and acute kidney injury may have a low heritability in this population. These results suggest that susceptibility is only minimally influenced by baseline genetic predisposition and that clinical risk factors, some of which are modifiable, may play a more influential role in predicting this complication. The overall impact of genetics in overall risk for cardiac surgery-associated acute kidney injury may be small compared to clinical risk factors.

Keywords: acute kidney injury; anesthesiology [H02.403.066]; cardiac surgery-associated acute kidney injury; perioperative genomics; polygenic risk score (PRS); precision medicine and genomics.

Grants and funding

ND received support from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (1 K08 DK131346-01) and a Foundation for Anesthesia Education and Research (FAER) - Mentored Research Training Grant (MRTG). DL received funding from the National Institute of General Medical Sciences (T32-GM108554). LB received funding from the National Library of Medicine (R01-LM010685-11). MM received grant funding support from the National Heart, Lung, and Blood Institute, Grants 1K01HL141701-03 (MM). Additional support from the University of Michigan and Vanderbilt University Departments of Anesthesiology and Vanderbilt Institute for Clinical and Translational Research.