Postoperative AKI After Open-Heart Surgery: What Else Can We Do?

Abstract

Background: Cardiac surgery is a procedure that is commonly performed worldwide. Despite of technical advances, cardiac surgery remained to be a high-risk surgery with amounts of post-operative complications, such as acute kidney injury (AKI). Currently, the early diagnosis of postoperative AKI and the effect of Nitric oxide (NO) on renal function after cardiac surgery still need further determined. Methods: To determine whether free hemoglobin (fHb) ratio could predict AKI after open-heart surgery, we conducted a secondary analysis on the control arm of a randomized controlled trial, comparing the effect of nitric oxide (intervention) versus nitrogen (control) on AKI after cardiac surgery. First, we determined whether fHb ratio (i.e., levels of fHb at the end of CPB divided by baseline fHb) was associated with AKI via univariable and multivariable analyses. Second, we verified whether fHb ratio could predict AKI and incorporation of fHb ratio could improve predictive performance of AKI at an early stage, compared with urinary biomarkers alone. We conducted restricted cubic spline in logistic regression for model development. We used bootstrap-based internal validation for validation. We also employed concordance (c) statistic, area under curve (AUC) test, resampling model calibration, and likelihood ratio test to compare the predictive performance (i.e., discrimination and calibration) between competing models. To determine the effect of NO gas on renal function and other clinical outcomes in patients requiring cardiopulmonary bypass (CPB), we performed a systematic meta-analysis and trial sequential analysis. The primary outcome was the relative risk (RR) of acute kidney injury (AKI), irrespective of the AKI stage. The secondary outcome was the mean difference (MD) in the length of ICU and hospital stay, the RR of postoperative hemorrhage, and the MD in levels of Methemoglobin. Trial sequential analysis (TSA) was performed for the primary outcome. Results: In the secondary analysis, data stratified by median fHb ratio showed that subjects with an fHb ratio >2.23 presented higher incidence of AKI (80.0% vs. 49.1%, p=0.001), more need of renal replacement therapy (10.9% vs. 0%, p=0.036), and higher 28-day mortality (10.9% vs. 0%, p=0.036) than subjects with an fHb ratio ≤2.23. fHb ratio was associated with AKI after adjustment for pre-established factors. Levels of fHb ratio peaked immediately at the end of CPB, while levels of urinary biomarkers did not surge until the admission to the ICU. Among the four biomarkers measured at the end of CPB, fHb ratio outperformed other biomarkers with the highest AUROC of 0.703 (0.600-0.806), best calibration, and minimal optimism (bootstrap-adjusted AUROC 0.704, 95% CI 0.592-0.804). Incorporation of fHb ratio at the end of CPB achieved better predictive performance in terms of better discrimination (0.771 versus 0.653, p= 0.012) and calibration (p<0.001). In the meta-analysis, 54 Trials were assessed for eligibility and 5 studies (579 patients) were eligible for meta-analysis. NO was associated with reduced risk of AKI (RR 0.76, 95% confidential interval [CI], 0.62 to 0.93, I2 =0%). In the subgroup analysis by NO initiation timing, NO did not decrease the risk of AKI when started at the end of CPB (RR 1.20, 95% CI, 0.52 to 2.78, I2=0%). However, NO did significantly reduce the risk of AKI when started from the beginning of CPB (RR 0.71, 95% CI, 0.54 to 0.94, I2=10%). We conducted TSA based on three trials (400 patients) using KDIGO criteria and with low risk of bias. TSA indicated a CI of 0.50 to 1.02 and an optimal information size of 589 patients, suggesting a lack of definitive conclusion. Furthermore, NO does not affect the length of ICU and hospital stay or the risk of postoperative hemorrhage. NO slightly increased the level of methemoglobin at the end of CPB (MD 0.52%, 95%CI 0.27% to 0.78%, I2=90%), but it was clinically negligible. Conclusions: In the secondary analysis, fHb ratio at the end of CPB is a novel biomarker for AKI after open-heart surgery and incorporation of fHb ratio can achieve better predictive performance at an early stage, compared with prediction using urinary biomarkers alone. In the meta-analysis, NO appeared to reduce the risk of postoperative AKI in patients undergoing CPB. Additional studies are required to ascertain the finding and further determine the dosage, timing and duration of NO administration.