Response: <scp>AKI</scp> During Cardiac Surgery—Still to Be Solved

We thank Dr. Guillermo Lema for his remarks [1] on our recent publication, The Role of Other Major Postoperative Complications in Determining Outcomes of Acute Kidney Injury after Coronary Artery Bypass Surgery [2], and appreciate the opportunity to address several of the concerns he raised. It is true that our cohort spans two decades during which gradual shifts in patient characteristics and perioperative practices have occurred, including perfusion technology. However, we believe that the changes in our center have been modest, and unlikely to influence our main findings. Patient selection was similar during the study period, and the same applies to renal replacement therapy, perioperative use of inotropic drugs and antibiotics. We believe this also holds true for the perfusion techniques used, both regarding the cardiopulmonary bypass machines and oxygenators, and there were no major changes in the use of cardioplegia. Off-pump surgery was more frequent during earlier periods, but conventional on-pump CABG became the standard approach to surgical revascularization after 2010. This variable was balanced between the study groups in the present analysis, and prior analyses of this cohort have demonstrated that off-pump CABG did not affect the rate of AKI during the earlier study period [3]. Finally, while changes in the patient population, medical or surgical treatment during the study period may have resulted in changes in frequency of complications, it is unlikely to affect the impact of different complications on outcome. The objective of our study was not to investigate risk factors for AKI, but to examine how other major complications influence the relationship between AKI and clinical outcomes. To further elaborate on Dr. Lema's comment, we performed stratified analyses by surgical period to evaluate potential temporal variation. As illustrated in Figure 1, we found consistent short-term results with modest variation but also a somewhat paradoxical increase in long-term risk of mortality and MACCE in more recent years. These results highlight that isolated and otherwise uncomplicated AKI may have limited immediate prognostic implications [4], yet remains clinically relevant given its association with long-term renal and cardiovascular risk, possibly through chronic kidney disease or related downstream sequelae [5]. We agree with Dr. Lema that reliance on serum creatinine alone may underestimate renal injury, and that the use of urine output criteria, new biomarkers or alternative classification systems may offer improved sensitivity. However, in our setting only creatinine-based definitions could be applied consistently across the entire cohort. Therefore, we adhered to the KDIGO criteria, which remain the international standard in large-scale observational research [6], and have been used in many comparable studies. Still, we agree with Dr. Lema that the KDIGO criteria have shortcomings, and that there is a need for more sensitive and specific biomarkers for AKI than creatinine. Yet, although novel markers such as NGAL and KIM-1 are increasingly studied, they have not yet been widely adopted in routine clinical practice and were not available in our data. As highlighted by Dr. Lema, we also agree that causality inherently cannot be established in observational data. Therefore, we explicitly acknowledge in the discussions section of our manuscript that the study design and uncertain temporal relationship between AKI and major complications precludes causal inference. We are also aware that it is not possible for us to account for all confounders that interrelate with isolated AKI and outcome, such as intraoperative blood pressure targets. However, a multitude of key pre- and intraoperative variables were accounted for using propensity scores, and our results were largely consistent in the primary and sensitivity analyses. Therefore, we have interpreted our findings cautiously and have underscored that they are strictly presented as associative. Finally, we appreciate Dr. Lema's constructive perspective and share his view that, despite advances in technique and monitoring, the mechanisms and clinical implications of cardiac-surgery-associated AKI remain an important area of ongoing investigation. Hopefully our study will contribute to this discussion and stimulate further collaborative research in this important field. L.A.H.: data curation, formal analysis, validation, writing – original draft, writing – review and editing. N.S.: validation, writing – review and editing. S.H.: validation, writing – review and editing. O.S.I.: validation, writing – review and editing. T.G.: data curation, validation, writing – review and editing. D.H.: project administration, data curation, formal analysis, validation, writing – original draft, writing – review and editing. The authors have nothing to report. The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.