This study identified CAR as a significant risk factor for 28-day ICU mortality in patients receiving cardiac surgery. It was found that higher CAR levels correlated to increased 28-day ICU mortality risks, and patients in tertile 3 (CAR ≥ 0.31) had worst outcomes. RCS analysis highlighted that there was a non-linear dose–response relationship between higher CAR levels and worse outcomes, and the extent of the increase in risk varied with different CAR ranges. Cox regression analysis further validated that CAR could be used as an independently predictor for 28-day ICU mortality in postoperative patients. Moreover, subgroup analysis revealed that no significant associations were found between CAR and most demographic or clinical data.

Cr is primarily filtered and excreted by the glomeruli, and it serves as an indicator of renal function. Cardiac surgeries, particularly those requiring extracorporeal circulation, can cause renal injury, leading to excess fluid state, electrolyte imbalance, and increased mortality. Elevation of Cr during cardiac surgery often suggests renal dysfunction, which can impede the clearance of drugs and metabolites and then affect recovery. Cardiopulmonary bypass can cause hemolysis. Free hemoglobin and reactive iron released during hemolysis generate hydroxyl radicals through Fenton-type Haber–Weiss reactions, in turn causing damages to renal function [29]. Kolli H et al. found that slight elevations of Cr postoperatively correlated to increased 90-day mortality rates and prolonged hospital stays in patients [30]. Moreover, elevated serum Cr and blood urea nitrogen concentrations also impair glucose, lipid, protein, and amino acid metabolisms, disrupting cellular energy utilization and metabolism [31]. Collectively, elevation of Cr adversely impacts fluid balance, electrolyte stability, drug metabolism, inflammatory response, and clearance of metabolic byproducts, thereby influencing renal function and then postoperative survival in patients.

Alb is known to be a marker of nutritional and inflammatory status, and it plays critical roles in preserving colloid osmotic pressure and delivering hormones and drugs [32, 33]. Alb is a negative acute-phase reactant associated with disease severity, prognosis, and mortality [34]. During cardiac procedures, Alb outperforms crystalloids in maintaining hemodynamics, mitigating platelet count reduction, and preventing fluid overload. Hypoalbuminemia is widely recognized as an indicator of poor outcomes in critically ill patients, including those receiving cardiac surgery. It is established that patients with hypoalbuminemia have poor nutritional reserves and heightened systemic inflammation. Moreover, hypoalbuminemia leads to a reduction in free radical clearance while an increase in renal tubular apoptosis, which makes it an important risk factor for AKI following cardiac surgery [35]. Alb is involved in phosphoinositide 3-kinase activation, nitric oxide synthesis, renal tubular cell proliferation, and renal blood flow [36, 37]. Hypoalbuminemia causes damage to the endothelial cell barrier, resulting in inadequate renal perfusion [38]. Furthermore, hypoalbuminemia is associated with fluid shifts and edema, which may pose heavy burdens on cardiac and respiratory systems post-surgery. A meta-analysis reported that the incidence of complications and all-cause mortality rose by 89% and 137% per 10 g/L drop in serum Alb, respectively [39]. Moguel-González et al. conducted a prospective study in 164 adult patients receiving cardiac surgery and found that low Alb, high blood urea nitrogen, and elevated Cr were major risk factors for mortality [40].

CAR is a combination of Cr and Alb that has much more significant implications for postoperative risk assessment. It was reported Alb alone was less effective than CAR in predicting mortality [41]. In addition, Alb in combination with Cr was reported to be superior to Alb or Cr alone in predicting 30-day all-cause mortality [42]. An elevated value of CAR indicates concurrent renal dysfunction and systemic inflammation, both of which exacerbate organ dysfunction and increase mortality risk. Research also shows that CAR is associated with glycemic control in T2DM patients [43]. These research findings demonstrate a clear dose–response association between CAR and short-term mortality in patients receiving cardiac surgery, highlighting the role of CAR as a marker of physiological stress. Consistently, the longitudinal study in 11,200 atherosclerosis patients made by Grams ME et al. reported a positive relationship between CAR and AKI risk [44]. Compared to similar studies in other populations, the predictive value of CAR has also been validated across various disease contexts. For instance, in patients with acute pancreatitis, CAR has been shown to be an independent predictor of both short-term and long-term all-cause mortality, demonstrating superior predictive performance over individual markers such as Cr and Alb [45]. This further supports the potential and reliability of CAR as a risk assessment tool in diverse clinical settings. The link between CAR and poor outcomes in patients receiving cardiac surgery may be attributed to several mechanisms. First, elevated Cr levels and decreased Alb levels are closely associated with inflammatory responses. Inflammation is triggered and maintained through cytokines such as TNF-α, IL-6, and IL-1β, which activate the NF-κB pathway [46]. Hypoalbuminemia limits the proliferation and differentiation of immune cells, impairing their function by suppressing the activity of T cells, B cells, and macrophages, ultimately weakening the intensity and duration of the immune response and negatively affecting patient survival [47]. Second, high creatinine levels induce oxidative stress, which promotes cell apoptosis and tissue damage through endoplasmic reticulum stress and mitochondrial dysfunction [48]. Additionally, reactive oxygen species (ROS) activate signaling molecules such as PKC and MAPK, further driving apoptosis and inflammation [49]. Oxidative stress may also impair Alb synthesis, creating a self-reinforcing vicious cycle that exacerbates the condition [50]. Third, inflammation and surgical trauma increase vascular endothelial permeability and cause the shedding of the glycocalyx, facilitating the leakage of fluid from blood vessels into the interstitial spaces [51]. This activates the renin–angiotensin–aldosterone system (RAAS) and the antidiuretic hormone (ADH) system, which aggravates fluid overload and contributes to postoperative cardiovascular and respiratory complications [52]. Fourth, elevated Cr and decreased Alb levels may also result in insufficient microvascular perfusion, worsening ischemia, and increasing tissue hypoxia and cell death, which ultimately impair wound healing. Alb levels influence the function of dermal fibroblasts, and low Alb levels promote ferroptosis, delaying ischemic wound healing [52]. Furthermore, persistent inflammation and alterations in the protein hydrolysis balance in chronic wounds hinder the healing process [53]. Taken together, CAR serves as a significant biomarker for adverse outcomes in patients following cardiac surgery.

In this study, mediation analysis revealed that CAR affected the 28-day ICU mortality in postoperative patients through biomarkers such as chloride, glucose, potassium, and sodium. Changes in these biomarkers may reflect the indirect effect of CAR on patient prognosis. For example, chloride and sodium levels may indicate electrolyte and acid–base disorders, which is common in critically ill patients. Elevated glucose and potassium levels may signal stress response or metabolic disturbances, which affects outcomes in high-risk cases receiving cardiac surgery. These findings offer new perspectives on the relationship between CAR and mortality in postoperative patients, and they may guide the development of therapeutic strategies for improvement of patient outcomes. CAR is superior to other indicators in specificity and sensitivity, making it a more accurate indicator of postoperative mortality in patients receiving cardiac surgery.

As a biomarker for predicting 28-day ICU mortality, CAR exhibits several advantages. First, tests for both serum Cr and Alb are easily accessible and cost-effective, facilitating its widespread application in preoperative and perioperative settings. Second, in postoperative cardiac surgery patients in the ICU, an elevated CAR often indicates a higher risk of complications. This highlights the need for enhanced hemodynamic monitoring, incorporating dynamic parameters (e.g., pulse pressure variation or central venous oxygen saturation) to optimize fluid management and avoid overhydration or underhydration. Active nutritional support, including early enteral or parenteral nutrition and supplementation with specific nutrients, is essential for improving protein metabolism. For patients with elevated creatinine levels, early identification of AKI risk is crucial, necessitating the implementation of kidney-protective strategies such as restrictive fluid management and continuous renal replacement therapy [54]. Third, preoperative optimization of patient conditions can mitigate the risks associated with an elevated CAR. This includes albumin supplementation, medication adjustments, and anti-inflammatory treatment for patients with chronic inflammation. Perioperative management is equally critical, involving stringent control of cardiopulmonary bypass duration and cross-clamp time, as well as the adoption of renal-protective measures (e.g., temperature regulation and fluid strategies) to minimize intraoperative damage [55]. Postoperatively, early interventions with renal-protective medications and nutritional support can further reduce complication risks. Dynamic monitoring of inflammatory markers and renal function indicators enables timely adjustments to treatment plans based on observed changes. Forth, the clinical application of CAR demonstrates its potential as a risk stratification and decision-making tool. Dynamic CAR assessment helps clinicians identify high-risk patients, allocate them to higher-level monitoring units, and implement targeted multi-organ protective strategies. CAR trends also provide guidance for modifying treatment plans, such as intensifying renal protective measures or enhancing nutritional support when CAR levels remain elevated. Integrated with existing scoring systems (e.g., EuroSCORE), CAR complements these tools by addressing gaps in postoperative dynamic assessments, enhancing risk prediction accuracy, and optimizing postoperative ICU management. These measures underscore CAR's capacity to drive precision management in the ICU and deliver more comprehensive, individualized care for cardiac surgery patients.

This study also has several limitations. First, the causality between CAR and mortality was not involved due to the retrospective nature of the study, requiring prospective studies for confirmation. Second, electrolyte and glucose levels were identified as mediators in the mediation analysis, but the underlying biological mechanisms remain unclear and require further investigation. Third, Despite efforts to maximize sample collection from the MIMIC database, power analysis indicates the sample size remains insufficient for robust calculations, leaving the risk of a Type II error due to low statistical power. Fourth, although the MIMIC-IV database is comprehensive, it originates from a single center, which may not fully represent global or regional patient populations, as there are significant differences in medical practices, patient baseline characteristics, and surgical techniques across regions. Moreover, the data from a single center may be influenced by selection biases and specific treatment strategies, limiting the generalizability of the findings. Furthermore, although the CAR demonstrated potential predictive value for 28-day mortality in ICU patients following cardiac surgery, the exclusion of a large number of patients due to missing Cr or Alb data may have introduced selection bias. Despite employing appropriate statistical methods to enhance the reliability and generalizability of our results, future studies should aim to optimize data collection and handling techniques to minimize the impact of missing data on research outcomes. Future research should consider addressing these limitations, which may enhance the reliability and clinical utility of CAR as a prognostic biomarker.