Cardiac surgery induces activation of various cells within the circulatory system, leading to the secretion of multiple cytokines, chemokines, reactive oxygen species, and other inflammatory factors. These inflammatory factors can trigger various postoperative complications (1–3). Meanwhile most cardiac surgeries require the use of cardiopulmonary bypass (CPB). During the CPB process, there is a significant increase in the expression of inflammatory mediators such as interleukins (IL), tumor necrosis factor-alpha (TNF-α), and kinins, including bradykinin, by the leukocytes (4–6). This exacerbates the inflammatory response during the cardiac surgery and leads to severe complications (7–9).

The occurrence rate of acute kidney injury (AKI) following cardiac surgery, which is a frequent perioperative complication, ranges between 5 and 42% (10–12). It associated with higher mortality rates, prolonged hospital stays, and increased healthcare expenses (12, 13). The underlying mechanisms of cardiac surgery-associated acute kidney injury (CSA-AKI) are still not completely elucidated, and it is a complex condition likely influenced by multiple factors, which may include hypoperfusion, ischemia–reperfusion injury, neurohumoral activation, inflammation, oxidative stress, nephrotoxins, and mechanical factors (12).

Cold-induced RNA-binding protein (CIRP), belonging to the cold shock protein family, is the first cold shock protein discovered in mammalian cells (14). It has been subsequently found to be regulated by various stress conditions, including hypoxia, UV radiation, glucose deprivation, heat stress, H₂O₂ (15, 16). This indicates that CIRP functions as a broad stress-response protein. In-depth investigation of CIRP has revealed that its functionality depends on the protein’s distribution location, exerting its effects through both intracellular and extracellular forms. Intracellular CIRP translocates from the nucleus to the cytoplasm, where it binds to and stabilizes various messenger RNAs (mRNAs) within the cell, thereby promoting translation to cope with various external stressors, such as hypoxia, hypothermia and oxidative stress (17–19). Extracellular CIRP has been identified as a novel inflammatory mediator that can stimulate the release of pro-inflammatory cytokines from microglia/macrophages, thereby exacerbating organ damage (17, 20, 21). During cardiac surgery and CPB, the host is subjected to hypothermia and inadequate organ perfusion, resulting in an upregulation of CIRP secretion. In animal experiments, it has been demonstrated that mice with knocked-out CIRP gene exhibited milder renal inflammation and lower levels of inflammatory markers (22). Ischemia–reperfusion injury and CIRP release may occur after the body receives pulsating blood perfusion (23).

This study enrolled patients who underwent cardiac surgery and detected their serum CIPR levels before and after surgery, aiming to evaluate whether the elevated level of extracellular CIRP is a risk factor for the postoperative development of AKI.

AKI is a severe postoperative complication following cardiac surgery, leading to increased postoperative ICU stay, prolonged total hospitalization duration, and decreased postoperative survival rates. CIRP secretion increases with prolonged CPB time after cardiac surgery, and its secretion level is positively correlated with the duration of CPB. Cardiac surgeries requiring longer CPB durations exhibit significantly higher levels of CIRP compared to non-CPB surgeries. Elevation of CIRP levels is an independent risk factor for the occurrence of AKI and can exacerbate the severity of AKI and lead to poorer in-hospital outcomes for patients. Therefore, CIRP can serve as a predictive marker for postoperative AKI and in-hospital outcomes in cardiovascular surgery.

A meta-analysis has pointed out several risk factors for CSA-AKI. These include the presence of pulmonary hypertension, cyanotic heart disease, univentricular heart, administration of nephrotoxic drugs, use of vasopressors, CPB time, reoperation, low preoperative creatinine, high preoperative eGFR and sepsis (24). The pathophysiological mechanisms of CSA-AKI are not fully understood, but currently, they mainly involve nephrotoxins, ischemia and reperfusion, cardiac dysfunction, venous congestion, inflammation, and oxidative stress (25). In recent years, there has been increasing recognition that the systemic inflammatory response syndrome observed in response to CPB is characterized by widespread manifestations throughout the body (1). It has become evident that individual patients exhibit significant heterogeneity in the extent to which distinct inflammatory pathways are activated. However, CIRP secreted by various organs during cardiac surgery is also an important factor that cannot be ignored. In the univariate analysis of this study, the levels of CIRP were significantly higher in the AKI group compared to the non-AKI group. In the multivariate analysis, elevated levels of CIRP were identified as an independent risk factor for AKI. The mice experiment conducted by Siskind et al. confirmed that CIRP can induce acute kidney injury by activating renal TREM-1 (26, 27). Moreover, a prospective observational study conducted by Xia et al. demonstrated that post-CPB levels of CIRP are associated with an increased risk of pulmonary dysfunction. CIRP can serve as one of the indicators for predicting postoperative lung injury (28). So, CIRP may serve as a marker of organ damage after heart surgery.

CIRP is an intracellular stress-response protein and a specific type of damage-associated molecular pattern (DAMP). Wang et al. provided evidence showing that Extracellular CIRP (eCIRP) can act as a DAMP, initiating the activation of innate Toll-like receptor 4 (TLR4)/MD2-mediated pro-inflammatory signaling, which subsequently induces inflammation (29). Furthermore, studies have indicated that eCIRP can modulate the promotion of macrophages and neutrophils in immune responses and inflammation through the TREM-1 signaling pathway. (30, 31).It exhibits the ability to respond to diverse stress stimuli by modulating its expression and mRNA stability. In this study, we found that patients with high levels of CIRP experienced longer CPB times and lower CPB temperatures. It was also found in this study that patients with higher CIRP levels had a higher incidence of ALI and a higher SOFA score. This is consistent with the research conclusion of Xia et al. (28). During cardiac arrest and CPB, organs are under conditions of non-pulsatile blood flow, inadequate perfusion, and exposure to hypothermic stimuli, all of which can lead to significant secretion of CIRP by the body. Extracellular CIRP (eCIRP) is associated with a range of conditions and can activate immune and inflammatory responses (32). After the cardiac arrest, the organ experiences ischemia reperfusion injury, and a large amount of CIRP will aggravate the ischemia reperfusion injury and further aggravate the organ function impairment (33, 34). Patients with higher CIRP level take longer time to recover. In this study, it was found that patients with higher CIRP levels experience longer mechanical ventilation time, higher cystatin C levels and incidence of ALI, longer ICU stay and hospital stay. During the follow-up, we did not find that a high level of CIRP would affect the long-term survival rate of patients, which may be related to the fact that CIRP is mainly a stress-response protein, which mainly increases during and after the operation and gradually returns to normal level within 3 days after the operation (28), which is not enough to cause long-term postoperative changes, but in this study, we found that it can predict the short-term postoperative outcome. Research has also found that inhibiting the expression or function of CIRP can attenuate the severity organ damage (22, 34, 35). Targeting CIRP with pharmacological or genetic interventions may reduce inflammation, alleviate renal tissue damage, and improve kidney function. Despite the association between CIRP and postoperative AKI, research in this field is still in its early stages, and further studies and validations are needed to elucidate the specific mechanisms and treatment strategies. Therefore, in clinical practice, more research and validation are required for CIRP-targeted intervention therapies to determine their potential role in postoperative acute kidney injury following cardiac surgery.

There are certain limitations in this study. We employed the median method to distinguish high and low levels of CIRP, which, due to the sample size, has limited clinical significance. In the future, larger sample sizes are needed to establish more precise cutoff values. Additionally, the mechanisms by which CIRP mediates acute kidney injury have not been clearly elucidated in this article, and current available evidence does not establish a causal relationship between the two, warranting further investigation.

CIRP levels were positively correlated with CPB time during the cardiac surgery. This study demonstrated that patients with elevated level of CIRP before and after cardiac surgery are more prone to experiencing poorer in-hospital outcomes and developing AKI, especially severe AKI. The elevated levels of CIRP may be an independent risk factor for AKI and were associated with adverse in-hospital outcomes.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The study was approved by the Ethics Committee of the First Affiliated Hospital of Xi’an Jiaotong University (Approval No. XJTU1AF2021LSL-028), and informed consent was obtained from all patients.

ZF: Data curation, Formal analysis, Investigation, Methodology, Software, Writing – original draft. XC: Data curation, Methodology, Writing – review & editing. CZ: Data curation, Methodology, Writing – review & editing. JN: Data curation, Methodology, Writing – review & editing. YY: Methodology, Supervision, Writing – review & editing. TS: Supervision, Data curation, Writing – review & editing. JH: Supervision, Methodology, Writing – review & editing. XZ: Supervision, Conceptualization, Funding acquisition, Project administration, Resources, Writing – review & editing.