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Association between initial serum cystatin C level and prognosis of aneurysmal subarachnoid hemorrhage

BMC Neurology volume 25, Article number: 151 (2025) Cite this article

Abstract

Background

Aneurysmal subarachnoid hemorrhage (aSAH) patients usually suffer poor survival outcome and severe morbidity. Evaluating prognosis of aSAH patients in acute phase is essential for physicians to make suitable treatments strategies. This study was performed to explore the relation between initial serum cystatin C level and outcome of aSAH patients.

Methods

Three hundred seven aSAH patients were included. Univariate and multivariate logistic regression were used to analyze the relationship between initial serum cystatin C level with mortality and unfavorable functional outcome of aSAH patients. Receiver operating characteristic curve (ROC) was drawn and area under the ROC curve (AUC) was calculated to evaluate the prognostic value of serum cystatin C in aSAH.

Results

The incidence of mortality and unfavorable functional outcome in included 307 aSAH patients was 18.2% and 49.2%. Compared with survivors or patients with mRS < 3, non-survivors or those with mRS ≥ 3 had lower GCS and higher WFNS, Hunt-Hess, mFisher score. Serum cystatin C level was also higher in non-survivors or whose mRS ≥ than survivors or whose mRS < 3. Multivariate logistic regression showed serum cystatin C was significantly associated with mortality (p = 0.012) but not unfavorable functional outcome (p = 0.053) of aSAH. The AUC of serum cystatin C for predicting mortality and unfavorable functional outcome of aSAH patients was 0.718 and 0.669, respectively.

Conclusions

Initial serum cystatin C level is positively associated with mortality of aSAH patients. Evaluating serum cystatin C level is useful for clinicians to risk the severity of aSAH patients and therefore make personalized treatments regimen.

Peer Review reports

Introduction

The aneurysmal subarachnoid hemorrhage (aSAH) is a severe neurological disease which accounts for 5% to 10% among all stroke patients. It has been investigated the annual incidence of aSAH is 9.1 per 100 thousand persons and the mortality of aSAH ranged from 8.3 to 66.7% [1, 2]. And those survived patients would sustain poor functional outcome and impaired cognitive status. Early recognizing the aSAH patients with high risk of poor prognosis is beneficial for physicians to make personalized therapeutic regimen and strengthen clinical care. Some clinical scores have been designed and commonly used to evaluate the aSAH severity such as WFNS, Hunt-Hess and modified Fisher. While these scores were developed only including physical symptoms and signs, or radiological signs. Abnormalities of laboratory index may reflect the pathophysiological metabolic changes after brain injury and be associated with brain injury severity. Incorporating laboratory index into conventional scores may improve the value on predicting prognosis of aSAH patients.

As a part of cysteine proteinase inhibitor widely presenting in nucleated cells and body fluids of various tissues, the cystatin C plays important role on the catabolism of intracellular proteins and peptides. The significance of cystatin C on occurrence and development of various diseases has been gradually realized and discovered. Previous studies have showed increased cystatin C level was correlated with higher risk of mortality and complications in other neurological patients such as ischemic stroke and intracerebral hemorrhage [3,4,5,6,7,8,9,10]. Cystatin C would be produced by neuronal cells after ischemic brain injury to inactivate cathepsin which could aggravate oxidative stress injury, inflammation and neuronal death [11,12,13]. These pathological processes also occurred during the progression of aSAH [14,15,16]. Therefore, cystatin C may also increase after aSAH as a response to inhibit these pathological processes, and act as a marker of cerebral injury severity. While there is still no study exploring the prognostic value of cystatin C in aSAH patients. We design this study to verify the association between serum cystatin C level and outcome of aSAH patients and develop prognostic models incorporating serum cystatin C for aSAH patients.

Materials and methods

Patients

SAH patients treated in the neuro-intensive care unit (NICU) of West China hospital between January 2017 and June 2019 were identified for this study. The aSAH diagnosis of patients taken into the emergency department of our hospital with suspected symptoms or signs of SAH such as severe headache, neck stiffness and pain, consciousness disorders, nausea and vomiting, other neurological symptoms would be confirmed by computed tomography angiography (CTA) or digital subtraction angiography (DSA). Confirmed aSAH patients in the emergency department of our hospital would receive neurosurgical interventions within 24 h after admission and be transferred to ICU after interventions based on the aSAH severity. A part of patients were excluded from this study if they met following criteria: (1) SAH caused by other diseases including cerebral vascular malformation, moyamoya disease and trauma; (2) history of other neurologic diseases such as intracranial tumor and stroke within three months; (3) history of renal disease with impaired renal function; (4) admitted to our hospital 24 h after initial symptoms onset; (5) transferred from other medical centers; (6) incomplete records of included variables. After screening, 307 aSAH patients were finally included in this study. This study was approved by the ethics committee of West China hospital. All procedures involved in this study accorded with the ethical standards of the Helsinki declaration. Informed consent forms of each patient about participating observational study were signed by patients themselves or their legal representative once they admitted to West China hospital.

Data collection

Previous history including smoking, alcoholism, comorbidities including diabetes mellitus and hypertension were recorded. Vital signs on admission including systolic blood pressure, diastolic blood pressure and heart rate were collected. Conventionally used scores in the clinical practice of aSAH patients including GCS, WFNS, Hunt-Hess and mFisher were included in this study. Radiological information including intraventricular hemorrhage (IVH) and aneurysm location were also collected. Laboratory tests (glucose, platelet, cystatin C) were obtained by analyzing the first blood sample once admitted. Complications during hospitalizations including delayed cerebral ischemia (DCI), pneumonia and intracranial infection were evaluated and recorded in electronic medical records system (EMRS) by experienced physicians. The pneumonia was confirmed based on the criteria previously defined: At least 1 of the following: (1) Fever (> 38 °C) with no other recognized cause; (2) Leukopenia (< 4000 WBC/mm3) or leukocytosis (> 12,000 WBC/mm3); (3) For adults ≥ 70 y old, altered mental status with no other recognized cause. And at least 2 of the following: (1) New onset of purulent sputum, or change in character of sputum over a 24 h period, or increased respiratory secretions, or increased suctioning requirements; (2) New onset or worsening cough, or dyspnea, or tachypnea (respiratory rate > 25/min); (3) Rales, crackles, or bronchial breath sounds (4) Worsening gas exchange (O2 desaturation [PaO2/FiO2 ≤ 240], increased oxygen requirements). And ≥ 2 serial chest radiographs with at least 1 of the following: New or progressive and persistent infiltrate, consolidation, or cavitation. In patients without underlying pulmonary or cardiac disease, 1 definitive chest radiograph is acceptable [17]. The intracranial infection was confirmed based on typical symptoms and signs, abnormal results of cerebrospinal fluid examination, head imaging, and blood WBC > 109/L. The DCI was diagnosed based on one of the following criteria: (1) occurrence of focal neurological impairment; (2) a dramatic decrease of GCS at least 2 points (decrease of total score or one component of GCS, and excluded other causes discovered by clinical assessments and brain image). Outcomes of this study were in-hospital mortality and unfavorable functional outcome (mRS < 3) 3 months after admission.

Statistical analysis

Normality of variables was tested by Kolmogorov–Smirnov test. Variables of normal distribution and non-normal distribution were showed as mean ± standard deviation and median (interquartile range), respectively. Categorical variables were presented as numbers (percentage). Independent Student’s t-test and Mann–Whitney U test were respectively applied to compare the difference between two groups of normally distributed and non-normally distributed variables. χ2 test or Fisher test was conducted to analyze the difference of categorical variables. Univariate logistic regression was firstly used to find potential risk factors of outcome in included aSAH patients. Next, significant factors (p < 0.05) in univariate analysis were included into multivariate logistic regression for adjusting confounding effects. Finally, independent factors in multivariate logistic regression were selected to construct models for predicting outcome of included patients using logistic regression. Receiver operating characteristics (ROC) curves of single cystatin C value, several conventional severity scores and constructed predictive models were drawn and area under the ROC curve (AUC) of them was calculated and compared. The best cut off value of cystatin C for predicting outcome was also calculated. We divided patients into two groups according to the best cut off value and compared the survival difference between these two groups through Kaplan–Meier curve.

Two-sided P value < 0.05 was considered being statistically significant. SPSS 22.0 Windows software (SPSS, Inc, Chicago, IL) was applied for all statistical analyses and figures drawing.

Results

Patients characteristics

Three hundred seven aSAH patients were included in this study with mortality of 18.2% (Table 1). 151 patients suffered unfavorable functional outcome with rate of 49.2%. The mean age was significanlty higher in non-survivors and those mRS ≥ 3 than non-survivors (p = 0.043) and mRS < 3 (p < 0.001). Incidence of smoking, alcoholism, diabetes mellitus and hypertension did not difer between patients with favorable outcome and those with unfavorable outcome. Non-surivors and patients with mRS ≥ 3 had lower GCS (p < 0.001), higher WFNS (p < 0.001), Hunt-Hess (p < 0.001) and mFisher (p < 0.001). The incidence of IVH was significanlty higher in non-surivors (p = 0.028) and patients with mRS ≥ 3 (p = 0.039). Additionally, the level of glucose and cystatin C was both higher in non-surivors (p < 0.001) and patients with mRS ≥ 3 (p < 0.001). Regarding complications after aneurysm rupture, delayed cerebral ischemic and pneumonia were both more likely be observed in non-surivors and patients with mRS ≥ 3. Finally, non-survivors had significant shorter length of hospital stay than survivors (p < 0.001) while patients with mRS ≥ 3 had significant longer length of ICU stay (p < 0.001) and hospital stay (p = 0.015) than those with mRS < 3.

Table 1 Clinical characteristics of included aSAH patients
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Association between cystatin C and other factors of aSAH patients

Spearman correlation analysis showed age (r = 0.241, p < 0.001), male gender (r = 0.227, p < 0.001), smoking (r = 0.157, p = 0.006), hypertension (r = 0.164, p = 0.004), systolic blood pressure (r = 0.124, p = 0.030), diastolic blood pressure (r = 0.166, p = 0.004), heart rate (r = 0.200, p < 0.001), GCS (r = − 0.250, p < 0.001), WFNS (r = 0.253, p < 0.001), Hunt-Hess (r = 0.222, p < 0.001), mFisher (r = 0.222, p = 0.001), delayed cerebral ischemic (r = 0.135, p = 0.018), pneumonia (r = 0.170, p = 0.003) were all weakly related with initial serum cystatin C level (Table 2 and Fig. 1).

Table 2 Correlation between serum cystatin C level and other factors
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Fig. 1
figure 1

A Correlation between serum cystatin C level and GCS score. B Correlation between serum cystatin C level and WFNS score. C Correlation between serum cystatin C level and Hunt-Hess score. D Correlation between serum cystatin C level and mFisher score

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Association between cystatin C and prognosis of aSAH patients

Univariate logistic regression indicated that age (p = 0.044), GCS (p < 0.001), WFNS (p < 0.001), Hunt-Hess (p < 0.001), mFisher (p < 0.001), IVH (p = 0.017), aneurysm location (p = 0.038), glucose (p = 0.002), cystatin C (p < 0.001), delayed cerebral ischemia (p < 0.001) and pneumonia (p = 0.031) were significantly associated with mortality of included aSAH patients (Table 3). While after adjusting confounding effects by multivariate logistic regression, only GCS (p = 0.016), mFisher (p = 0.027), cystatin C (p = 0.009) and delayed cerebral ischemia (p < 0.001) were independently associated with mortality of aSAH patients.

Table 3 Logistic regression of risk factors for mortality in aSAH patients
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Furthermore, univariate logistic regression showed that age (p < 0.001), diastolic blood pressure (p = 0.047), GCS (p < 0.001), WFNS (p < 0.001), Hunt-Hess (p < 0.001), mFisher (p < 0.001), IVH (p = 0.029), glucose (p < 0.001), cystatin C (p < 0.001), delayed cerebral ischemia (p < 0.001) and pneumonia (p < 0.001) were significant risk factors of unfavorable functional outcome in aSAH patients (Table 4). However, multivariate logistic regression adjusting confounding effects finally confirmed four factors including age (p < 0.001), GCS (p = 0.011), delayed cerebral ischemia (p < 0.001) and pneumonia (p = 0.021) were independently associated with unfavorable functional outcome in aSAH patients.

Table 4 Logistic regression of risk factors for unfavorable functional outcome (mRS 3–6) in aSAH patients
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Prognostic value of single cystatin C and predictive models for aSAH patients

Logistic predictive models for mortality and unfavorable functional outcome were constructed using significant factors in multivariate logistic regression. The AUC value of single cystatin C for predicting mortality of aSAH patients was 0.718 (Table 5 and Fig. 2). In addition, the best cut off value of cystatin C for predicting mortality was 0.76. Patients were divided into two groups based on the best cut off value. Patients with cystatin C ≥ 0.76 had significantly shorter survival than whose cystatin C < 0.76 (p < 0.001) (Fig. 3). The AUC of GCS, Hunt-Hess, WFNS and mFisher for predicting mortality was 0.800, 0.786, 0.791 and 0.692, respectively. Adding cystatin C into GCS could improve the AUC into 0.852. Composed of GCS, mFisher, cystatin C and delayed cerebral ischemia, the predictive model 1 could relatively accurately predict the mortality of included aSAH patients with AUC of 0.899. Regarding the unfavorable functional outcome, cystatin C could not accurately predict the outcome with AUC of 0.669 (Fig. 4). The AUC of GCS, Hunt-Hess, WFNS and mFisher for predicting unfavorable functional outcome was 0.749, 0.735, 0.750 and 0.640, respectively. Consisted of age, GCS, delayed cerebral ischemia and pneumonia, the predictive model 2 could predict the unfavorable functional outcome of included aSAH patients with AUC of 0.872.

Table 5 Value of cystatin C and other clinical scores for predicting mortality and unfavorable functional outcome of included aSAH patients
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Fig. 2
figure 2

A Receiver operating characteristic curves of single cystatin C and constructed predictive model 1 for predicting mortality of aSAH patients. B Receiver operating characteristic curves of clinical scores for predicting mortality of aSAH patients

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Fig. 3
figure 3

Survival curve comparison between different cystatin C level group judged by 0.76 using Kaplan–Meier method

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Fig. 4
figure 4

A Receiver operating characteristic curves of single cystatin C and constructed predictive model 2 for predicting unfavorable functional outcome of aSAH patients. B Receiver operating characteristic curves of clinical scores for predicting unfavorable functional outcome of aSAH patients

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Discussion

Among aSAH patients in this study, serum level of cystatin C was higher in non-survivors than survivors and it was independently associated with the mortality. Although serum cystatin C was higher in patients with mRS 3–6 than those with mRS 1–2, it was not independently correlated with the unfavorable functional outcome of aSAH patients after adjusting confounding factors. Composed of 122 amino acid residues, the cystatin C widely exists in nucleated cells and body fluids of various tissues. It is produced by all nucleated cells in the body with a constant rate and is cleared from the body through glomerular filtration. Therefore, the cystatin C is usually considered as an endogenous marker reflecting the change of glomerular filtration rate. Some studies have explored the improved value of cystatin C for detecting AKI in various patients [18,19,20,21,22,23]. Additionally, the cystatin C is also considered as a predictive marker of cardiovascular events.

Previous studies have discovered the serum cystatin C level was a risk factor of stroke events and prognostic factor for patients with ischemic stroke or intracerebral hemorrhage [3,4,5,6,7,8,9,10]. One study enrolling aSAH patients found higher cystatin C level was correlated with increased risk of delayed cerebral ischemia in patients receiving endovascular treatment [24]. The increased cystatin C level may not only act as an acute stress response in stroke patients, but also an indicator of higher severity of cerebral vessel damage [25]. It has been confirmed that the balance between cystatin C and cysteine protease played a critical role in the pathophysiological process of cerebral injury and subsequent rehabilitation [26, 27]. As a major part of lysosomal cysteine protease, the cathepsin B takes part in multiple processes such as inflammation, oxidative stress, and apoptosis and could aggravate the neuronal death after ischemic brain injury [11,12,13, 28, 29]. And as an inhibitor of cysteine-proteases, the cystatin C could be produced by neuronal cells after ischemic brain injury to prevent oxidative stress injury and inactivate cathepsin. Additionally, one study found that cystatin C could prevent the cerebral vasospasm caused by SAH through activating the autophagy pathway in the wall of basilar arteries [30].

In our study, the serum cystatin C level was significantly associated with the brain injury severity of aSAH though with relatively low correlation coefficient. The increased cystatin C level may reflect more severe damage of cerebral vessels and neuronal tissue after aSAH and consequently correlate with higher risk of poor outcomes. Cystatin C was independently related with the in-hospital mortality but not the 3-months functional outcome. Additionally, the AUC of cystatin C for predicting the in-hospital mortality was 0.718 while the AUC for predicting the 3-months unfavorable functional outcome (mRS < 3) was relatively lower with the 0.669. This result is similar to findings of another study which reported that higher cystatin C level was correlated with increased mortality risk but not with poor functional outcome in acute intracerebral hemorrhage patients [31]. After combining the cystatin C, the AUC of GCS could be elevated from 0.800 to 0.852. The predictive model for the in-hospital mortality incorporated cystatin C, GCS, mFisher, delayed cerebral ischemia, had the highest AUC value of 0.899 and the sensitivity of 0.804, which was beneficial for clinicians to evaluate the mortality risk of aSAH at the early stage and make personalized therapeutics. The relatively lower AUC of single cystatin C and absence of cystatin C in the predictive model for 3-months unfavorable functional outcome indicate initial cystatin C level may only reflect the severity of pathological changes during the acute stage after aSAH but not the subsequent long-term recovery of injured cerebral tissue. It is worthwhile to design studies exploring the value of sequential cystatin C change on predicting the 3-months unfavorable functional outcome. Four independent factors were finally incorporated into the model 2 including age, GCS, delayed cerebral ischemia and pneumonia. There is no doubt that older aSAH patients would be accompanied with more complications and exhibit poorer physical function, which significantly hinders their ability to recover functional status. Additionally, nosocomial pneumonia is prevalent among hospitalized aSAH patients due to multiple causes including consciousness disorders, aspiration, long-term bed rest, mechanical ventilation, neurogenic pulmonary edema, and immune suppression, and would delay the recovery of functional status by increasing the energy consumption with the deteriorating nutritional status and immune function, extending the hospitalization time and bed rest time with the muscle atrophy and joint stiffness, decreasing the lung function with insufficient oxygen supply to brain tissue [32,33,34,35,36]. The predictive model for 3-months unfavorable functional outcome incorporated age, GCS, delayed cerebral ischemia and pneumonia had the AUC of 0.872, which was efficient in assessing the odds of long-term recovery after aSAH.

This study has several limitations. Firstly, aSAH patients in the study were collected from a single medical center. There are differences in severity and treatment strategies among different medical centers. The selection bias may not be avoided and conclusions of our study should be testified in future studies with larger sample sizes. Secondly, only initial serum cystatin C level on admission were recorded and changes of cystatin C level during hospitalizations were not collected so that we could not analyze the association between changes of cystatin C level and outcome of included aSAH patients. Thirdly, future interventional trials and animal studies are worthwhile to verify the effect of cystatin C injection on the prognosis of aSAH.

Conclusion

Higher initial serum cystatin C level is associated with mortality but not unfavorable functional outcome of aSAH patients. Measuring initial serum cystatin C level is helpful for clinicians to evaluate risk of poor outcome in aSAH patients and therefore make suitable therapeutic strategy.

Data availability

The datasets generated for this study are available on request to the corresponding author.

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Informed consent

Informed consent forms of each patient about participating observational study were signed by patients themselves or their legal representative once they admitted to West China hospital.

Funding

This study was supported by the Department of Science and Technology of Sichuan Province (24QYCX0411, 2024YFHZ0070), 1·3·5 projects for disciplines of excellence–Clinical Research Incubation Project, West China Hospital, Sichuan University (2020HXFH036), General Program of the National Natural Science Foundation of China (82173175).

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Authors and Affiliations

  1. Department of Neurosurgery, West China Hospital, Sichuan University, No.37, Guoxue Alley, Chengdu, Sichuan Province, 610041, China

    Ruoran Wang, Jing Zhang, Jianguo Xu & Min He

  2. Department of Critical Care Medicine, West China Hospital, Sichuan University, No.37, Guoxue Alley, Chengdu, Sichuan Province, 610041, China

    Min He

Authors
  1. Ruoran Wang
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  2. Jing Zhang
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  3. Jianguo Xu
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  4. Min He
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Contributions

Ruoran Wang: manuscript writing, methodology, data analysis, data acquisition, conception. Jing Zhang: Data acquisition. Jianguo Xu: manuscript review and editing, funding acquisition. Min He: manuscript review and editing, funding acquisition.

Corresponding authors

Correspondence to Jianguo Xu or Min He.

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Ethics approval and consent to participate

This study obtained approval from the West China hospital ethics committee (2021–1684).

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

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Wang, R., Zhang, J., Xu, J. et al. Association between initial serum cystatin C level and prognosis of aneurysmal subarachnoid hemorrhage. BMC Neurol 25, 151 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12883-025-04162-z

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12883-025-04162-z

Keywords

BMC Neurology

ISSN: 1471-2377

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