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Prognostic value of serum cystatin C in patients with sepsis


1 Department of Critical Care Medicine, Taizhou People's Hospital, Taizhou, Jiangsu, China
2 Department of Cardiovascular Medicine, Taizhou People's Hospital, Taizhou, Jiangsu, China

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Date of Submission09-Aug-2021
Date of Decision02-Sep-2021
Date of Acceptance08-Nov-2021
Date of Web Publication13-Jan-2023
 

   Abstract 


Background: Early identification and diagnosis of sepsis are very important because timely and appropriate treatment can improve the survival outcomes. Aim: The aim of this study was to explore the clinical significance of serum cystatin C level in sepsis. Methods: The levels of serum cystatin C, C-reactive protein (CRP), and procalcitonin (PCT) were measured via enzyme-linked immunosorbent assay (ELISA). The patients with sepsis were followed up for 30 days to record their survival conditions. Results: The expression level of cystatin C was remarkably elevated in patients with sepsis compared with that in healthy controls. The serum cystatin C level was significantly correlated with the SOFA score and CRP, PCT, and creatinine levels in patients with sepsis. The patients in death group had a markedly higher level of serum cystatin C than those in survival group. The area under curve (AUC) of cystatin C for assessing the 30-day mortality rate of sepsis patients was 0.765. Conclusion: The serum cystatin C level is elevated in patients with sepsis and it may serve as a biomarker for early diagnosis of sepsis and possess promising effects in assessing the severity of sepsis and the prognosis of patients.

Keywords: Cystatin C, diagnosis, prognosis, sepsis


How to cite this URL:
Hu C, Zhang Z, Hou B, Xue H, Pu X, Ye J. Prognostic value of serum cystatin C in patients with sepsis. Indian J Pathol Microbiol [Epub ahead of print] [cited 2023 Feb 2]. Available from: https://www.ijpmonline.org/preprintarticle.asp?id=367708





   Introduction Top


Sepsis is the leading cause of death of patients with severe disease in the world, whose mortality rate is 30–50% among the hospital deaths.[1] It is a life-threatening organ dysfunction caused by abnormal response of the body to infection, and systemic inflammatory response is an important pathophysiological mechanism of the occurrence and development of the disease.[2] In spite of great development and advancement in anti-infective drugs and life-sustaining treatments in recent years, no breakthroughs have been achieved in the treatment of sepsis so far. Therefore, it is particularly important for clinicians to find a new marker that is capable of rapidly recognizing and judging prognosis.

Cystatin C, a member of the cysteine proteinase inhibitor superfamily, is expressed in all nucleated cells.[3] As a low-molecular-weight protein with a relative molecular weight of merely 13.3 kDa, cystatin C has been acknowledged as a sensitive indicator for evaluation of early renal damage.[4] Studies have demonstrated that cystatin C can act as a favorable predictor for the occurrence of acute kidney injury in critically ill patients.[5] However, there are few reports about cystatin C in evaluating the survival rate of adult patients with sepsis at present. Therefore, the present study aims to explore the correlations of the serum cystatin C level with the severity and survival rate of patients with sepsis.


   Methods Top


Patient selection

A total of 108 patients hospitalized in the Intensive Care Unit (ICU) of our hospital from January 2016 to January 2019 and diagnosed with sepsis were selected as the subjects, and 30 healthy people receiving physical examination during the same time period were enrolled as the controls. Sepsis was diagnosed by reference to the diagnostic criteria formulated by the 2001 International Sepsis Definitions Conference.[6] This study conformed to the medical ethical standards and was approved by the Ethics Committee of our hospital, and all the subjects or their families signed the informed consent.

Laboratory measurements

Blood samples were extracted from septic patients within 24 hours after ICU admission. Subsequently, the plasma was isolated by centrifugation at 4°C and 2,500 g for 15 minutes and then stored at −80°C until detection. The detection reagent for serum cystatin C was provided by Dabe Behring (Germany), enzyme-linked immunosorbent assay (ELISA) was performed to detect and quantify cystatin C, C-reactive protein (CRP), and procalcitonin (PCT) in accordance with the manufacturer's protocols.

Statistical analysis

SPSS 19.0 software was employed for statistical analysis. Pearson's χ2 test was used for categorical data. Continuous variables were expressed as median (25th–75th percentiles) and analyzed by Mann–Whitney U test. Survival analysis was carried out using the Kaplan–Meier method and log-rank (Mantel–Cox) test. Spearman correlation analysis was used to examine the correlations between serum cystatin C concentration and other parameters. P < 0.05 suggested significant differences.


   Results Top


Baseline characteristics of sepsis patients

The comparisons of general data among different groups are shown in [Table 1]. There were no statistically significant differences in the gender, age, and infection site among groups (P > 0.05). The intergroup comparisons manifested that Sequential Organ Failure Assessment (SOFA) score, serum CRP, PCT, and creatinine exhibited statistically significant differences among the three groups (P < 0.05). Moreover, sepsis group had the lowest SOFA score and levels of CRP and PCT, while septic shock group had the highest levels of those indexes (P < 0.05).
Table 1: Characteristics of the study subjects

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The serum cystatin C level was elevated in sepsis patients

The concentration of serum cystatin C in healthy controls and patients with sepsis is shown in [Figure 1]a. The level of cystatin C was increased notably in the patients with sepsis compared with that in healthy controls [1.23 (0.82–1.68) mg/L vs. 0.48 (0.31–0.67) mg/L] (P < 0.05).
Figure 1: Cystatin C levels in septic patients and healthy controls. (a) Serum Cystatin C levels are higher in septic patients than in healthy controls (P < 0.05). (b) Serum Cystatin C levels are related to the severity of sepsis. (c) Serum Cystatin C levels are higher in nonsurvivors than in survivors (P < 0.05). *P < 0.05

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Elevated serum cystatin C was related to the severity of sepsis

As shown in [Figure 1]b, the level of cystatin C was 0.8 (0.64–0.98) mg/L, 1.24 (0.93–1.53) mg/L, and 1.8 (1.59–2.1) mg/L in sepsis group, severe sepsis group, and septic shock group, respectively (P < 0.05).

Correlations of serum cystatin C with other quantitative indicators in patients with sepsis

In order to investigate the correlations of cystatin C with other molecular indexes in the serum of sepsis patients, Spearman correlation analysis was performed. The results demonstrated that the expression level of serum cystatin C was distinctly correlated with the SOFA score (r = 0.856, P < 0.01), serum creatinine (r = 0.81, P < 0.01), CRP (r = 0.782, P < 0.01), and PCT (r = 0.794, P < 0.01) in patients [Figure 2].
Figure 2: The increased Cystatin C is positively associated with SOFA score, CRP, Creatinine, and PCT level in patients with sepsis

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Relationship between serum cystatin C level and patient's outcome

The survival status within 30 days was further recorded. Forty-one patients died within 30 days and 67 patients survived. There were 31 cases of survival and 9 cases of death in sepsis group, 24 cases of survival and 12 cases of death in severe sepsis group, and 12 cases of survival and 20 cases of death in septic shock group. The results confirmed that the death rate of the patients rose along with the aggravation of sepsis (P < 0.05). We also find that the death group had a higher level of cystatin C than survival group [1.0 (0.76–1.5) mg/L vs. 1.5 (1.2–2.0) mg/L] (P < 0.05) [Figure 1]c. Subsequently, multivariate logistic regression model was applied to assess the clinical value of cystatin C in evaluating the 30-day mortality. The area under curve (AUC) of cystatin C level for predicting 30-day mortality rate of sepsis patients was 0.765 [95% confidence interval (CI): 0.663–0.848] [Figure 3]a. With 1.13 mg/L as the cutoff level, the sensitivity of serum cystatin C was 80.6% and its specificity was 56.9%. The Kaplan–Meier survival curve manifested that the 30-day mortality rate of sepsis patients with a cystatin C level >1.13 mg/L was higher than those with a cystatin C level ≤1.13 mg/L (P < 0.05) [Figure 3]b.
Figure 3: Relationship between serum cystatin C level and patient's outcome. (a) Receiver operating characteristic curve for Cystatin C as a predictor of 30-day survival in patients with sepsis. (b) Kaplan–Meier survival curves show that patients with a cystatin C level >1.13 mg/L has an increased mortality compared with patients with a cystatin C level ≤1.13 mg/L

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   Discussion Top


Currently, the diagnosis of sepsis primarily depends on the detection of pathogenic microorganisms, but conventional pathogenic microorganism detection consumes much time and produces a low positive rate. The percentage of neutrophils, white blood cell count, CRP, and PCT are traditional inflammatory indexes, but they lack certain specificity in diagnosing sepsis.[7]

As a cysteine proteinase inhibitor, cystatin C participates in such processes as extracellular matrix degradation, cell apoptosis, and inflammatory reaction.[8] Powell reported that elevated cystatin C is associated with the increased long-term incidence rate of community-acquired sepsis,[9] suggesting that cystatin C plays a definite role in the occurrence and development of sepsis.

In this study, we found the level of serum cystatin C in the patients with sepsis was remarkably higher than that in healthy controls, implying the serum cystatin C can be taken as a new indicator for sepsis diagnosis. Furthermore, the cystatin C level was raised gradually in sepsis group, severe sepsis group, and septic shock group. The SOFA is a scoring method utilized to reflect the severity of disease in critically ill patients.[10] Through analyzing the relation between cystatin C level and SOFA score, the cystatin C level was positively correlated with the SOFA score. The above results illustrate that the sepsis patients with a higher cystatin C level may have a severer disease, suggesting that cystatin C can serve as a potential index for the judgment of severity of sepsis.

According to previous studies, relatively high levels of CRP, PCT, and creatinine are detected in the serum of sepsis patients, which indicate poor prognosis.[7],[11],[12] Similar conclusion can also be made from this study. It was discovered in correlation analysis that the cystatin C level had positive correlations with CRP, PCT, and creatinine levels. All those results suggest that there may be certain interactions among cystatin C, CRP, and PCT in a sepsis-induced inflammatory environment, which jointly promote the development of sepsis. The cystatin C level was increased distinctly in death group in comparison with that in the survival group. Moreover, the analysis results of ROC curves displayed that the AUC of cystatin C for predicting the 30-day mortality rate of sepsis patients was 0.765, elucidating that the cystatin C level possesses a favorable application value in prognosis assessment of sepsis patients. It was also manifested in survival analysis that the sepsis patients with a high cystatin C level exhibited a lower 30-day survival rate, elucidating that cystatin C is closely correlated with the prognosis of sepsis patients. In conclusion, the cystatin C level is raised prominently in patients with sepsis, and its elevation is related to the severity of the disease and obviously associated with patient's prognosis at the same time.

Acknowledgment

The authors thank all the participants for their cooperation in this study.

Declaration of patient consent

This study conformed to the medical ethical standards and was approved by the Ethics Committee of our hospital, and all the subjects or their families signed the informed consent.

Financial support and sponsorship

Nil.

Conflict of interest

There are no conflicts of interest.



 
   References Top

1.
Vincent JL, Rello J, Marshall J, Silva E, Anzueto A, Martin CD, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA 2009;302:2323-9.  Back to cited text no. 1
    
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Gotts JE, Matthay MA. Sepsis: Pathophysiology and clinical management. BMJ 2016;353:i1585.  Back to cited text no. 2
    
3.
Abrahamson M, Alvarez-Fernandez M, Nathanson CM. Cystatins. Biochem Soc Symp 2003:179-99. doi: 10.1042/bss0700179.  Back to cited text no. 3
    
4.
Bilgili B, Haliloglu M and Cinel I. Sepsis and Acute Kidney Injury. Turk J Anaesthesiol Reanim 2014;42:294-301.  Back to cited text no. 4
    
5.
Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, Morgera S, et al. Acute renal failure in critically ill patients: A multinational, multicenter study. JAMA 2005;294:813-8.  Back to cited text no. 5
    
6.
Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions conference. Crit Care Med 2003;31:1250-6.  Back to cited text no. 6
    
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Opal SM, Wittebole X. Biomarkers of infection and sepsis. Crit Care Clin 2020;36:11-22.  Back to cited text no. 7
    
8.
Magister S, Kos J. Cystatins in immune system. J Cancer 2013;4:45-56.  Back to cited text no. 8
    
9.
Powell TC, Donnelly JP, Gutierrez OM, Griffin RL, Safford MM, Wang HE. Cystatin C and long term risk of community-acquired sepsis: A population-based cohort study. BMC Nephrol 2015;16:61.  Back to cited text no. 9
    
10.
Lambden S, Laterre PF, Levy MM, Francois B. The SOFA score-development, utility and challenges of accurate assessment in clinical trials. Crit Care 2019;23:374.  Back to cited text no. 10
    
11.
Mustafic S, Brkic S, Prnjavorac B, Sinanovic A, Porobic JH, Salkic S. Diagnostic and prognostic value of procalcitonin in patients with sepsis. Med Glas (Zenica) 2018;15:93-100.  Back to cited text no. 11
    
12.
Lichtenstern C, Brenner T, Bardenheuer HJ, Weigand MA. Predictors of survival in sepsis: what is the best inflammatory marker to measure? Curr Opin Infect Dis 2012;25:328-36.  Back to cited text no. 12
    

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Correspondence Address:
Jilu Ye,
Department of Critical Care Medicine, Taizhou People's Hospital, Taizhou, Jiangsu
China
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpm.ijpm_804_21



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