Cystatin C is a moderate predictor of acute kidney injury in the early stage of traumatic hemorrhagic shock

Introduction

Acute kidney injury (AKI) is a common complication in trauma due to hemorrhage. Despite advances in the provision of hospital emergency procedures, the incidence of AKI is increasing and remains an independent predictor of morbidity and mortality (1–3). An impediment toward improving outcomes has been the continued reliance on outdated and unreliable markers, and there has long been a requirement for a marker that accurately responds to changes in glomerular function

Cystatin C (CysC) is a 13-kDa endogenous cysteine proteinase inhibitor that plays a major role in the intracellular catabolism of various peptides and proteins (4). CysC is synthesized at a relatively constant rate by all nucleated cells in the human body, and is then released into the plasma. In excess of 99% of CysC undergoes filtration by the glomeruli, prior to being reabsorbed by proximal renal tubular epithelial cells and catabolized (5). Levels of CysC can therefore be used to measure glomerular function. Furthermore, since an increased presence of CysC in the urine may indicate damage to the tubular epithelium, the protein has been proposed as an additional urine biomarker for AKI (6).

Estimates for the glomerular filtration rate (GFR) based on measurements of CysC have been suggested to be superior to those based on serum creatinine (SCr) in selected patient populations, such as the elderly and children, as well as transplant, cirrhotic and hypertensive patients (7–10); however, the results in cardiac surgery and critically ill patients are inconclusive (11–15). Several studies have also shown that serum CysC has a similar, and not necessarily superior, value to SCr for the detection of AKI in the early stage of the disease. Patients with traumatic hemorrhagic shock are highly susceptible to the development of AKI, but little data are available regarding the changes in CysC in patients with traumatic hemorrhagic shock. The aim of the present study, therefore, was to investigate whether CysC has a higher value than SCr and urea for use in monitoring glomerular function in traumatic hemorrhagic shock.

Patients and methods

Subject population

For the experimental group, diagnostic serum samples were obtained from 57 patients who were diagnosed with traumatic hemorrhagic shock in the Emergency Center of the First Affiliated Hospital of Xinjiang Medical University (Ürümqi, China). All patients admitted to the Emergency Center between July 1, 2012 and July 1, 2013 were included in the cohort, which comprised 41 men and 16 women, aged 34.49±17.28 years. A total of 57 normal serum samples were randomly collected from individuals during the same period to form a control group. The control group also consisted of 41 men and 16 women, aged 36.24±15.22 years. All of the patients and volunteers provided written informed consent, and the study was approved by the University and Institutional Review Board (First Affiliated Hospital of Xinjiang Medical University). No significant differences in gender and age were found between the groups. The initial values of CysC, SCr and urea in the patients with trauma and normal subjects were measured.

Definitions

For inclusion in the experimental group, patients had to exhibit at least one of the following injuries: Fracture to the pelvis, two or more long bones or multiple ribs; pulmonary contusion; or major blunt or penetrating trauma to the extremities or torso (16). In addition, patients had to have two systolic blood pressure measurements of <90 mmHg or a base deficit of ≥6 mEq/l within 60 min of arrival at the Emergency Center. All of the samples were collected within the first 8 h after trauma. Patients who succumbed prior to reaching the Emergency Center were excluded from the study.

Normal subjects were defined as those without the following conditions: High blood pressure; diabetes; liver, kidney, heart and infectious diseases; acute infection within the past month; and any malignancy. AKI was defined as an SCr increase of ≥50% or ≥27 mmol/l within 48 h. SCr was measured using the isotope dilution mass spectrometry traceable enzymatic method (Roche Diagnostics, Mannheim, Germany), urea was measured using an enzymatic kit (Roche) and CysC was measured by nephrometric assay (Dade Behring, Pittsburgh, PA, USA) according to the manufacturer's instructions.

Statistical analysis

Data are expressed as the mean ± standard deviation and were analyzed using SPSS 17.0 statistical software (SPSS, Inc., Chicago, IL, USA). Comparisons between groups were made using the t-test or one-way analysis of variance for continuous variables and either the Fisher's exact or χ2 test for categorical variables. Correlation analysis for quantitative data was performed using Pearson's test. To investigate the diagnostic value of serum CysC, SCr and urea as predictors of AKI, receiver operating characteristic (ROC) curve analysis was performed; these data are expressed as the area under the curve (AUC) and 95% confidence interval (CI). Multivariate logistic regression analysis was used to investigate the association between these values and mortality. P<0.05 was considered to indicate a statistically significant difference.

Results

Characteristics of the study subjects

Table I shows the characteristics of the experimental group subjects. The mean CysC value of the female patients was lower compared with the male patients (0.96±0.22 vs. 1.16±0.39 mg/l, respectively), but no significant difference was found (P>0.05). The CysC level was not significantly affected by age, mechanism of injury or time between injury and arrival at the Emergency Center.

Table I. Characteristics of the study subjects.

Table I.

Characteristics of the study subjects.

Clinical parameter	N	CysC (mg/l)	P-value
Gender			0.066
Male	41	1.16±0.39
Female	16	0.96±0.22
Age (years)			0.110
0 to <20	10	1.04±0.23
20 to <40	23	0.97±0.24
40 to <60	20	1.26±0.48
≥60	4	1.27±0.33
Mechanism of injury			0.865
Blunt	41	1.09±0.38
Penetrating	6	1.17±0.35
Both	10	1.12±0.34
Time between injury and arrival (h)			0.623
0 to <5	28	1.07±0.38
5–8	29	1.13±0.35

The CysC level of the patients with traumatic hemorrhagic shock was significantly higher than that of the normal subjects (1.10±0.36 vs. 0.91±0.34 mg/l). The SCr and urea levels in the experimental group were also significantly increased compared with those in the control group (Table II).

Table II. Comparative analysis of levels of CysC, SCr and urea between patients with traumatic hemorrhagic shock and normal subjects.

Table II.

Comparative analysis of levels of CysC, SCr and urea between patients with traumatic hemorrhagic shock and normal subjects.

Parameter	Experimental group	Control group	P-value
CysC (mg/l)	1.10±0.36	0.91±0.34	0.004
SCr (µmol/l)	81.93±41.35	58.15±16.13	<0.001
Urea (mmol/l)	5.06±1.95	3.89±1.07	<0.001

[i] CysC, cystatin C; SCr, serum creatinine.

Association between AKI and SCr, serum CysC and urea

A total of 18 of the 57 patients with traumatic hemorrhagic shock enrolled in the study had AKI (SCr increase of ≥50% or ≥27 mmol/l within 48 h). Fourteen of these 18 patients with AKI had elevated SCr concentrations in the first 6 h of trauma, whereas 13 had elevated serum CysC levels at that time. Only 10 of the patients had elevated urea levels.

Nonparametric ROC plots of the sensitivity and specificity of SCr, CysC and urea for the detection of AKI are shown in Fig. 1. The AUCs for SCr, CysC and urea were 0.901 (95% CI, 0.791–1.000), 0.728 (95% CI, 0.570–0.886) and 0.709 (95% CI, 0.552–0.865), respectively (Table III and Fig. 1).

Figure 1. Receiver operating characteristic curve of CysC, SCr and urea. The area under the curve for the three indicators was as follows: SCr, 0.901 (95% CI, 0.791–1.000); CysC, 0.728 (95% CI, 0.570–0.886); and urea, 0.709 (95% CI, 0.552–0.865). CysC, cystatin C; SCr, serum creatinine; CI, confidence interval.

Table III. Area under the curve values for CysC, SCr and urea.

Table III.

Area under the curve values for CysC, SCr and urea.

Variable	Area	P-value	95% CI
CysC	0.728	0.006	0.570–0.886
SCr	0.901	<0.001	0.791–1.000
Urea	0.709	0.012	0.552–0.865

[i] CysC, cystatin C; SCr, serum creatinine; CI, confidence interval.

Correlation analysis for serum indicators

Pearson correlation analysis was used to evaluate the correlations among the quantitative data. A significant correlation was found between any two of CysC, SCr and urea (P<0.01; Table IV).

Table IV. Pearson correlation analysis of CysC, SCr and urea.

Table IV.

Pearson correlation analysis of CysC, SCr and urea.

Parameter	CysC	SCr	Urea
CysC
Pearson correlation	1.000	0.457	0.369
P-value		0.000a	0.005a
SCr
Pearson correlation	0.457	1.000	0.439
P-value	0.000a		0.001a
Urea
Pearson correlation	0.369	0.439	1.000
P-value	0.005a	0.001a

a P<0.01. CysC, cystatin C; SCr, serum creatinine.

Association between serum indicators and mortality

Six of the 57 patients enrolled in the study succumbed. Using multivariate logistic regression analysis, the association between mortality and the levels of CysC, SCr and urea was determined in the study population. The three variables were excluded from the multivariate model, and no significant correlation was found between mortality and the levels of CysC, SCr and urea.

Discussion

AKI is commonly encountered in cases of traumatic hemorrhagic shock. The development of AKI is associated with poorer clinical outcomes, including a prolonged period of hospitalization, a dependence upon renal replacement therapy, the development of chronic kidney disease and an increased risk of mortality (2,3,16).

Traditionally, the diagnosis of AKI has been dependent upon the use of surrogate markers to detect abnormalities in kidney function, such as elevations in SCr or urea. Although considerable research has been performed in this area, the diagnosis of AKI still relies on the same surrogates of kidney function, which often are poor markers of early kidney injury; therefore, the identification of novel kidney-specific biomarkers for the early detection of AKI and kidney dysfunction is considered to be a priority.

CysC is easy to measure and has been regarded as an ideal marker of kidney function (17). Data suggest that CysC is modified by gender, age, muscle mass, obesity, smoking status, thyroid function, inflammation and malignancy (18). In the present study, the levels of CysC detected were highest in male patients and patients aged >40 years; however, the level of CysC was not significantly associated with gender, age, mechanism of injury or time between injury and arrival at the Emergency Center in the patients with traumatic hemorrhagic shock.

Normal serum samples, collected during the same period as that during which the patient samples were collected, were used to form the control group; the two groups were matched in terms of gender and age. The early stage of traumatic hemorrhagic shock is associated with a decline in kidney function and, in the present study, it was found that the levels of CysC, SCr and urea in the patients with traumatic hemorrhagic shock were significantly higher than those in the normal subjects.

The GFR in individuals suffering from critical trauma can change rapidly, and changes in the SCr can be apparent for several days until the stabilization phase is reached (19). In the present study, 18 out of the 57 (31.6%) enrolled subjects developed AKI and exhibited high SCr levels within 48 h. This result was similar to findings in other studies (20,21). The diagnostic utility of CysC (AUC, 0.728) observed in the present study was similar to that of urea (AUC, 0.709); however, SCr (AUC, 0.901) remained the most suitable marker for the prediction of AKI. Although previous reports have suggested that CysC represents a better marker than SCr in several fields, the present findings have shown the diagnostic utility of CysC to be lower than that of SCr in the early stage of traumatic hemorrhagic shock.

A strong correlation between any two of CysC, SCr and urea was found in this study. This result was similar to findings in other studies (22–24). None of the serum indicators, however, showed a significant correlation with mortality. Previous reports have found that approximately one-third of patients with traumatic hemorrhagic shock develop AKI (25–27). Hospital care should be adjusted accordingly, but the incidence of AKI cannot be use to predict mortality in cases of traumatic hemorrhagic shock.

In conclusion, the present data indicate that CysC levels are increased significantly in the early stage of traumatic hemorrhagic shock. CysC can be used as a marker to predict AKI, but the diagnostic utility of CysC remains lower than that of SCr in the early stage of traumatic hemorrhagic shock.

References