Next Article in Journal
Electromyographic Analysis of Shoulder Neuromuscular Activity in Women Following Breast Cancer Treatment: A Cross-Sectional Descriptive Study
Previous Article in Journal
The Enemy Which Sealed the World: Effects of COVID-19 Diffusion on the Psychological State of the Italian Population
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JCM
Volume 9
Issue 6
10.3390/jcm9061803
jcm-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

High Preoperative Serum Syndecan-1, a Marker of Endothelial Glycocalyx Degradation, and Severe Acute Kidney Injury after Valvular Heart Surgery

by
Hye-Bin Kim
1,
Sarah Soh
1,
Young-Lan Kwak
1,
Jae Chan Bae
2,
Sang Hwa Kang
3 and
Jong Wook Song
1,*
1
Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul 03722, Korea
2
Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul 03722, Korea
3
Department of Anesthesiology and Pain Medicine, National Health Insurance Service Ilsan Hospital, Goyang 10444, Korea
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2020, 9(6), 1803; https://doi.org/10.3390/jcm9061803
Submission received: 2 May 2020 / Revised: 6 June 2020 / Accepted: 8 June 2020 / Published: 10 June 2020
(This article belongs to the Section Anesthesiology)
Browse Figures
Versions Notes

Abstract

:
Degradation of endothelial glycocalyx (EG) is associated with inflammation and endothelial dysfunction, which may contribute to the development of acute kidney injury (AKI). We investigated the association between a marker of EG degradation and AKI after valvular heart surgery. Serum syndecan-1 concentrations were measured at induction of anesthesia and discontinuation of cardiopulmonary bypass in 250 patients. Severe AKI was defined as Kidney Disease: Improving Global Outcomes Criteria Stage 2 or 3. Severe AKI occurred in 13 patients (5%). Receiver operating characteristic analysis of preoperative syndecan-1 to predict severe AKI showed area under curve of 0.714 (95% confidence interval (CI), 0.575–0.853; p = 0.009). The optimal cut-off value was 90 ng/mL, with a sensitivity of 61.5% and specificity of 78.5%. In multivariable analysis, both preoperative syndecan-1 ≥ 90 ng/mL and Cleveland Clinic Foundation score independently predicted severe AKI. Severe tricuspid regurgitation was more frequent (42.4% vs. 17.8%, p < 0.001), and baseline right ventricular systolic pressure (41 (33–51) mmHg vs. 33 (27–43) mmHg, p = 0.001) and TNF-α (1.85 (1.37–2.43) pg/mL vs. 1.45 (1.14–1.92) pg/mL, p <0.001) were higher in patients with high preoperative syndecan-1. Patients with high preoperative syndecan-1 had longer hospital stay (16 (12–24) days vs. 13 (11–17) days, p = 0.001). In conclusion, a high preoperative syndecan-1 concentration greater than 90 ng/mL was able to predict severe AKI after valvular heart surgery and was associated with prolonged hospitalization.

1. Introduction

Acute kidney injury (AKI) is a common complication after cardiac surgery, with an incidence of 5–42% depending on the definition of AKI, extent of the procedure, and patients’ characteristics [1]. AKI after cardiac surgery, including a modest elevation in serum creatinine, is independently associated with increased mortality and morbidity [2]. However, the prognosis of severe AKI is even worse, as mortality increases sharply with more advanced stages of AKI [3]. Furthermore, AKI severity is associated with incremental risk of progression to chronic kidney disease [4]. As there are no proven remedies to treat AKI, strategies to prevent it and alleviate its severity are crucial. Preoperative risk stratification and early detection of injury may aid in the early implementation of such strategies and optimization of patient care.
Endothelial glycocalyx (EG) is a gel-like structure covering the luminal surface of the endothelium. It consists of various glycosaminoglycans and associated plasma membrane-bound proteoglycans [5]. EG is involved in essential endothelial function and vascular homeostasis, including the regulation of vascular permeability, mechanotransduction of blood flow-induced shear stress, and interactions between leukocytes and endothelium [6]. EG is degraded under oxidative stress, ischemia-reperfusion, and inflammation, resulting in increased vascular permeability and interstitial edema, an exaggerated inflammatory response involving the upregulation of various cell membrane adhesion molecules and leukocyte-endothelial cell interactions [7,8]. These changes are implicated in the development of AKI in the context of endothelial dysfunction [9].
EG degradation has been observed in critically ill patients and is associated with poor outcomes [10,11,12,13]. It has also been observed in cardiac and major vascular surgery as a perioperative increase in serum concentrations of EG constituents, e.g., syndecan-1 [14,15,16,17,18]. However, evidence regarding its impact on perioperative outcomes of cardiac surgical patients is limited. Because the conditions that induce EG breakdown and its pathophysiologic consequences are closely related to cardiac surgery-associated AKI, we hypothesized that perioperative EG degradation may be associated with AKI development after valvular heart surgery. Thus, we aimed to investigate the association between syndecan-1, a marker of EG degradation, and AKI in patients undergoing valvular heart surgery.

2. Materials and Methods

2.1. Participants

This prospective, observational study was conducted at Severance Cardiovascular Hospital, Yonsei University Health System, Seoul, Republic of Korea, approved by our institutional review board (IRB no.: 4-2017-0340) and registered at ClinicalTrials.gov (NCT03197051) before recruitment started. A total of 250 patients older than 20 years scheduled for elective valvular heart surgery between June 2017 and July 2018 were enrolled after obtaining written informed consent. Exclusion criteria were minimally invasive surgery, chronic kidney disease stage ≥ 4 (estimated glomerular filtration rate < 30 mL/min/1.73 m2) or preoperative AKI, infective endocarditis, malignancies, or preoperative mechanical circulatory support.

2.2. Protocol

All patients received standardized perioperative management according to institutional guidelines. Anesthesia was induced by intravenous midazolam (0.05–0.07 mg/kg) and sufentanil (1.5–2 μg/kg) and maintained with inhaled sevoflurane and continuous infusion of sufentanil. Heparin was administered at an initial dosage of 300 IU/kg to achieve an activated clotting time above 480 s. The cardiopulmonary bypass (CPB) circuit was primed with a 1.6-L priming solution consisting of 100 mL of 20% albumin, 20% mannitol (0.5 g/kg), sodium bicarbonate (20 mEq), heparin (2000 IU), and plasmalyte (Plasma Solution A Inj.; CJ Pharma, Seoul, Korea). A non-pulsatile pump flow rate was maintained at 2.0–2.4 L/min/m2 under mild hypothermia (32–33 °C) using alpha-stat management. After weaning from CPB, heparin was antagonized by protamine sulphate (3 mg/kg). All patients were transferred to the intensive care unit (ICU) postoperatively.
Norepinephrine (up to 0.5 μg/kg/min) and vasopressin (up to 4 IU/h) were used as primary and second-line vasopressors, respectively. Milrinone was administered to treat ventricular systolic dysfunction. Hematocrit levels were maintained above 20% during CPB and 25% before and after CPB with the transfusion of packed red blood cells and ultrafiltration/reinfusion of intraoperatively salvaged blood during CPB. For fluid resuscitation, plasmalyte and synthetic balanced colloid solution (6% hydroxyethyl starch 130/0.4, Volulyte; Fresenius Kabi, Seoul, Korea; up to a maximal dose of 20 mL/kg/d) were used. Allogeneic plasma products including fresh frozen plasma, platelet concentrate, and cryoprecipitate were transfused at the discretion of the attending physician based on thromboelastography, prothrombin time, and platelet count.

2.3. Measurements

Arterial blood samples were taken at the induction of anesthesia and after the reversal of heparinization with protamine, centrifuged at 1000 × g for 15 min, and stored at −80 °C for subsequent analysis. Enzyme-linked immunosorbent assay was used to measure the serum concentrations of syndecan-1 (Abcam, Cambridge, MA, USA, Cat No. ab46506, sensitivity: 4.94 ng/mL), heparan sulfate (MyBioSource, San Diego, CA, USA, MBS267373), tumor necrosis factor-α (TNF-α; R&D Systems, Minneapolis, MN, USA, HSTA00E), and interleukin-6 (IL-6; R&D Systems, HS600B).
Serum creatinine concentrations were assessed 1 day before surgery and postoperatively at 6, 24, and 48 h. Additional measurements were performed at the discretion of the attending physician, with values measured within 7 postoperative days used for the diagnosis and staging of AKI. C-reactive protein (CRP) and hematologic variables including leukocyte count, hematocrit, and platelet count were assessed 1 day before surgery and postoperatively at 6, 24, and 48 h. Perioperative fluid balance, transfusion requirements, and vasopressor and inotropic drug requirements were recorded for 48 h postoperatively. Hemodynamic parameters, including mean arterial pressure, cardiac index, heart rate, central venous pressure (CVP), mean pulmonary arterial pressure, and mixed venous oxygen saturation, were recorded after induction of anesthesia, at the discontinuation of CPB, and postoperatively at 6 and 24 h.
Postoperative 30-day morbidity end points, including mortality, permanent stroke, reoperation due to bleeding, deep sternal wound infection, prolonged mechanical ventilation > 24 h, and length of intensive care unit (ICU) and hospital stays, were also assessed.
The primary endpoint was the association between perioperative serum syndecan-1 concentration, a marker of EG degradation, and the incidence of AKI after valvular heart surgery. Kidney Disease: Improving Global Outcomes (KDIGO) criteria was used to define AKI (Stages 1–3) and severe AKI (Stages 2–3), as follows: Stage 1, 1.5–1.9 times baseline or ≥ 0.3 mg/dL increase in serum creatinine or urine output < 0.5 mL/kg/h for 6–12 h; Stage 2, serum creatinine 2.0–2.9 times baseline or urine output < 0.5 mL/kg/h for ≥ 12 h; Stage 3, serum creatinine 3.0 times baseline or increase in serum creatinine to ≥ 4.0 mg/dL or initiation of renal replacement therapy or urine output <0.3 mL/kg/h for ≥24 h or anuria for ≥12 h.

2.4. Statistical Analysis

We assumed that the incidence of severe AKI would be 10% and a detectable odds ratio (OR) corresponding to an increase of one standard deviation from the mean value of syndecan-1 would be 2.0. With a Type I error of 0.05 and power of 95%, 237 subjects were required. Considering the dropout rate, we decided to enroll 250 patients.
Continuous variables are shown as mean (standard deviation) or median with interquartile range (25th–75th percentile). Categorical variables are expressed as number of patients and percentages. The association between serum syndecan-1 and severe AKI was analyzed by logistic regression analysis, and the optimal cut-off value for predicting severe AKI was assessed by receiver operating characteristic (ROC) analysis. Multivariable analysis was performed by considering the serum syndecan-1 concentration along with the Cleveland Clinic Foundation score, which is a previously acknowledged clinical prediction model for acute renal failure after cardiac surgery [19]. Continuous variables were compared using independent Student’s t or Mann–Whitney U tests depending on the results of Shapiro–Wilk tests for normality, and categorical variables were compared using chi-square or Fisher’s exact tests as appropriate. Repeated measures analysis of variance (ANOVA) or Friedman’s test was used to analyze repeatedly measured variables, then p values of post hoc tests were adjusted with the Bonferroni’s method. SPSS version 23.0 (SPSS Inc., Chicago, IL, USA) and NCSS 12 (NCSS LLC, Kaysville, UT, USA) were used for analysis. Differences with p < 0.05 were considered statistically significant except comparisons between high vs. low syndecan-1 groups, in which p < 0.01 were considered statistically significant.

3. Results

3.1. Prediction of Postoperative Severe AKI

AKI and severe AKI occurred in 47 (18.8%) and 13 (5.2%) patients, respectively. The median serum syndecan-1 concentration was 51 (34–88) ng/mL at induction and increased to 241 (140–423) ng/mL after CPB (p < 0.001; Figure 1A). The median serum heparan sulfate concentration was 39.1 (16.1–116.1) ng/mL at induction and decreased to 8.3 (1.5–21.6) ng/mL after CPB (p < 0.001); Figure 1B). In univariable logistic regression, neither preoperative nor post-CPB syndecan-1 concentration was associated with the incidence of AKI (preoperative; OR, 1.002; 95% confidence interval (CI), 0.999–1.004; p = 0.290, post-CPB; OR, 1.000; 95% CI, 0.557–1.392; p = 0.587). Preoperative syndecan-1 concentration showed a non-significant association with the incidence of severe AKI (OR, 1.003; 95% confidence interval (CI), 1.000–1.006; p = 0.065), and post-CPB syndecan-1 concentration was significantly associated with the incidence of severe AKI (OR, 1.002; 95% CI, 1.000–1.005; p = 0.024). The fold increase of syndecan-1 was not associated with the incidence of severe AKI (OR, 0.934; 95% CI, 0.815–1.070; p = 0.323). The areas under the ROC curve (AUCs) of the preoperative and post-CPB syndecan-1 concentrations to predict severe AKI were 0.714 (95% CI, 0.575–0.853; p = 0.009) and 0.653 (95% CI, 0.497–0.809; p = 0.063), respectively (Figure 2). The optimal cut-off value of preoperative syndecan-1 for the prediction of severe AKI was 90 ng/mL, with a sensitivity of 61.5% and specificity of 78.5%. The Cleveland Clinic Foundation score for the prediction of acute renal failure after cardiac surgery [19] had an AUC of 0.714 (95% CI, 0.560–0.869; p = 0.009) in this study population (Figure 2). Multivariable logistic regression showed that both preoperative syndecan-1 concentration greater than 90 ng/mL (OR, 4.231; 95% CI, 1.249–14.33; p = 0.020) and Cleveland Clinic Foundation score (OR, 2.011; 95% CI, 1.202–3.364; p = 0.008) were independent predictors of severe AKI. Inclusion of these two variables in the prediction model yielded an AUC of 0.807 (95% CI, 0.690–0.924; p < 0.001), which was higher than the AUC of the Cleveland Clinic Foundation score alone, but not significantly so (p = 0.181; Figure 2). The preoperative syndecan-1 greater than 90 ng/mL also remained an independent predictor (OR, 4.650; 95% CI, 1.402–15.43; p = 0.012) after multivariable logistic regression analysis with the preoperative serum creatinine (OR, 6.951; 95% CI, 0.833–58.27; p = 0.080).

3.2. Comparison Between Low and High Preoperative Syndecan-1 Groups

According to ROC analysis, patients were divided into low (<90 ng/mL) and high (≥90 ng/mL) preoperative syndecan-1 groups. The preoperative characteristics of patients with low and high preoperative syndecan-1 concentrations are shown in Table 1. The proportion of patients with elevated preoperative serum creatinine was higher in the high syndecan-1 group with a borderline statistical significance (13.6% vs. 3.7%, p = 0.010). In the high syndecan-1 group, severe tricuspid regurgitation (42.4% vs. 17.8%, p < 0.001) was more frequent when compared with the low syndecan-1 group. Patients with high preoperative syndecan-1 had greater preoperative right ventricular systolic pressure than those with low syndecan-1 (41 (33–51) mmHg vs. 33 (27–43) mmHg, p = 0.001).
The overall incidence of AKI was significantly higher in patients with high preoperative syndecan-1 (32.2% vs. 14.7%, p = 0.003). The requirement for postoperative renal replacement therapy was 5.1% vs. 0.0%, high vs. low preoperative syndecan-1, respectively (p = 0.013, Table 2), and the incidence of oliguria was 6.8% vs. 1.5%, high vs. low preoperative syndecan-1, respectively (p = 0.025; Table 2). Changes in serum creatinine concentrations throughout the study period were comparable between groups (p = 0.621; Table 2).
Patients with high preoperative syndecan-1 received more crystalloid fluid (6406 (5248–7554) mL vs. 5791 (4703–5791) mL, p = 0.010) and allogeneic plasma product (260 (0–1280)) mL vs. 0 (0–260) mL, p < 0.001), and had greater urine output (7000 (6165–7650) mL vs. 6175 (5340–7230) mL, p = 0.007), whereas synthetic colloid fluid administration, red blood cell transfusion, vasopressor and inotrope requirements, were not different between the two groups during the perioperative 48 h (Table 3).
Patients with high preoperative syndecan-1 also showed higher syndecan-1 concentrations post-CPB than those with low preoperative syndecan-1 (383 (293–617) ng/mL vs. 198 (120–363) ng/mL, p < 0.001). Preoperative serum concentrations of TNF-α (1.85 (1.37–2.43) pg/mL vs. 1.45 (1.14–1.92) pg/mL, p <0.001) was higher in patients with high preoperative syndecan-1 (Table 4). Hematologic variables including hematocrit and leukocyte and platelet counts were similar between the groups, except the lower preoperative leukocyte count (5228 ± 2061 /μL vs. 6212 ± 1773 /μL, p = 0.004) and platelet count (178 ± 64 × 103/μL vs. 195 ± 63 × 103/μL, p = 0.004) in patients with high preoperative syndecan-1 (Supplementary Table S1). Hemodynamic variables including mean arterial pressure, heart rate, central venous pressure, mean pulmonary arterial pressure and cardiac index were also not different between the groups (Supplementary Table S2).
Patients with high preoperative syndecan-1 had longer hospital stay (16 (12–24) days vs. 13 (11–17) days, p = 0.001) when compared with those with low syndecan-1 (Table 5). Postoperative outcomes including stroke, sternal infections, hemostatic reoperation, mechanical ventilation >24 h, and mortality were comparable between groups (Table 5).

4. Discussion

In this observational study, preoperative syndecan-1 concentration greater than 90 ng/mL predicted severe AKI after valvular heart surgery, independently of a previously acknowledged clinical scoring system. Severe tricuspid regurgitation was more frequent, and baseline right ventricular systolic pressure was significantly greater in patients with high preoperative syndecan-1. Baseline serum inflammatory cytokine TNF-α concentration was also elevated in patients with high preoperative syndecan-1. Postoperatively, preoperative syndecan-1 greater than 90 ng/mL was associated with longer duration of hospital stay.
The pathogenesis of AKI in association with cardiac surgery involves a complex interplay of direct damage, hemodynamics, ischemia-reperfusion, and inflammation [1]. Endothelial damage plays a central role in the development of AKI, leading to disruption of the permeability of the glomerulus and peritubular capillaries, facilitating leukocyte adhesion and migration, intravascular coagulation, platelet aggregation, loss of vasomotor autoregulation, and reduced perfusion [9]. Therefore, the conditions that induce EG degradation and its pathophysiological consequences are closely related to endothelial dysfunction in AKI. Indeed, endothelial injury characterized by EG disruption has been demonstrated in a swine model of CPB-induced AKI [20]. Thus, we initially hypothesized that increased serum markers of EG degradation may be associated with AKI after cardiac surgery.
Although the perioperative degradation of EG in cardiac surgery has been established in a number of studies [14,15,16,17,18], few have investigated its prognostic implications in the context of cardiac surgery-associated AKI. In a study by de Melo Bezerra Cavalcante and colleagues [21], elevated syndecan-1 concentrations in blood collected within 2 h postoperatively were independently associated with KDIGO Stage 2 or 3 AKI in patients undergoing pediatric cardiac surgery. They also showed that addition of syndecan-1 to their clinical AKI risk prediction model, which included age, sex, preoperative renal function, surgical complexity, and use and duration of CPB, improved the predictive performance of the model. However, they did not assess preoperative syndecan-1 concentrations, which may naturally influence its post-CPB concentration considering that it also reflects the degree of inflammatory tone [7,8]. In agreement with that study [21], post-CPB syndecan-1 concentrations were associated with KDIGO Stage 2 or 3 AKI in our study; however, only preoperative syndecan-1 exhibited significant predictive power in the ROC analysis. The fold increase in syndecan-1 also showed no association with AKI. The preoperative and post-CPB syndecan-1 concentrations showed significant correlation (Spearman’s ρ, 0.442; 95% CI, 0.331–0.541; p < 0.001). Therefore, post-CPB increase in syndecan-1 reflects mostly the preoperative state. It is unclear what causes elevation in syndecan-1 concentration even preoperatively and how it is implicated in the development of AKI postoperatively. As degradation of EG occurs under inflammation, high syndecan-1 concentration may reflect more pro-inflammatory condition. Pesonen and colleagues [22] reported that perioperative syndecan-1 concentration was positively correlated with pro-inflammatory cytokines in patients underwent cardiac surgery with CPB. Likewise, TNF-α concentration was elevated preoperatively in patients with high preoperative syndecan-1 and positively correlated with preoperative syndecan-1 (Supplementary Table S3) in our study, implying more pro-inflammatory condition in these patients. Thus, our results suggest that preoperative inflammatory tone as reflected by increased syndecan-1 conveys significant influence on the degree of ensuing post-CPB inflammation that is associated with dismal prognosis. This association also empowers the role of preoperative syndecan-1 in accurate risk stratification.
In addition, high preoperative syndecan-1 may reflect baseline endothelial dysfunction. We found that elevated preoperative serum creatinine was more frequent in patients with high preoperative syndecan-1 with a borderline statistical significance. In congruence with our study, Padberg and colleagues [23] demonstrated that plasma syndecan-1 levels increased across chronic kidney disease stages and were independently associated with renal dysfunction. However, the 24-h clearance of syndecan-1 was not associated with that of creatinine, excluding the possibility that elevations in serum syndecan-1 result from reduced glomerular filtration. Furthermore, they confirmed correlations between elevated syndecan-1 levels and several endothelial activation markers. However, in our study, preoperative syndecan-1 predicted severe AKI independently of the preoperative serum creatinine. Thus, the predictive ability of preoperative syndecan-1 may not be explained by preoperatively impaired kidney function alone.
Systemic elevation of syndecan-1 was also observed in other end-organ damage including lung and liver [24]. Because the serum syndecan-1 is not specifically originated from the kidney vasculature, it may represent endothelial dysfunction and microcirculatory disturbance at an end-organ level in general, and AKI can be regarded as an example of frequently developing, accurately measurable end-organ dysfunction after cardiac surgery.
Our results also showed that severe tricuspid regurgitation was more frequent in patients with high preoperative syndecan-1. Reduced renal perfusion pressure due to severe tricuspid regurgitation may contribute to the deterioration of renal function [25]. The causal relationship between increased EG degradation and severe tricuspid regurgitation has not been verified, but it can be speculated that atrial stretch induces the release of atrial natriuretic peptide (ANP), which is known to cause EG degradation [26]. It may also be speculated that venous congestion resulting in increased capillary pressure leads to microcirculatory EG degradation and endothelial dysfunction. The greater right ventricular systolic pressure in patients with high preoperative syndecan-1 suggest more congestion in those patients.
Notably, unlike in previous studies, heparan sulfate concentrations decreased post-CPB from baseline in our study. The reason for this discrepancy is unclear but may be related to the cross-reactivity of protamine to heparan sulfate and exogenous heparin [27], or kinetics of heparan sulfate released into circulation. Heparan sulfate may be rapidly excreted, or sequestered in other organs, for example liver, as shown in liver transplantation resulting in low serum heparan sulfate post-reperfusion [28]. Considering that syndecan-1 contains chondroitin/dermatan sulfate chains as well, measuring these glycosaminoglycans in addition to heparan sulfate might have given us more insights regarding its unexpected decrease after CPB, which remains to be elucidated through a further study.
Fluid resuscitation is an essential part of anesthesiology practice, and EG is thought to play a central role in maintaining the oncotic pressure gradient between intravascular and interstitial space. In our study, the amounts of allogeneic plasma product transfusion and urine output were greater in patients with high preoperative syndecan-1 concentration. The amount of crystalloid fluid administration was also numerically higher in patients with high preoperative syndecan-1. Considering many possible confounding factors, it is hard to relate these observed differences with perioperative EG degradation or increased vascular permeability, which is beyond the scope of the current study. Moreover, preoperative level of syndecan-1 cannot be a measure of degree of perioperative EG degradation.
This study has several limitations. First, it was a single-center study. However, the incidence of AKI was similar to that in previous studies [29,30]. Second, the degree of EG degradation was assessed by measuring serum concentrations of released EG constituents, including syndecan-1 and heparan sulfate. Serum concentrations of EG constituents have been widely used as markers for EG degradation. However, this method is not without drawbacks, as it represents the balance between the rate of degradation and excretion but does not reflect the rate of EG restoration. Furthermore, fold increase or difference between the measurements are disproportionally influenced by the value of initial measurement. Therefore, increased EG constituent concentrations may not accurately represent current EG dimensions or amount of loss, especially in the course of the ongoing processes of degradation and restoration. Third, the method for serum syndecan-1 measurement is not standardized. Therefore, the absolute values presented in this study are not directly applicable to other studies or clinical practice. Finally, this study is not sufficiently powered for multiple subgroup comparisons. Thus, any differences between the low and high syndecan-1 group is not conclusive and should be viewed as exploratory.

5. Conclusions

In conclusion, a high preoperative syndecan-1 concentration greater than 90 ng/mL was an independent predictor of severe AKI after valvular heart surgery, and was associated with increased preoperative inflammatory tone and prolonged postoperative hospitalization.

Supplementary Materials

The following are available online at https://www.mdpi.com/2077-0383/9/6/1803/s1, Table S1. Hematologic variables, Table S2. Hemodynamic variables, Table S3. Correlations with the preoperative syndecan-1.

Author Contributions

Conceptualization, J.W.S. and H.-B.K.; formal analysis, H.-B.K. and S.S.; investigation, H.-B.K., J.C.B. and S.H.K.; resources, H.-B.K. and S.S.; data curation, J.W.S. and H.-B.K.; writing—original draft preparation, H.-B.K.; writing—review and editing, J.W.S. and Y.-L.K.; supervision, J.W.S. and Y.-L.K.; project administration, J.W.S; funding acquisition, J.W.S. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by a faculty research grant from the Yonsei University College of Medicine (grant number: 6-2018-0002).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Thiele, R.H.; Isbell, J.M.; Rosner, M.H. AKI associated with cardiac surgery. Clin. J. Am. Soc. Nephrol. 2015, 10, 500–514. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Liotta, M.; Olsson, D.; Sartipy, U.; Holzmann, M.J. Minimal changes in postoperative creatinine values and early and late mortality and cardiovascular events after coronary artery bypass grafting. Am. J. Cardiol. 2014, 113, 70–75. [Google Scholar] [CrossRef] [Green Version]
  3. Robert, A.M.; Kramer, R.S.; Dacey, L.J.; Charlesworth, D.C.; Leavitt, B.J.; Helm, R.E.; Hernandez, F.; Sardella, G.L.; Frumiento, C.; Likosky, D.S.; et al. Cardiac surgery-associated acute kidney injury: A comparison of two consensus criteria. Ann. Thorac. Surg. 2010, 90, 1939–1943. [Google Scholar] [CrossRef] [PubMed]
  4. Cho, J.S.; Shim, J.K.; Lee, S.; Song, J.W.; Choi, N.; Lee, S.; Kwak, Y.L. Chronic progression of cardiac surgery associated acute kidney injury: Intermediary role of acute kidney disease. J. Thorac. Cardiovasc. Surg. 2019. [Google Scholar] [CrossRef]
  5. Reitsma, S.; Slaaf, D.W.; Vink, H.; van Zandvoort, M.A.; oude Egbrink, M.G. The endothelial glycocalyx: Composition, functions, and visualization. Pflügers Archiv. Eur. J. Physiol. 2007, 454, 345–359. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Song, J.W.; Zullo, J.; Lipphardt, M.; Dragovich, M.; Zhang, F.X.; Fu, B.; Goligorsky, M.S. Endothelial glycocalyx-the battleground for complications of sepsis and kidney injury. Nephrol. Dial. Transplant. 2018, 33, 203–211. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Kolarova, H.; Ambruzova, B.; Svihalkova Sindlerova, L.; Klinke, A.; Kubala, L. Modulation of endothelial glycocalyx structure under inflammatory conditions. Mediat. Inflamm. 2014, 2014, 694312. [Google Scholar] [CrossRef] [PubMed]
  8. Alphonsus, C.S.; Rodseth, R.N. The endothelial glycocalyx: A review of the vascular barrier. Anaesthesia 2014, 69, 777–784. [Google Scholar] [CrossRef] [PubMed]
  9. Verma, S.K.; Molitoris, B.A. Renal endothelial injury and microvascular dysfunction in acute kidney injury. Semin. Nephrol. 2015, 35, 96–107. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  10. Johansson, P.I.; Stensballe, J.; Rasmussen, L.S.; Ostrowski, S.R. A high admission syndecan-1 level, a marker of endothelial glycocalyx degradation, is associated with inflammation, protein c depletion, fibrinolysis, and increased mortality in trauma patients. Ann. Surg. 2011, 254, 194–200. [Google Scholar] [CrossRef] [PubMed]
  11. Anand, D.; Ray, S.; Srivastava, L.M.; Bhargava, S. Evolution of serum hyaluronan and syndecan levels in prognosis of sepsis patients. Clin. Biochem. 2016, 49, 768–776. [Google Scholar] [CrossRef]
  12. Schmidt, E.P.; Overdier, K.H.; Sun, X.; Lin, L.; Liu, X.; Yang, Y.; Ammons, L.A.; Hiller, T.D.; Suflita, M.A.; Yu, Y.; et al. Urinary glycosaminoglycans predict outcomes in septic shock and acute respiratory distress syndrome. Am. J. Respir. Crit. Care Med. 2016, 194, 439–449. [Google Scholar] [CrossRef] [PubMed]
  13. Nelson, A.; Berkestedt, I.; Schmidtchen, A.; Ljunggren, L.; Bodelsson, M. Increased levels of glycosaminoglycans during septic shock: Relation to mortality and the antibacterial actions of plasma. Shock 2008, 30, 623–627. [Google Scholar] [CrossRef] [PubMed]
  14. Rehm, M.; Bruegger, D.; Christ, F.; Conzen, P.; Thiel, M.; Jacob, M.; Chappell, D.; Stoeckelhuber, M.; Welsch, U.; Reichart, B.; et al. Shedding of the endothelial glycocalyx in patients undergoing major vascular surgery with global and regional ischemia. Circulation 2007, 116, 1896–1906. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Svennevig, K.; Hoel, T.; Thiara, A.; Kolset, S.; Castelheim, A.; Mollnes, T.; Brosstad, F.; Fosse, E.; Svennevig, J. Syndecan-1 plasma levels during coronary artery bypass surgery with and without cardiopulmonary bypass. Perfusion 2008, 23, 165–171. [Google Scholar] [CrossRef] [PubMed]
  16. Bruegger, D.; Rehm, M.; Abicht, J.; Paul, J.O.; Stoeckelhuber, M.; Pfirrmann, M.; Reichart, B.; Becker, B.F.; Christ, F. Shedding of the endothelial glycocalyx during cardiac surgery: On-pump versus off-pump coronary artery bypass graft surgery. J. Thorac. Cardiovasc. Surg. 2009, 138, 1445–1447. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  17. Bruegger, D.; Brettner, F.; Rossberg, I.; Nussbaum, C.; Kowalski, C.; Januszewska, K.; Becker, B.F.; Chappell, D. Acute degradation of the endothelial glycocalyx in infants undergoing cardiac surgical procedures. Ann. Thorac. Surg. 2015, 99, 926–931. [Google Scholar] [CrossRef] [PubMed]
  18. Nussbaum, C.; Haberer, A.; Tiefenthaller, A.; Januszewska, K.; Chappell, D.; Brettner, F.; Mayer, P.; Dalla Pozza, R.; Genzel-Boroviczeny, O. Perturbation of the microvascular glycocalyx and perfusion in infants after cardiopulmonary bypass. J. Thorac. Cardiovasc. Surg. 2015, 150, 1474–1481.e1471. [Google Scholar] [CrossRef] [PubMed]
  19. Thakar, C.V.; Arrigain, S.; Worley, S.; Yared, J.P.; Paganini, E.P. A clinical score to predict acute renal failure after cardiac surgery. J. Am. Soc. Nephrol. 2005, 16, 162–168. [Google Scholar] [CrossRef] [Green Version]
  20. Qureshi, S.H.; Patel, N.N.; Murphy, G.J. Vascular endothelial cell changes in postcardiac surgery acute kidney injury. Am. J. Physiol. Ren. Physiol. 2018, 314, F726–F735. [Google Scholar] [CrossRef]
  21. de Melo Bezerra Cavalcante, C.T.; Castelo Branco, K.M.; Pinto Junior, V.C.; Meneses, G.C.; de Oliveira Neves, F.M.; de Souza, N.M.; Penaforte, K.L.; Martins, A.M.; Liborio, A.B. Syndecan-1 improves severe acute kidney injury prediction after pediatric cardiac surgery. J. Thorac. Cardiovasc. Surg. 2016, 152, 178–186.e172. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Pesonen, E.; Passov, A.; Andersson, S.; Suojaranta, R.; Niemi, T.; Raivio, P.; Salmenpera, M.; Schramko, A. Glycocalyx degradation and inflammation in cardiac surgery. J. Cardiothorac. Vasc. Anesthesia 2019, 33, 341–345. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Padberg, J.S.; Wiesinger, A.; di Marco, G.S.; Reuter, S.; Grabner, A.; Kentrup, D.; Lukasz, A.; Oberleithner, H.; Pavenstadt, H.; Brand, M.; et al. Damage of the endothelial glycocalyx in chronic kidney disease. Atherosclerosis 2014, 234, 335–343. [Google Scholar] [CrossRef]
  24. Murphy, L.S.; Wickersham, N.; McNeil, J.B.; Shaver, C.M.; May, A.K.; Bastarache, J.A.; Ware, L.B. Endothelial glycocalyx degradation is more severe in patients with non-pulmonary sepsis compared to pulmonary sepsis and associates with risk of ards and other organ dysfunction. Ann. Intensive Care 2017, 7, 102. [Google Scholar] [CrossRef] [PubMed]
  25. Maeder, M.T.; Holst, D.P.; Kaye, D.M. Tricuspid regurgitation contributes to renal dysfunction in patients with heart failure. J. Card. Fail. 2008, 14, 824–830. [Google Scholar] [CrossRef] [PubMed]
  26. Bruegger, D.; Jacob, M.; Rehm, M.; Loetsch, M.; Welsch, U.; Conzen, P.; Becker, B.F. Atrial natriuretic peptide induces shedding of endothelial glycocalyx in coronary vascular bed of guinea pig hearts. Am. J. Physiol. Heart Circ. Physiol. 2005, 289, H1993–H1999. [Google Scholar] [CrossRef] [PubMed]
  27. Hubbard, A.R.; Jennings, C.A. Neutralisation of heparan sulphate and low molecular weight heparin by protamine. Thromb. Haemost. 1985, 53, 86–89. [Google Scholar] [CrossRef] [PubMed]
  28. Passov, A.; Schramko, A.; Makisalo, H.; Nordin, A.; Andersson, S.; Pesonen, E.; Ilmakunnas, M. Graft glycocalyx degradation in human liver transplantation. PLoS ONE 2019, 14, e0221010. [Google Scholar] [CrossRef] [PubMed]
  29. Susantitaphong, P.; Cruz, D.N.; Cerda, J.; Abulfaraj, M.; Alqahtani, F.; Koulouridis, I.; Jaber, B.L. World incidence of AKI: A meta-analysis. Clin. J. Am. Soc. Nephrol. 2013, 8, 1482–1493. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  30. Hu, J.; Chen, R.; Liu, S.; Yu, X.; Zou, J.; Ding, X. Global incidence and outcomes of adult patients with acute kidney injury after cardiac surgery: A systematic review and meta-analysis. J. Cardiothorac. Vasc. Anesthesia 2016, 30, 82–89. [Google Scholar] [CrossRef]
Jcm 09 01803 g001 550
Figure 1. Serum concentrations of syndecan-1 (A) and heparan sulfate (B). The samples were drawn at the induction of anesthesia (preoperative) and after the reversal of heparinization with protamine (post-cardiopulmonary bypass (CPB)). Syndecan-1 was increased from its preoperative value whereas heparan sulfate decreased; * p < 0.001 vs. preoperative concentration. Abbreviation: CPB, cardiopulmonary bypass.
Figure 1. Serum concentrations of syndecan-1 (A) and heparan sulfate (B). The samples were drawn at the induction of anesthesia (preoperative) and after the reversal of heparinization with protamine (post-cardiopulmonary bypass (CPB)). Syndecan-1 was increased from its preoperative value whereas heparan sulfate decreased; * p < 0.001 vs. preoperative concentration. Abbreviation: CPB, cardiopulmonary bypass.
Jcm 09 01803 g001
Jcm 09 01803 g002 550
Figure 2. Receiver operating characteristic (ROC) curves for severe acute kidney injury (AKI) with each potential predictors. Blue line: preoperative syndecan-1 concentration (area under the ROC curve (AUC), 0.714; 95% CI, 0.575–0.853; p = 0.009); green line: post-CPB syndecan-1 concentration (AUC, 0.653; 95% CI, 0.497–0.809; p = 0.063); grey line: Cleveland Clinic Foundation score (AUC, 0.714; 95% CI, 0.560–0.869; p = 0.009); red line: Cleveland Clinic Foundation score + preoperative syndecan-1 concentration ≥ 90 ng/mL (AUC, 0.807; 95% CI, 0.690–0.924; p < 0.001). Abbreviations: AKI, acute kidney injury; AUC, area under the ROC curve; CI, confidence interval; CPB, cardiopulmonary bypass.
Figure 2. Receiver operating characteristic (ROC) curves for severe acute kidney injury (AKI) with each potential predictors. Blue line: preoperative syndecan-1 concentration (area under the ROC curve (AUC), 0.714; 95% CI, 0.575–0.853; p = 0.009); green line: post-CPB syndecan-1 concentration (AUC, 0.653; 95% CI, 0.497–0.809; p = 0.063); grey line: Cleveland Clinic Foundation score (AUC, 0.714; 95% CI, 0.560–0.869; p = 0.009); red line: Cleveland Clinic Foundation score + preoperative syndecan-1 concentration ≥ 90 ng/mL (AUC, 0.807; 95% CI, 0.690–0.924; p < 0.001). Abbreviations: AKI, acute kidney injury; AUC, area under the ROC curve; CI, confidence interval; CPB, cardiopulmonary bypass.
Jcm 09 01803 g002
Table
Table 1. Demographic and clinical subject characteristics.
Table 1. Demographic and clinical subject characteristics.
Total
(5–884 ng/mL)
(N = 250)		Low SDC-1 Group
(0–89 ng/mL)
(N = 191)		High SDC-1 Group
(90–884 ng/mL)
(N = 59)		p Value
Age (years)66 (57–73)66 (57–73)65 (56–74)0.648
Male (n (%))118 (47.2)87 (45.5)31 (52.5)0.347
Body mass index (kg/m2) 23.9 ± 3.824.0 ± 4.023.7 ± 2.90.567
Hypertension133 (53.2)108 (56.5)25 (42.4)0.057
Diabetes mellitus48 (19.2)36 (18.8)12 (20.3)0.799
Chronic obstructive lung disease9 (3.6)6 (3.1)3 (5.1)0.690
Preoperative serum Cr >1.2 mg/dL15 (6.0)7 (3.7)8 (13.6)0.010
Prior myocardial infarction8 (3.2)6 (3.1)2 (3.4)0.924
Congestive heart failure55 (22.0)38 (19.9)17 (28.8)0.148
Coronary artery occlusive disease35 (14.0)28 (14.7)7 (11.9)0.589
Peripheral artery occlusive disease3 (1.2)2 (1.0)1 (1.7)>0.999
Liver cirrhosis9 (3.6)4 (2.1)5 (8.5)0.036
Preoperative steroid use5 (2.0)5 (2.6)0 (0.0)0.344
Preoperative inotrope use9 (3.6)5 (2.6)4 (6.8)0.221
Severe aortic stenosis62 (24.8)47 (24.6)15 (25.4)0.899
Severe aortic regurgitation54 (21.6)44 (23.0)10 (16.9)0.321
Severe mitral stenosis25 (10.0)15 (7.9)10 (16.9)0.042
Severe mitral regurgitation75 (30)65 (34.0)10 (16.9)0.012
Severe tricuspid regurgitation59 (23.6)34 (17.8)25 (42.4)<0.001
Type of surgery 0.238
Mitral valve repair/replacement116 (46.4)84 (44.0)32 (54.2)
Aortic valve replacement72 (28.8)62 (32.5)10 (16.9)
Double valve surgery23 (9.2)16 (8.4)7 (11.9)
Valve + CABG22 (8.8)16 (8.4)6 (10.2)
Valve + aorta17 (6.8)13 (6.8)4 (6.8)
Left ventricular ejection fraction (%)62 ± 1162 ± 1260 ± 90.175
LA volume index (mL/m2)64 (43–94)59 (39–88)67 (52–112)0.067
RV systolic pressure (mmHg)36 (28–46)33 (27–43)41 (33–51)0.001
Cleveland score2 (2–3)2 (1–3)2 (2–3)0.088
EuroSCORE5 (3–7)5 (3–7)5 (3–8)0.371
Pre-operative medication
Beta-blockers95 (38.0)70 (36.6)25 (42.4)0.429
RAS antagonists137 (54.8)109 (57.1)28 (47.5)0.195
Calcium-channel blockers59 (23.6)51 (26.7)8 (13.6)0.053
Antiplatelet agent57 (22.8)49 (25.7)8 (13.6)0.075
Heparin77 (30.8)45 (23.6)32 (54.2)<0.001
Diuretics154 (61.6)110 (57.6)44 (74.6)0.019
Statins94 (37.6)75 (39.3)19 (32.2)0.328
Digoxin41 (16.4)28 (14.7)13 (22.0)0.181
Note: Data are expressed as n (%), mean ± standard deviation or median (interquartile range). Abbreviations: SDC-1, syndecan-1; Cr, creatinine; CABG, coronary artery bypass graft; LA, left atrium; RV, right ventricle; RAS, renin-angiotensin system.
Table
Table 2. Degree of renal injury and changes in renal function.
Table 2. Degree of renal injury and changes in renal function.
Total
(N = 250)		Low SDC-1
(N = 191)		High SDC-1
(N = 59)		p Value
Acute kidney injury47 (18.8)28 (14.7)19 (32.2)0.003
Stage 134 (13.6)23 (12.0)11 (18.6)
Stage 26 (2.4)2 (1.0)4 (6.8)
Stage 37 (2.8)3 (1.6)4 (6.8)
Oliguria7 (2.8)3 (1.5)4 (6.8)0.025
Renal replacement therapy3 (1.2)0 (0.0)3 (5.1)0.013
Serum creatinine (mg/dL)
Baseline0.83 ± 0.230.81 ± 0.200.92 ± 0.270.024
Postoperative 6 h0.74 ± 0.280.71 ± 0.260.84 ± 0.320.024
Postoperative 24 h0.97 ± 0.710.91 ± 0.751.14 ± 0.520.048
Postoperative 48 h0.93 ± 1.210.89 ± 1.361.05 ± 0.430.688
Note: Data are expressed as n (%) or mean ± standard deviation. Acute kidney injury, Oliguria and need for renal replacement therapy were assessed during postoperative 48 h. Oliguria was defined as urine output <0.5 mL/kg/h for 6 h. Abbreviation: SDC-1, syndecan-1.
Table
Table 3. Intraoperative and 48 h postoperative data.
Table 3. Intraoperative and 48 h postoperative data.
Total
(N = 250)		Low SDC-1
(N = 191)		High SDC-1
(N = 59)		p Value
Duration of CPB (min)95 (70–120)90 (70–120)105 (75–136)0.131
Crystalloid (mL)5859 (4784–6982)5791 (4703–5791)6406 (5248–7554)0.010
Colloid (mL)600 (450–1000)600 (450–980)650 (450–1100)0.260
Patients requiring pRBC transfusion (n (%))148 (59.2)111 (58.1)37 (62.7)0.530
Amount of pRBC transfusion (mL)280 (0–560)280 (0–280)280 (0–560)0.107
Patients requiring
FFP/cryoprecipitate/platelet transfusion (n (%))		91 (36.4)58 (30.3)33 (55.9)<0.001
Amount of
FFP/cryoprecipitate/platelet transfusion (mL)		0 (0–608)0 (0–260)260 (0–1280)<0.001
Urine output (mL)6358 (5430–7408)6175 (5340–7230)7000 (6165–7650)0.007
Chest tube drainage (mL)470 (307–645)440 (290–617)532 (360–721)0.022
Furosemide dose (mg)55 (25–80)50 (20–75)60 (40–100)0.019
Norepinephrine dose (μg)972 (424–3329)882 (416–2875)1235 (469–3760)0.339
Vasopressin dose (unit)1.0 (0–3.3)0.9 (0–3.2)1.0 (0–3.7)0.274
Patients requiring inotrope (n (%))112 (44.8)80 (41.8)32 (54.2)0.100
Note: Data are expressed as n (%) or median (interquartile range). Abbreviations: SDC-1, syndecan-1; CPB, cardiopulmonary bypass; pRBC, packed red blood cell; FFP, fresh frozen plasma.
Table
Table 4. Inflammatory markers.
Table 4. Inflammatory markers.
Total
(N = 250)		Low SDC-1
(N = 191)		High SDC-1
(N = 59)		p Value
TNF-α (pg/mL)
Post-induction1.58 (1.17–2.06)1.45 (1.14–1.92)1.85 (1.37–2.43)<0.001
Post-CPB6.00 (3.77–9.59)5.92 (3.39–9.61)6.20 (3.90–9.55)0.738
IL-6 (pg/mL)
Post-induction3.43 (2.18–6.72)3.10 (2.05–6.28)4.93 (2.71–9.68)0.018
Post-CPB92.1 (26.6–283.7)84.9 (23.1–247.8)198.4 (53.1–308.7)0.062
C-reactive protein (mg/L)
Preoperative1.3 (0.6–2.9)1.2 (0.6–2.6)1.8 (0.9–5.4)0.060
Postoperative 6 h10.3 (2.8–18.2)9.0 (3.2–19.9)10.4 (2.5–18.0)>0.999
Postoperative 24 h75.9 (52.7–105.5)75.2 (50.8–98.5)86.1 (65.5–147.1)0.040
Postoperative 48 h164.7 (131.8–204.6)162.3 (131.0–206.3)175.6 (135.6–204.0)>0.999
Note: Data are expressed as mean ± standard deviation or median (interquartile range). Abbreviations: SDC-1, syndecan-1; TNF-α, tumor necrosis factor-α; IL-6, interleukin-6; CPB, cardiopulmonary bypass.
Table
Table 5. Postoperative outcomes.
Table 5. Postoperative outcomes.
Total
(N = 250)		Low SDC-1
(N = 191)		High SDC-1
(N = 59)		p Value
Stroke2 (0.8)1 (0.5)1 (1.7)0.417
Sternal infection0 (0.0)0 (0.0)0 (0.0)>0.999
Hemostatic reoperation5 (2.0)4 (2.1)1 (1.7)>0.999
Mechanical ventilation >24 h15 (6.0)8 (4.2)7 (11.9)0.053
Mortality2 (0.8)2 (1.0)0 (0.0)>0.999
Length of ICU stay (day)3 (2–3)3 (2–3)3 (2–4)0.019
Length of hospital stay (day)14 (11–18)13 (11–17)16 (12–24)0.001
Note: Data are expressed as n (%) or median (interquartile range). Abbreviations: SDC-1, syndecan-1; ICU, intensive care unit.

Share and Cite

MDPI and ACS Style

Kim, H.-B.; Soh, S.; Kwak, Y.-L.; Bae, J.C.; Kang, S.H.; Song, J.W. High Preoperative Serum Syndecan-1, a Marker of Endothelial Glycocalyx Degradation, and Severe Acute Kidney Injury after Valvular Heart Surgery. J. Clin. Med. 2020, 9, 1803. https://doi.org/10.3390/jcm9061803

AMA Style

Kim H-B, Soh S, Kwak Y-L, Bae JC, Kang SH, Song JW. High Preoperative Serum Syndecan-1, a Marker of Endothelial Glycocalyx Degradation, and Severe Acute Kidney Injury after Valvular Heart Surgery. Journal of Clinical Medicine. 2020; 9(6):1803. https://doi.org/10.3390/jcm9061803

Chicago/Turabian Style

Kim, Hye-Bin, Sarah Soh, Young-Lan Kwak, Jae Chan Bae, Sang Hwa Kang, and Jong Wook Song. 2020. "High Preoperative Serum Syndecan-1, a Marker of Endothelial Glycocalyx Degradation, and Severe Acute Kidney Injury after Valvular Heart Surgery" Journal of Clinical Medicine 9, no. 6: 1803. https://doi.org/10.3390/jcm9061803

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop