Effects of Ulinastatin on Postoperative Renal Function in Patients Undergoing Cardiac Surgery With Cardiopulmonary Bypass: a Prospective Cohort Study

Effects of Ulinastatin on Postoperative Renal Function in Patients Undergoing Cardiac Surgery With Cardiopulmonary Bypass: a Prospective Cohort Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research article Effects of Ulinastatin on Postoperative Renal Function in Patients Undergoing Cardiac Surgery With Cardiopulmonary Bypass: a Prospective Cohort Study Hong Lv, Huanran Lv, Yuda Fei, Qian Li, Peng zhang, Liang Cao, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1049165/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background : Ulinastatin is a serine protease inhibitor with anti-inflammatory effects. Evidence for the effects of ulinastatin on renal outcomes remains sparse in patients receiving cardiac surgery with cardiopulmonary bypass (CPB). Methods : This prospective cohort study evaluated 413 patients aged 18–70 years who underwent cardiac surgery with CPB, from Aug 2008 to Jul 2019 in Fuwai Hospital, Beijing ,China. The ulinastatin group included 135 patients who received intravenous ulinastatin (1×106 U) after induction of anesthesia. The remaining 278 patients without ulinastatin served as the control group. The primary outcome was the rate of new-onset postoperative acute kidney injury (AKI). The secondary outcome was renal replacement therapy(RRT). Serum creatinine, plasma NGAL, and serum IL-6 levels were evaluated and the CSANGAL Score was calculated. In addition, in-hospital mortality, morbidity, adverse outcomes and 10-year follow-up the survival rate was analyzed. Results: Rate of new-onset AKI was significantly lower in the ulinastatin group than in the control group (20.00% vs. 32.40%, p=0.009). There was no significant difference of RRT between the two groups (0.00% vs. 2.16%, p=0.09). In-hospital mortality, morbidity, and adverse outcomes were comparable between the two groups except for a significantly lower incidence of respiratory failure in the ulinastatin group compared with the control group (0.76% vs. 5.40%, p=0.02). The 10-year follow-up survival rates did not differ significantly between the two groups. Conclusions: Ulinastatin significantly reduced postope rative AKI and respiratory failure in patients receiving cardiac surgery with CPB. But ulinastatin did not reduce ICU and hospital stay and mortality. Clinical trial registration: NCT01060189 Cardiothoracic Surgery ulinastatin acute kidney injury cardiac surgical procedures cardiopulmonary bypass Figures Figure 1 Figure 2 Figure 3 Introduction Cardiac surgery-associated acute kidney injury (CSA-AKI) is a frequent and severe complication in adult patients undergoing cardiac surgery with cardiopulmonary bypass (CPB)[ 1 ] and the second most common cause of AKI in the intensive care unit (ICU). Notably, AKI is independently associated with the increased need for renal replacement therapy (RRT), length of hospital stay, hospitalization cost, and mortality[ 2 ]. However, to date, efficacious drugs that can reduce the incidence of AKI and the requirement for RRT remain limited [ 3 ]. Prior investigations indicated that CSA-AKI has associations with systemic inflammatory response syndrome (SIRS), renal ischemia-reperfusion injury, renal hypoperfusion, blood transfusion, and nephrotoxic drugs[ 4 ]. Moreover, CPB-induced inflammatory responses are associated with kidney dysfunction[4, 5].CSA-AKI was defined according to the KDIGO criteria in the present study. The KDIGO criteria define AKI severity according to serum creatinine (SCr) and urinary output. However, SCr increases relatively late after the onset of kidney injury without specific symptoms, leading to limitations in the SCr-based definition of AKI. Neutrophil gelatinase-associated lipocalin (NGAL) is one AKI biomarker that shows promising for identifying acute tubular damage, especially in the subclinical AKI stage, and can represent acute tubular damage before the presence of clinical renal dysfunction[ 6 ]. Ulinastatin is a glycoprotein purified from healthy human urine as a broad spectrum protease inhibitor, which was demonstrated to reduce complications in patients undergoing cardiac surgery with CPB through its anti-inflammatory and antioxidant activities[ 7 ]. However, it remains controversial whether ulinastatin has benefits for renal function and can reduce morbidity and mortality associated with AKI in patients undergoing cardiac surgery procedures with CPB. The present study aimed to determine the potential effects of ulinastatin on renal function and long-term survival in patients receiving cardiac surgery with CPB. Patients And Methods This single-center prospective cohort study was approved by the Ethics Committee of Fuwai Hospital, Patients aged 18–70 years who underwent cardiac surgery with CPB from Aug 2008 to Jul 2019 in Fuwai Hospital, Beijing ,China were enrolled. Patients with preoperative renal dysfunction were excluded. For inclusion criteria, the patients required: diagnosis of coronary heart disease, valvular heart disease, congenital heart disease, or complex heart disease; cardiac surgery necessitating CPB; normal renal function with GFR ≥60 mL/min/1.73 m2, calculated by the Chronic Kidney Disease Epidemiology Collaboration equation; and no kidney transplantation within the past 365 days. Finally, 413 patients were included in the study, and they were divided into the ulinastatin group (n=135) or the control group (n=278) (Figure 1), according to whether the ulinastatin was used during the surgery or not. The participants did not experience any events that resulted in AKI during the preoperative and intraoperative periods, including hypotension, shock, and use of nephrotoxic drugs, which will be excluded from the whole trials. According to the routine practices in our institution, blood samples were taken before anesthesia induction (T0), on arrival at the ICU (T1), and at 6 (T2), 12 (T3), and 24 hours (T4) after surgery. The primary outcome of the study was the rate of new-onset AKI ,which was defined by the KDIGO criteria after surgery. The secondary outcome was the need for RRT. In-hospital mortality and morbidity and adverse outcomes were observed. The CSA-NGAL Score is a tubular damage score based on the level of NGAL and a clinical index for early prediction of subclinical AKI. SCr, pNGAL, and serum IL-6 concentrations were detected by ELISA for each sample, in which pNGAL and IL-6 were detected by emulsion enhanced immune turbidimetry assay and double antibody sandwich ELISA, separately. A 10-year follow-up was achieved by telephone call, outpatient service, face-to-face visit, QQ, or WeChat. The data ascertained by the follow-up team were as follows: onset of death, loss to follow-up, and renal dysfunction; presence or absence of heart failure, hematosepsis, or re-hospitalization for renal dysfunction, RRT, intermittent hemodialysis, or potential nephrotoxic drugs; levels of blood glucose; and results for renal function. All of these items were recorded. In death cases, information on the date and the primary and secondary causes of death were obtained. Statistical Analysis For continuous variables, the Shapiro–Wilk test was used to estimate the normal distribution assumption, and the Levene test was applied to assess the equal variance assumption. Differences in these characteristics between the two groups were evaluated by an independent two-sample t-test or one-way ANOVA. Categorical variables were summarized by frequency or percentage and compared by the chi-square test or Fisher’s exact test. Inter-group differences in serum IL-6, pNGAL, and SCr were assessed by two-way repeated-measures analysis of variance (ANOVA) with a Bonferroni post-hoc test. Survival analysis was performed using the Kaplan–Meier method and a log-rank test. All statistical analyses were performed using SPSS Version 18.0 software (SPSS Inc., Chicago, IL). Values of p<0.05 were considered statistically significant. Results Demographic Data There were no significant differences in the demographic characteristics between the two groups, Preoperative diagnoses comparable between the two groups (Table 1 ). Table 1 Demographic and Preoperative Characteristics Ulinastatin Group (n=135) Control Group (n=278) p Value Male, n (%) 56 (41.5) 133 (47.8) 0.22 Age, y 49.1±14.4 49.6±12.6 0.83 Body mass index 22.8 (20.3, 25.4) 22.4 (20.3, 25.2) 0.52 Hypertension, n (%) 30(22.2) 68 (24.5) 0.62 Diabetes, n (%) 5 (3.7) 10 (3.6) 0.96 Stroke, n (%) 7 (5.2) 5 (1.8) 0.06 Chronic pulmonary disease, n (%) 10 (7.4) 34 (12.2) 0.14 Liver dysfunction, n (%) 0 (0) 0 (0) - Diagnosis, n (%) 0.31 Coronary heart disease 15 (11.1) 32 (11.5) Valvular heart disease Mitral valve lesion 69 (51.1) 128 (46.0) Aortic valve lesion 21 (15.6) 41 (14.8) Combined lesion 21 (15.6) 38 (13.7) Congenital heart disease Atrial septal defect 0 (0) 9 (3.2) Ventricular septal defect 4 (3.0) 10(3.6) Other 5 (3.7) 20 (7.2) NYHA class, n (%) 0.42 I 9 (6.7) 34 (12.2) II 76 (56.3) 151 (54.3) III 40 (29.6) 70 (25.2) IV 10 (7.4) 23 (8.3) EuroSCORE II 2.4±1.9 2.6±1.7 0.34 Data for age and EuroSCORE II are shown as mean ± SD. NYHA class, New York Heart Association Functional Classification; EuroSCORE, European System for Cardiac Operative Risk Evaluation. Perioperative Data The intraoperative and the postoperative data were comparable between the two groups (Table 2 ). Table 2 Intraoperative and Postoperative Data Ulinastatin Group (n=135) Control Group (n=278) p Value Aortic cross-clamp time, min 70.0 (50.0, 96.0) 63.0 (44.3, 92.0) 0.25 CPB time, min 97.0 (72.0.125.0) 87.0 (65.0,120.0) 0.27 Operation time, min 215.0 (175.0, 245.0) 195.0 (160.0, 240.0) 0.08 Operative mortality, n (%) 0 (0) 0 (0) - Surgical Type, n (%) 0.35 Coronary artery bypass grafting 16 (11.9) 32 (11.5) Mitral valvuloplasty or replacement 65 (48.1) 124 (44.6) Aortic valve replacement 20 (14.8) 39 (14.0) Mitral and aortic valve replacement 17 (12.6) 30 (10.8) CABG and valvular procedure 10 (7.4) 14 (5.0) Repair of atrial septal defect 0 (0) 9 (3.2) Repair of ventricular septal defect 4 (3.0) 10 (3.6) Other 5 (3.7) 20 (7.2) Postoperative data Mechanical ventilation, h 13.0 (11.0, 18.0) 13.0 (10.0, 17.0) 0.36 ICU stay, h 25.0 (18.0, 56.0) 25.5 (17.0, 58.3) 0.53 Hospital length of stay, h 7.0 (7.0, 8.0) 7.0 (7.0, 9.0) 0.39 The differences in these characteristics between the two groups were evaluated by an independent two-sample t -test or one-way ANOVA. Categorical variables were summarized as frequency or percentage and compared by the chi-square test or Fisher’s exact test. CPB, cardiopulmonary bypass; CABG, coronary artery bypass grafting; ICU, intensive care unit. There was no significant differences in the intraoperative and postoperative data ( p >0.05). Renal Function Outcomes The incidence of AKI in the ulinastatin group was significantly lower than that in the control group (20.00% vs. 32.37%, p=0.009)). Furthermore, a significant difference was observed between the two groups (p=0.002) about the subclinical acute kidney injury, calculated by CSA-NGAL Scores (Table 3 ). Six of 278 patients in the control group and no patients in the ulinastatin group required RRT, but the difference was not significant (p=0.09). Table 3 CSA-NGAL Scores and KDIGO Scores at 24 Hours Postoperatively CSA-NGAL Score, n (%) Ulinasatin Group (n=135) Control Group (n=278) 0 61 (45.2) 96(34.5) 1 48 (35.6) 77(27.7) 2 22 (16.3) 86(31.0) 3 4 (3.0) 19(6.8 ) KDIGO Score, n (%) Ulinastatin Group (n=135) Control Group (n=278) P value 0 108 (80.0) 188 (67.6) 1 20 (14.8) 63 (22.7) 2 5 (3.7) 18 (6.5) 3 2 (1.5) 9 (3.2) AKI 27 (20.0) 90 (32.4) 0.009* There was a significant difference between the two groups in the CSA-NGAL Scores at 24 hours postoperatively ( p =0.002). There was no significant difference in the KDIGO Scores between the two groups and in comparisons of pairs ( p =0.07). CSA-NGAL Score, cardiac surgery-associated NGAL score; NGAL, neutrophil gelatinase-associated lipocalin; KDIGO Score, Kidney Disease-Improving Global Outcomes score. On arrival at the ICU and at 6, 12, and 24 hours after surgery, the pNGAL levels in the ulinastatin group versus control group were 89.78±114.23 vs. 129.41±163.58 ng/mL (p=0.005), 135.20±248.96 vs. 247.92±445.87 ng/mL (p=0.001), 131.06±208.67 vs. 212.16±333.11 ng/mL (p<0.001), and 110.32±147.00 vs. 159.78±245.23 ng/mL (p=0.04), respectively. Moreover, the mean time between the end of CPB and the first measurement of NGAL between ulinastatin group and control group was 64.83704± 25.8575 min vs. 65.3777 ±27.96383 min. The corresponding IL-6 levels were 0.37±0.24 vs. 0.40±0.25 pg/mL (p=0.30), 0.78±0.51 vs. 0.93±0.62 pg/mL (p=0.02), 0.83±0.51 vs. 1.05±0.74 pg/mL (p=0.02), and 0.58±0.35 vs. 0.89±0.65 pg/mL (p<0.001), respectively, and the corresponding SCr levels were 1.07±0.30 vs. 1.08±0.35 mg/dL (p=0.86), 1.46±0.65 vs. 1.55±0.69 mg/dL (p=0.17), 1.46±0.72 vs. 1.57±0.77 mg/dL (p=0.14), and 1.28±0.43 vs. 1.32±0.61 mg/dL (p=1.00) respectively. The postoperative SCr levels did not differ significantly between the two groups (p=0.23; Figure 2 a), while the postoperative pNGAL levels (p=0.007; Figure 2 b) and IL-6 levels (p=0.001; Figure 2 c) were significantly lower in the ulinastatin group than in the control group. The CSA-NGAL Score was significantly lower in the ulinastatin group than in the control group (p=0.002; Table 3 ), while the KDIGO Score did not differ significantly between the two groups (p=0.07; Table 3 ) during the first 24 hours after surgery. Mortality and Other Adverse Outcomes The in-hospital mortality rate was 1 case (0.74%) in the ulinastatin group and 1 case (0.36%) in the control group, with no significant difference between the two groups (p=0.60). In addition, length of ICU stay, length of mechanical ventilation, and length of hospital stay did not differ significantly between the two groups. The two groups also showed no significant differences in postoperative complications like stroke, postoperative myocardial infarction, cardiac arrest, deep sternal infection, ICU readmission, surgery-associated reoperation, and RRT, IABP, and ECMO (p>0.05; Tables 2 and 4 ). Notably, the incidence of respiratory failure was significantly lower in the ulinastatin group than in the control group (p=0.02; Table 4 ). Table 4 Adverse Events Adverse events, n (%) Mortality in-hospital 1 (0.7) 1 (0.4) 0.60 Stroke 0 (0) 3 (1.1) 0.23 Postoperative MI 0 (0) 3 (1.1) 0.23 Respiratory failure 1(0.7) 15 (5.4) 0.02* Sudden cardiac arrest 0 (0) 3 (1.1) 0.23 Readmission to ICU 2 (1.5) 4 (1.4) 0.97 Reoperation for surgical cause 2 (1.5) 2 (0.7) 0.46 RRT 0 (0) 6 (2.2) 0.09 IABP 1 (0.7) 5 (1.8) 0.40 ECMO 0 (0) 0 (0) -- Deep sternal infection 1(0.7) 1 (0.4) 0.60 *There were significant differences between the two groups in the incidences of AKI ( p =0.009) and morbidity of respiratory failure ( p =0.022). There were no significant differences between the two groups in mortality and other postoperative adverse events ( p >0.05). AKI, acute kidney injury; MI, myocardial infarction; ICU, intensive care unit; RRT, renal replacement treatment; IABP, intra-aortic balloon pump; ECMO, extracorporeal membrane oxygenation. Discussion CSA-AKI is a severe complication in adult patients undergoing cardiac surgery with CPB, resulting in prolonged ICU stay and increased short-term and long-term morbidity[ 8 ]. Several processes to reduce CSA-AKI incidence have been established, and the efficacy of ulinastatin has been examined in recent years[ 3 , 9 ]. In the present study, we found that ulinastatin significantly reduced the incidence of CSA-AKI diagnosed according to the KDIGO criteria. In our study, the incidences of AKI were 20.00% in the ulinastatin group and 32.40% in the control group, consistent with the findings in recent studies[ 3 ]. Nakanishi et al.[ 10 ] demonstrated that ulinastatin administered before CPB could decrease postoperative elevation of IL-6 and IL-8 in patients undergoing cardiac surgery with CPB, while Song et al.[ 11 ] found that ulinastatin has no effect on attenuation of IL-6, TNF-α, and improvements in renal function. Wang et al. [ 12 ]. Indicated that ulinastatin could reduce inflammation and dose dependently attenuate CPB-induced kidney injury in infant piglets. Wan et al.[ 13 ] performed a propensity score-matched study and showed that administration of ulinastatin during CPB is associated with a lower incidence of CSA-AKI. Other studies have indicated that ulinastatin can inhibit polymorphonuclear neutrophils, which is helpful to reduce the risk of bleeding and the requirement for blood transfusion after surgery[ 14 , 15 ]. Although AKI is a complex pathophysiological process rather than a specific syndrome, especially following cardiac surgery[ 16 ], SIRS arising after cardiac surgery plays a pivotal role in AKI development[ 17 , 18 ]. The pathogenesis of SIRS is associated with multiple factors, including surgical trauma, transfusion, hypothermia, blood loss, ischemia-reperfusion injury, immune system activation, and endotoxemia[ 19 ]. Ulinastatin has anti-inflammatory properties by inhibiting the activation of various inflammatory pathways[ 14 , 20 , 21 ]. Thus, serum IL-6 levels were evaluated in this study and found to be significantly lower in the ulinastatin group compared with the control group (p=0.001; Figure 2 c). The effect of ulinastatin on reducing CSA-AKI is considered to involve the inhibition of inflammation. Evidence suggests that the KDIGO criteria are superior to other criteria, but have less sensitivity to detect early-stage tubular damage. The KDIGO criteria are based on the SCr level for diagnosis of AKI, and changes in SCr often occur 48 hours to 7 days after the original damage. Furthermore, SCr levels are affected by many related factors, and rescue interventions may be too late to prevent early perioperative AKI. These limitations drive us to search for new biomarkers that reflect early AKI. In addition to the KDIGO criteria, pNGAL, a newly discovered biomarker, was tested to predict kidney injury and prove previous findings[ 22 ]. NGAL plays a role in the early detection of AKI and can be upregulated at an earlier stage than elevation of SCr to meet the KDIGO criteria. NGAL in plasma and urine is upregulated when acute tubular damage occurs, but pNGAL is detectable earlier than uNGAL when tubular damage occurs. In a previous study, pNGAL was used to predict AKI based on the CSA NGAL Score, and the results were proven to be similar to those based on the KDIGO Score[ 6 ]. According to the KDIGO criteria and CSA-NGAL Score criteria, the incidences of CSA-AKI were similar in the present study. However, according to the CSA-NGAL Score criteria, 48 (35.60%) patients in the ulinastatin group and 77 (27.70%) patients in the control group were in the region of possible tubular damage, so-called subclinical AKI that is a separate entity and provides a warning to trigger awareness and appropriate clinical therapeutic modifications[ 6 ]. Respiratory failure in the present study was defined as prolonged ventilation support for more than 48 hours. The findings demonstrated that ulinastatin could reduce the incidence of respiratory failure, consistent with previous studies[ 23 ]. Xu et al.[ 24 ] suggested that ulinastatin inhibits the release of proinflammatory cytokines and PMNE, reduces pulmonary injury, and improves pulmonary function after CPB, thereby shortening the intubation time and length of ICU stay. The lung-protective effect of ulinastatin is dose dependent and a lower-than-effective dose could lead to negative results. The survival rate after ten years of follow-up did not differ significantly between the two groups. According to previous studies, the effect of ulinastatin may be diminished depending on the duration of administration[ 25 ], which is ascribed to the fact that ulinastatin is administered through a bolus injection rather than a continuous infusion[ 26 ]. Another reason is that the half-life of ulinastatin is about 40 minutes in healthy adults[ 27 ], while the duration of CPB is often longer than 40 minutes and the peak of IL-6 occurs at 4–6 hours postoperatively[ 28 ]. A meta-analysis showed that ulinastatin could reduce inflammatory cytokines but does not affect hospital mortality[ 29 ]. There are some limitations to the present study. First, the study was designed as a single-center prospective cohort design with less power than a randomized controlled trial. The rationale lay in the sparse evidence concerning the effect of ulinastatin on renal outcomes and the nature of a pilot study. It was in accordance with ethical considerations to conduct an observational study rather than an interventional study. Second, there were relatively high rates of loss to follow-up, comprising 14.20% (19/134) in the ulinastatin group and 14.10% (39/277) in the control group. It was a great challenge to achieve follow-up for as long as ten years. Nevertheless, the rates of loss to follow-up were comparable between the two groups and associated with less bias. Third, only SCr was evaluated for the AKI criteria in the present study. The urine output in the KDIGO criteria requires a state of oliguria or anuria lasting for more than 6, 12, or 24 hours, which was infeasible in postoperative ICU settings. For ethical considerations, oliguria and anuria would not be observed for such a long period and should be treated according to the institutional protocol promptly. Furthermore, assessment of AKI by SCr alone has been widely accepted in studies such as the BART study[ 30 ] and the ATACAS study[ 8 ]. In the present study, the SCr, pNGAL, and serum IL-6 were detected, and CSA-AKI incidences according to the KDIGO criteria and CSA-NGAL Score criteria were analyzed, of which differed significantly between the two groups, except for SCr. Meanwhile, respiratory failure in the ulinastatin group was considerably lower than that in the control group. In summary, ulinastatin can significantly reduce the incidence of early postoperative AKI during cardiac surgery with CPB without affecting the long-term survival rate. Declarations Acknowledgments The authors thank Alison Sherwin, PhD, from Liwen Bianji, Edanz Group China (www.liwenbianji.cn/ac) for editing the English text of a draft of this manuscript. Authors’ contributions Author Jia Shi and author Hong Lv, Huanran Lv, Yuda Fei, have given substantial contributions to the conception or the design of the manuscript, author Qian Li, Peng Zhang, Liang Cao, and author Lihuan Li to acquisition, analysis and interpretation of the data. All authors have participated to drafting the manuscript, author Jia Shi revised it critically. All authors read and approved the final version of the manuscript. All authors contributed equally to the manuscript and read and approved the final version of the manuscript. There is no Conflict of Interest. References Hobson CE, Yavas S, Segal MS, et al: Acute kidney injury is associated with increased long-term mortality after cardiothoracic surgery. Circulation 2009, 119(18):2444-2453. 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He QL, Zhong F, Ye F, et al: Does intraoperative ulinastatin improve postoperative clinical outcomes in patients undergoing cardiac surgery: a meta-analysis of randomized controlled trials. BioMed research international 2014, 2014:630835. Myles PS, Smith JA, Forbes A, et al: Tranexamic Acid in Patients Undergoing Coronary-Artery Surgery. The New England journal of medicine 2017, 376(2):136-148. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1049165","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research article","associatedPublications":[],"authors":[{"id":63337323,"identity":"9e29e9f1-2c1b-4c62-a9d5-2563ea1b3a08","order_by":0,"name":"Hong Lv","email":"","orcid":"","institution":"Chinese Academy of Medical Sciences \u0026 Peking Union Medical College Fuwai Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hong","middleName":"","lastName":"Lv","suffix":""},{"id":63337324,"identity":"de936b3c-0783-412b-a956-96af3994757a","order_by":1,"name":"Huanran Lv","email":"","orcid":"","institution":"Chinese Academy of Medical Sciences \u0026 Peking Union Medical College Fuwai Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Huanran","middleName":"","lastName":"Lv","suffix":""},{"id":63337325,"identity":"aaa5660d-b075-4db8-a663-cbc5da8d8d4a","order_by":2,"name":"Yuda Fei","email":"","orcid":"","institution":"China Xiehe Medical University: Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yuda","middleName":"","lastName":"Fei","suffix":""},{"id":63337326,"identity":"6e6bc9e6-702d-43af-b40b-3ac78ec55d8f","order_by":3,"name":"Qian Li","email":"","orcid":"","institution":"Chinese Academy of Medical Sciences \u0026 Peking Union Medical College Fuwai Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Qian","middleName":"","lastName":"Li","suffix":""},{"id":63337327,"identity":"c4fbae02-9a23-4a20-a434-b600a6455c35","order_by":4,"name":"Peng zhang","email":"","orcid":"","institution":"Chinese Academy of Medical Sciences \u0026 Peking Union Medical College Fuwai Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Peng","middleName":"","lastName":"zhang","suffix":""},{"id":63337328,"identity":"4f7e2170-3e49-4f40-b447-dc9ce74ba93e","order_by":5,"name":"Liang Cao","email":"","orcid":"","institution":"Chinese Academy of Medical Sciences \u0026 Peking Union Medical College Fuwai Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Liang","middleName":"","lastName":"Cao","suffix":""},{"id":63337329,"identity":"5f411b06-f57b-419a-a88b-f96f6b4ffd1c","order_by":6,"name":"LiHuan Li","email":"","orcid":"","institution":"Chinese Academy of Medical Sciences \u0026 Peking Union Medical College Fuwai Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"LiHuan","middleName":"","lastName":"Li","suffix":""},{"id":63337330,"identity":"65f04dd0-40c0-40a9-aa34-94d388d115ff","order_by":7,"name":"Jia Shi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAuklEQVRIiWNgGAWjYDACCcYGgwQGG34Q+wApWtIkG0jQAiYPg7UQB+RnNzcUPKg5L2FwI/nhAYYam2iCWgzuHAQ67NhtoJY0gwMMx9JyCVpnIJEI1MJ2u87gdoLBAcaGw4S1yM8Aafl3TsLgdvoH4rQw3ABqSWw7ANSSQ6QtBmAtfckSkvffFBxIIMYv8jPSnxn++GYnwXfm+OYPH2psiHAYAwObAZyZQIRyEGB+QKTCUTAKRsEoGKkAAFuNRkvQLsNeAAAAAElFTkSuQmCC","orcid":"","institution":"Chinese Academy of Medical Sciences \u0026 Peking Union Medical College Fuwai Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Jia","middleName":"","lastName":"Shi","suffix":""}],"badges":[],"createdAt":"2021-11-04 07:04:06","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1049165/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1049165/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":15596198,"identity":"b6fc1195-ba20-4745-acde-983e266605c2","added_by":"auto","created_at":"2021-11-16 15:28:51","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":40189,"visible":true,"origin":"","legend":"Scheme of patient recruitment. Ulinastatin group: patients with ulinastatin administration; Control group: patients without ulinastatin administration.","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1049165/v1/5521e5feb8ded73b1283805a.jpg"},{"id":15596199,"identity":"50290cf0-aad7-4108-8ffe-071575351d0c","added_by":"auto","created_at":"2021-11-16 15:28:51","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":78061,"visible":true,"origin":"","legend":"Changes in measured levels. (A) SCr levels. (B) pNGAL levels. (C) IL-6 levels. Data are expressed as mean ± SD. There are significant differences in the levels of IL-6 and pNGAL between the two groups (p\u003c0.05). There is no significant difference in the levels of SCr between the two groups (p=0.23). T0, before anesthesia induction; T1, on arrival at the ICU; T2, at 6 hours after surgery; t3, at 12 hours after surgery; T4, at 24 hours after surgery. *p\u003c0.05, significant difference between the two groups.","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1049165/v1/e7c55c68f2ae14599c9a0583.jpg"},{"id":15596200,"identity":"16dee25d-950b-4eb7-8a69-65d25b03d474","added_by":"auto","created_at":"2021-11-16 15:28:51","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":24806,"visible":true,"origin":"","legend":"Survival rates. The survival rates did not differ significantly between the two groups (log-rank test, p=0.756).","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1049165/v1/86abf6195f30b459c0a1eea5.jpg"},{"id":20572644,"identity":"095b0cb1-9c27-40d9-95af-b9a8883a5e32","added_by":"auto","created_at":"2022-04-20 19:21:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":431945,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1049165/v1/6dea0396-744e-4465-b090-a585212c8be4.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eEffects of Ulinastatin on Postoperative Renal Function in Patients Undergoing Cardiac Surgery With Cardiopulmonary Bypass: a Prospective Cohort Study\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCardiac surgery-associated acute kidney injury (CSA-AKI) is a frequent and severe complication in adult patients undergoing cardiac surgery with cardiopulmonary bypass (CPB)[\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e] and the second most common cause of AKI in the intensive care unit (ICU). Notably, AKI is independently associated with the increased need for renal replacement therapy (RRT), length of hospital stay, hospitalization cost, and mortality[\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e]. However, to date, efficacious drugs that can reduce the incidence of AKI and the requirement for RRT remain limited [\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e]. Prior investigations indicated that CSA-AKI has associations with systemic inflammatory response syndrome (SIRS), renal ischemia-reperfusion injury, renal hypoperfusion, blood transfusion, and nephrotoxic drugs[\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e]. Moreover, CPB-induced inflammatory responses are associated with kidney dysfunction[4, 5].CSA-AKI was defined according to the KDIGO criteria in the present study. The KDIGO criteria define AKI severity according to serum creatinine (SCr) and urinary output. However, SCr increases relatively late after the onset of kidney injury without specific symptoms, leading to limitations in the SCr-based definition of AKI. Neutrophil gelatinase-associated lipocalin (NGAL) is one AKI biomarker that shows promising for identifying acute tubular damage, especially in the subclinical AKI stage, and can represent acute tubular damage before the presence of clinical renal dysfunction[\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eUlinastatin is a glycoprotein purified from healthy human urine as a broad spectrum protease inhibitor, which was demonstrated to reduce complications in patients undergoing cardiac surgery with CPB through its anti-inflammatory and antioxidant activities[\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e]. However, it remains controversial whether ulinastatin has benefits for renal function and can reduce morbidity and mortality associated with AKI in patients undergoing cardiac surgery procedures with CPB.\u003c/p\u003e\n\u003cp\u003eThe present study aimed to determine the potential effects of ulinastatin on renal function and long-term survival in patients receiving cardiac surgery with CPB.\u003c/p\u003e"},{"header":"Patients And Methods","content":"\u003cp\u003eThis single-center prospective cohort study was approved by the Ethics Committee of Fuwai Hospital, Patients aged 18\u0026ndash;70 years who underwent cardiac surgery with CPB from Aug 2008 to Jul 2019 in Fuwai Hospital, Beijing ,China were enrolled. Patients with preoperative renal dysfunction were excluded. For inclusion criteria, the patients required: diagnosis of coronary heart disease, valvular heart disease, congenital heart disease, or complex heart disease; cardiac surgery necessitating CPB; normal renal function with GFR \u0026ge;60 mL/min/1.73 m2, calculated by the Chronic Kidney Disease Epidemiology Collaboration equation; and no kidney transplantation within the past 365 days. Finally, 413 patients were included in the study, and they were divided into the ulinastatin group (n=135) or the control group (n=278) (Figure 1), according to whether the ulinastatin was used during the surgery or not. The participants did not experience any events that resulted in AKI during the preoperative and intraoperative periods, including hypotension, shock, and use of nephrotoxic drugs, which will be excluded from the whole trials.\u003c/p\u003e\n\u003cp\u003eAccording to the routine practices in our institution, blood samples were taken before anesthesia induction (T0), on arrival at the ICU (T1), and at 6 (T2), 12 (T3), and 24 hours (T4) after surgery.\u003c/p\u003e\n\u003cp\u003eThe primary outcome of the study was the rate of new-onset AKI ,which was defined by the KDIGO criteria after surgery. The secondary outcome was the need for RRT. In-hospital mortality and morbidity and adverse outcomes were observed. The CSA-NGAL Score is a tubular damage score based on the level of NGAL and a clinical index for early prediction of subclinical AKI. SCr, pNGAL, and serum IL-6 concentrations were detected by ELISA for each sample, in which pNGAL and IL-6 were detected by emulsion enhanced immune turbidimetry assay and double antibody sandwich ELISA, separately.\u003c/p\u003e\n\u003cp\u003eA 10-year follow-up was achieved by telephone call, outpatient service, face-to-face visit, QQ, or WeChat. The data ascertained by the follow-up team were as follows: onset of death, loss to follow-up, and renal dysfunction; presence or absence of heart failure, hematosepsis, or re-hospitalization for renal dysfunction, RRT, intermittent hemodialysis, or potential nephrotoxic drugs; levels of blood glucose; and results for renal function. All of these items were recorded. In death cases, information on the date and the primary and secondary causes of death were obtained.\u003c/p\u003e\n\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\n\u003cp\u003eFor continuous variables, the Shapiro\u0026ndash;Wilk test was used to estimate the normal distribution assumption, and the Levene test was applied to assess the equal variance assumption. Differences in these characteristics between the two groups were evaluated by an independent two-sample t-test or one-way ANOVA. Categorical variables were summarized by frequency or percentage and compared by the chi-square test or Fisher\u0026rsquo;s exact test. Inter-group differences in serum IL-6, pNGAL, and SCr were assessed by two-way repeated-measures analysis of variance (ANOVA) with a Bonferroni post-hoc test. Survival analysis was performed using the Kaplan\u0026ndash;Meier method and a log-rank test. All statistical analyses were performed using SPSS Version 18.0 software (SPSS Inc., Chicago, IL). Values of p\u0026lt;0.05 were considered statistically significant.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n\u003ch2\u003eDemographic Data\u003c/h2\u003e\n\u003cp\u003eThere were no significant differences in the demographic characteristics\u0026nbsp;between the two groups, Preoperative diagnoses comparable between the two\u0026nbsp;groups (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eDemographic and Preoperative Characteristics\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eUlinastatin Group (n=135)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eControl Group (n=278)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003ep\u003c/em\u003e Value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMale, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e56 (41.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e133 (47.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.22\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge, y\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e49.1\u0026plusmn;14.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e49.6\u0026plusmn;12.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.83\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBody mass index\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22.8 (20.3, 25.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22.4 (20.3, 25.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.52\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHypertension, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30(22.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e68 (24.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.62\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDiabetes, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (3.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10 (3.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.96\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eStroke, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (5.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (1.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.06\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eChronic pulmonary disease, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10 (7.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e34 (12.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.14\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLiver dysfunction, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eDiagnosis, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"3\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.31\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCoronary heart disease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (11.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32 (11.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"9\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eValvular heart disease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMitral valve lesion\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e69 (51.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e128 (46.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAortic valve lesion\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21 (15.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e41 (14.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCombined lesion\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21 (15.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e38 (13.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCongenital heart disease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAtrial septal defect\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 (3.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eVentricular septal defect\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (3.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10(3.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOther\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (3.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20 (7.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eNYHA class, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"3\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.42\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eI\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 (6.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e34 (12.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"4\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eII\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e76 (56.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e151 (54.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIII\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e40 (29.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e70 (25.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIV\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10 (7.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e23 (8.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eEuroSCORE II\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.4\u0026plusmn;1.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.6\u0026plusmn;1.7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.34\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\"\u003eData for age and EuroSCORE II are shown as mean \u0026plusmn; SD.\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\"\u003eNYHA class, New York Heart Association Functional Classification; EuroSCORE, European System for Cardiac Operative Risk Evaluation.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n\u003ch2\u003ePerioperative Data\u003c/h2\u003e\n\u003cp\u003eThe intraoperative and the postoperative data were comparable between\u0026nbsp;the two groups (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eIntraoperative and Postoperative Data\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eUlinastatin Group (n=135)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eControl Group (n=278)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003ep\u003c/em\u003e Value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAortic cross-clamp time, min\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e70.0 (50.0, 96.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e63.0 (44.3, 92.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.25\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCPB time, min\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e97.0 (72.0.125.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e87.0 (65.0,120.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.27\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOperation time, min\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e215.0 (175.0, 245.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e195.0 (160.0, 240.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.08\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOperative mortality, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eSurgical Type, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.35\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCoronary artery bypass grafting\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16 (11.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32 (11.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"8\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMitral valvuloplasty or replacement\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e65 (48.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e124 (44.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAortic valve replacement\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20 (14.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e39 (14.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMitral and aortic valve replacement\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17 (12.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30 (10.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCABG and valvular procedure\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10 (7.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14 (5.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRepair of atrial septal defect\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 (3.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRepair of ventricular septal defect\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (3.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10 (3.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOther\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (3.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20 (7.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ePostoperative data\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMechanical ventilation, h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13.0 (11.0, 18.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13.0 (10.0, 17.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.36\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eICU stay, h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e25.0 (18.0, 56.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e25.5 (17.0, 58.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.53\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHospital length of stay, h\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7.0 (7.0, 8.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7.0 (7.0, 9.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.39\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\"\u003eThe differences in these characteristics between the two groups were evaluated by an independent two-sample \u003cem\u003et\u003c/em\u003e-test or one-way ANOVA. Categorical variables were summarized as frequency or percentage and compared by the chi-square test or Fisher\u0026rsquo;s exact test.\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\"\u003eCPB, cardiopulmonary bypass; CABG, coronary artery bypass grafting; ICU, intensive care unit.\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\"\u003eThere was no significant differences in the intraoperative and postoperative data (\u003cem\u003ep\u003c/em\u003e\u0026gt;0.05).\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n\u003ch2\u003eRenal Function Outcomes\u003c/h2\u003e\n\u003cp\u003eThe incidence of AKI in the ulinastatin group was significantly lower than\u0026nbsp;that in the control group (20.00% vs. 32.37%, p=0.009)). Furthermore, a\u0026nbsp;significant difference was observed between the two groups (p=0.002) about\u0026nbsp;the subclinical acute kidney injury, calculated by CSA-NGAL Scores (Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u0026nbsp;Six of 278 patients in the control group and no patients in the ulinastatin\u0026nbsp;group required RRT, but the difference was not significant (p=0.09).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eCSA-NGAL Scores and KDIGO Scores at 24 Hours Postoperatively\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCSA-NGAL Score, n (%)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eUlinasatin Group\u003c/p\u003e\n\u003cp\u003e(n=135)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eControl Group\u003c/p\u003e\n\u003cp\u003e(n=278)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e61 (45.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e96(34.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e48 (35.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e77(27.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22 (16.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e86(31.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (3.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19(6.8 )\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eKDIGO Score, n (%)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eUlinastatin Group (n=135)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eControl Group (n=278)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eP value\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e108 (80.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e188 (67.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20 (14.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e63 (22.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (3.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18 (6.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (1.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 (3.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAKI\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27 (20.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e90 (32.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e0.009*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003eThere was a significant difference between the two groups in the CSA-NGAL Scores at 24 hours postoperatively (\u003cem\u003ep\u003c/em\u003e=0.002). There was no significant difference in the KDIGO Scores between the two groups and in comparisons of pairs (\u003cem\u003ep\u003c/em\u003e=0.07).\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003eCSA-NGAL Score, cardiac surgery-associated NGAL score; NGAL, neutrophil gelatinase-associated lipocalin; KDIGO Score, Kidney Disease-Improving Global Outcomes score.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOn arrival at the ICU and at 6, 12, and 24 hours after surgery, the pNGAL\u0026nbsp;levels in the ulinastatin group versus control group were 89.78\u0026plusmn;114.23 vs.\u0026nbsp;129.41\u0026plusmn;163.58 ng/mL (p=0.005), 135.20\u0026plusmn;248.96 vs. 247.92\u0026plusmn;445.87 ng/mL\u0026nbsp;(p=0.001), 131.06\u0026plusmn;208.67 vs. 212.16\u0026plusmn;333.11 ng/mL (p\u0026lt;0.001), and\u0026nbsp;110.32\u0026plusmn;147.00 vs. 159.78\u0026plusmn;245.23 ng/mL (p=0.04), respectively. Moreover, the\u0026nbsp;mean time between the end of CPB and the first measurement of NGAL\u0026nbsp;between ulinastatin group and control group was 64.83704\u0026plusmn; 25.8575 min vs. 65.3777 \u0026plusmn;27.96383 min. The corresponding IL-6 levels were 0.37\u0026plusmn;0.24 vs. 0.40\u0026plusmn;0.25 pg/mL (p=0.30), 0.78\u0026plusmn;0.51 vs. 0.93\u0026plusmn;0.62 pg/mL (p=0.02), 0.83\u0026plusmn;0.51\u0026nbsp;vs. 1.05\u0026plusmn;0.74 pg/mL (p=0.02), and 0.58\u0026plusmn;0.35 vs. 0.89\u0026plusmn;0.65 pg/mL (p\u0026lt;0.001),\u0026nbsp;respectively, and the corresponding SCr levels were 1.07\u0026plusmn;0.30 vs. 1.08\u0026plusmn;0.35\u0026nbsp;mg/dL (p=0.86), 1.46\u0026plusmn;0.65 vs. 1.55\u0026plusmn;0.69 mg/dL (p=0.17), 1.46\u0026plusmn;0.72 vs.\u0026nbsp;1.57\u0026plusmn;0.77 mg/dL (p=0.14), and 1.28\u0026plusmn;0.43 vs. 1.32\u0026plusmn;0.61 mg/dL (p=1.00)\u0026nbsp;respectively.\u003c/p\u003e\n\u003cp\u003eThe postoperative SCr levels did not differ significantly between\u0026nbsp;the two groups (p=0.23; Figure \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ea), while the postoperative pNGAL levels\u0026nbsp;(p=0.007; Figure \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eb) and IL-6 levels (p=0.001; Figure \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ec) were significantly\u0026nbsp;lower in the ulinastatin group than in the control group. The CSA-NGAL Score\u0026nbsp;was significantly lower in the ulinastatin group than in the control group\u0026nbsp;(p=0.002; Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e), while the KDIGO Score did not differ significantly between\u0026nbsp;the two groups (p=0.07; Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e) during the first 24 hours after surgery.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n\u003ch2\u003eMortality and Other Adverse Outcomes\u003c/h2\u003e\n\u003cp\u003eThe in-hospital mortality rate was 1 case (0.74%) in the ulinastatin group\u0026nbsp;and 1 case (0.36%) in the control group, with no significant difference between\u0026nbsp;the two groups (p=0.60). In addition, length of ICU stay, length of mechanical\u0026nbsp;ventilation, and length of hospital stay did not differ significantly between the\u0026nbsp;two groups. The two groups also showed no significant differences in\u0026nbsp;postoperative complications like stroke, postoperative myocardial infarction,\u0026nbsp;cardiac arrest, deep sternal infection, ICU readmission, surgery-associated\u0026nbsp;reoperation, and RRT, IABP, and ECMO (p\u0026gt;0.05; Tables \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). Notably, the\u0026nbsp;incidence of respiratory failure was significantly lower in the ulinastatin group\u0026nbsp;than in the control group (p=0.02; Table \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab4\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eAdverse Events\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth colspan=\"4\" align=\"left\"\u003e\n\u003cp\u003eAdverse events, n (%)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMortality in-hospital\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (0.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (0.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.60\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eStroke\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (1.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.23\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePostoperative MI\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (1.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.23\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRespiratory failure\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1(0.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (5.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.02*\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSudden cardiac arrest\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (1.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.23\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eReadmission to ICU\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (1.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (1.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.97\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eReoperation for surgical cause\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (1.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (0.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.46\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRRT\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (2.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.09\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIABP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (0.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (1.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.40\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eECMO\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0 (0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e--\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDeep sternal infection\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1(0.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (0.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.60\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\"\u003e*There were significant differences between the two groups in the incidences of AKI (\u003cem\u003ep\u003c/em\u003e=0.009) and morbidity of respiratory failure (\u003cem\u003ep\u003c/em\u003e=0.022). There were no significant differences between the two groups in mortality and other postoperative adverse events (\u003cem\u003ep\u003c/em\u003e\u0026gt;0.05).\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\"\u003eAKI, acute kidney injury; MI, myocardial infarction; ICU, intensive care unit; RRT, renal replacement treatment; IABP, intra-aortic balloon pump; ECMO, extracorporeal membrane oxygenation.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eCSA-AKI is a severe complication in adult patients undergoing cardiac surgery with CPB, resulting in prolonged ICU stay and increased short-term and long-term morbidity[\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e]. Several processes to reduce CSA-AKI incidence have been established, and the efficacy of ulinastatin has been examined in recent years[\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e]. In the present study, we found that ulinastatin significantly reduced the incidence of CSA-AKI diagnosed according to the KDIGO criteria. In our study, the incidences of AKI were 20.00% in the ulinastatin group and 32.40% in the control group, consistent with the findings in recent studies[\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e]. Nakanishi et al.[\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e] demonstrated that ulinastatin administered before CPB could decrease postoperative elevation of IL-6 and IL-8 in patients undergoing cardiac surgery with CPB, while Song et al.[\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e] found that ulinastatin has no effect on attenuation of IL-6, TNF-\u0026alpha;, and improvements in renal function. Wang et al. [\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e]. Indicated that ulinastatin could reduce inflammation and dose dependently attenuate CPB-induced kidney injury in infant piglets. Wan et al.[\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e] performed a propensity score-matched study and showed that administration of ulinastatin during CPB is associated with a lower incidence of CSA-AKI. Other studies have indicated that ulinastatin can inhibit polymorphonuclear neutrophils, which is helpful to reduce the risk of bleeding and the requirement for blood transfusion after surgery[\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e]. Although AKI is a complex pathophysiological process rather than a specific syndrome, especially following cardiac surgery[\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e], SIRS arising after cardiac surgery plays a pivotal role in AKI development[\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e]. The pathogenesis of SIRS is associated with multiple factors, including surgical trauma, transfusion, hypothermia, blood loss, ischemia-reperfusion injury, immune system activation, and endotoxemia[\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e]. Ulinastatin has anti-inflammatory properties by inhibiting the activation of various inflammatory pathways[\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e]. Thus, serum IL-6 levels were evaluated in this study and found to be significantly lower in the ulinastatin group compared with the control group (p=0.001; Figure \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ec). The effect of ulinastatin on reducing CSA-AKI is considered to involve the inhibition of inflammation.\u003c/p\u003e\n\u003cp\u003eEvidence suggests that the KDIGO criteria are superior to other criteria, but have less sensitivity to detect early-stage tubular damage. The KDIGO criteria are based on the SCr level for diagnosis of AKI, and changes in SCr often occur 48 hours to 7 days after the original damage. Furthermore, SCr levels are affected by many related factors, and rescue interventions may be too late to prevent early perioperative AKI. These limitations drive us to search for new biomarkers that reflect early AKI. In addition to the KDIGO criteria, pNGAL, a newly discovered biomarker, was tested to predict kidney injury and prove previous findings[\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e]. NGAL plays a role in the early detection of AKI and can be upregulated at an earlier stage than elevation of SCr to meet the KDIGO criteria. NGAL in plasma and urine is upregulated when acute tubular damage occurs, but pNGAL is detectable earlier than uNGAL when tubular damage occurs. In a previous study, pNGAL was used to predict AKI based on the CSA NGAL Score, and the results were proven to be similar to those based on the KDIGO Score[\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e]. According to the KDIGO criteria and CSA-NGAL Score criteria, the incidences of CSA-AKI were similar in the present study. However, according to the CSA-NGAL Score criteria, 48 (35.60%) patients in the ulinastatin group and 77 (27.70%) patients in the control group were in the region of possible tubular damage, so-called subclinical AKI that is a separate entity and provides a warning to trigger awareness and appropriate clinical therapeutic modifications[\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eRespiratory failure in the present study was defined as prolonged ventilation support for more than 48 hours. The findings demonstrated that ulinastatin could reduce the incidence of respiratory failure, consistent with previous studies[\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e]. Xu et al.[\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e] suggested that ulinastatin inhibits the release of proinflammatory cytokines and PMNE, reduces pulmonary injury, and improves pulmonary function after CPB, thereby shortening the intubation time and length of ICU stay. The lung-protective effect of ulinastatin is dose dependent and a lower-than-effective dose could lead to negative results.\u003c/p\u003e\n\u003cp\u003eThe survival rate after ten years of follow-up did not differ significantly between the two groups. According to previous studies, the effect of ulinastatin may be diminished depending on the duration of administration[\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e], which is ascribed to the fact that ulinastatin is administered through a bolus injection rather than a continuous infusion[\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e]. Another reason is that the half-life of ulinastatin is about 40 minutes in healthy adults[\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e], while the duration of CPB is often longer than 40 minutes and the peak of IL-6 occurs at 4\u0026ndash;6 hours postoperatively[\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e]. A meta-analysis showed that ulinastatin could reduce inflammatory cytokines but does not affect hospital mortality[\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eThere are some limitations to the present study. First, the study was designed as a single-center prospective cohort design with less power than a randomized controlled trial. The rationale lay in the sparse evidence concerning the effect of ulinastatin on renal outcomes and the nature of a pilot study. It was in accordance with ethical considerations to conduct an observational study rather than an interventional study. Second, there were relatively high rates of loss to follow-up, comprising 14.20% (19/134) in the ulinastatin group and 14.10% (39/277) in the control group. It was a great challenge to achieve follow-up for as long as ten years. Nevertheless, the rates of loss to follow-up were comparable between the two groups and associated with less bias. Third, only SCr was evaluated for the AKI criteria in the present study. The urine output in the KDIGO criteria requires a state of oliguria or anuria lasting for more than 6, 12, or 24 hours, which was infeasible in postoperative ICU settings. For ethical considerations, oliguria and anuria would not be observed for such a long period and should be treated according to the institutional protocol promptly. Furthermore, assessment of AKI by SCr alone has been widely accepted in studies such as the BART study[\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e] and the ATACAS study[\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eIn the present study, the SCr, pNGAL, and serum IL-6 were detected, and CSA-AKI incidences according to the KDIGO criteria and CSA-NGAL Score criteria were analyzed, of which differed significantly between the two groups, except for SCr. Meanwhile, respiratory failure in the ulinastatin group was considerably lower than that in the control group. In summary, ulinastatin can significantly reduce the incidence of early postoperative AKI during cardiac surgery with CPB without affecting the long-term survival rate.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank Alison Sherwin, PhD, from Liwen Bianji, Edanz Group China (www.liwenbianji.cn/ac) for editing the English text of a draft of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAuthor Jia Shi and author Hong Lv, Huanran Lv, Yuda Fei, have given substantial contributions to the conception or the design of the manuscript, author Qian Li, Peng Zhang, Liang Cao, and author Lihuan Li to acquisition, analysis and interpretation of the data. All authors have participated to drafting the manuscript, author Jia Shi revised it critically.\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003eAll authors contributed equally to the manuscript and read and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003eThere is no Conflict of Interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eHobson CE, Yavas S, Segal MS, et al: Acute kidney injury is associated with increased long-term mortality after cardiothoracic surgery. Circulation 2009, 119(18):2444-2453.\u003c/li\u003e\n \u003cli\u003eMao H, Katz N, Ariyanon W, Blanca-Martos L, et al: Cardiac surgery-associated acute kidney injury. Cardiorenal medicine 2013, 3(3):178-199.\u003c/li\u003e\n \u003cli\u003eHoste EAJ, Kellum JA, Selby NM, et al: Global epidemiology and outcomes of acute kidney injury. Nature reviews Nephrology 2018, 14(10):607-625.\u003c/li\u003e\n \u003cli\u003eGuan C, Li C, Xu L, et al: Risk factors of cardiac surgery-associated acute kidney injury:development and validation of a perioperative predictive nomogram. Journal of nephrology 2019, 32(6):937-945.\u003c/li\u003e\n \u003cli\u003eHe G, Li Q, Li W, et al: Effect of ulinastatin on interleukins and pulmonary function in bypass patients: a meta-analysis of randomized controlled trials. Herz 2020, 45(4):335-346.\u003c/li\u003e\n \u003cli\u003ede Geus HR, Ronco C, Haase M, et al: The cardiac surgery-associated neutrophil gelatinase-associated lipocalin (CSA-NGAL) score: A potential tool to monitor acute tubular damage. The Journal of thoracic and cardiovascular surgery 2016,151(6):1476-1481.\u003c/li\u003e\n \u003cli\u003eLiu Y, Wang YL, Zou SH, et al: Effect of high-dose ulinastatin on the cardiopulmonary bypass-induced inflammatory response in patients undergoing open-heart surgery.Chinese medical journal 2020, 133(12):1476-1478.\u003c/li\u003e\n \u003cli\u003eFergusson DA, H\u0026eacute;bert PC, Mazer CD, et al: A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. The New England journal of medicine 2008,358(22):2319-2331.\u003c/li\u003e\n \u003cli\u003eWetz AJ, Richardt EM, Schotola H,: Haptoglobin and free haemoglobin during cardiac surgery-is there a link to acute kidney injury? Anaesthesia and intensive care 2017,45(1):58-66.\u003c/li\u003e\n \u003cli\u003eNakahama H, Obata K, Sugita M: Ulinastatin ameliorates acute ischemic renal injury in rats. Renal failure 1996, 18(6):893-898.\u003c/li\u003e\n \u003cli\u003eSong J, Park J, Kim JY, et al: Effect of ulinastatin on perioperative organ function ands ystemic inflammatory reaction during cardiac surgery: a randomized double-blindedstudy. Korean journal of anesthesiology 2013, 64(4):334-340.\u003c/li\u003e\n \u003cli\u003eWang X, Xue Q, Yan F, et al: Ulinastatin Protects against Acute Kidney Injury in Infant Piglets Model Undergoing Surgery on Hypothermic Low-Flow Cardiopulmonary Bypass. PloS one 2015, 10(12):e0144516.\u003c/li\u003e\n \u003cli\u003eWan X, Xie X, Gendoo Y, et al: Ulinastatin administration is associated with a lower incidence of acute kidney injury after cardiac surgery: a propensity score matched study. Critical care (London, England) 2016, 20:42.\u003c/li\u003e\n \u003cli\u003eShu H, Liu K, He Q, et al: Ulinastatin, a protease inhibitor, may inhibit allogeneic blood transfusion-associated pro-inflammatory cytokines and systemic inflammatory response syndrome and improve postoperative recovery. Blood transfusion = Trasfusione del sangue 2014, 12 Suppl 1(Suppl 1):s109-118.\u003c/li\u003e\n \u003cli\u003eZhang P, Lv H, Qi X, et al: Effect of ulinastatin on post-operative blood loss and allogeneic transfusion in patients receiving cardiac surgery with cardiopulmonary bypass: a prospective randomized controlled study with 10-year follow-up. Journal of cardiothoracic surgery 2020, 15(1):98.\u003c/li\u003e\n \u003cli\u003eMutlu H, G\u0026uuml;nd\u0026uuml;z E, Titiz TA, et al İ: Investigation of AKI with Early Biomarkers After Cardiac Surgery. Brazilian journal of cardiovascular surgery 2020, 35(5):722-731.\u003c/li\u003e\n \u003cli\u003eGreenberg JH, Parsons M, Zappitelli M, et al: Cardiac Biomarkers for Risk Stratification of Acute Kidney Injury After Pediatric Cardiac Surgery. The Annals of thoracic surgery 2021, 111(1):191-198.\u003c/li\u003e\n \u003cli\u003eMcBride WT, Prasad PS, Armstrong M, et al: Cytokine phenotype, genotype, and renal outcomes at cardiac surgery. Cytokine 2013, 61(1):275-284.\u003c/li\u003e\n \u003cli\u003eCremer J, Martin M, Redl H, et al: Systemic inflammatory response syndrome after cardiac operations. The Annals of thoracic surgery 1996, 61(6):1714-1720.\u003c/li\u003e\n \u003cli\u003eInoue K, Takano H, Shimada A, et al: Urinary trypsin inhibitor protects against systemic inflammation induced by lipopolysaccharide. Molecular pharmacology 2005,67(3):673-680.\u003c/li\u003e\n \u003cli\u003eGao C, Huan J, Li W, et al : Protective effects of ulinastatin on pancreatic and renal damage in rats following early scald injury. Burns : journal of the International Society for Burn Injuries 2009, 35(4):547-552.\u003c/li\u003e\n \u003cli\u003eSinger E, Mark\u0026oacute; L, Paragas N, et al: Neutrophil gelatinase-associated lipocalin: pathophysiology and clinical applications. Acta physiologica (Oxford, England) 2013, 207(4):663-672.\u003c/li\u003e\n \u003cli\u003eZhang X, Zhu Z, Jiao W, et al: Ulinastatin treatment for acute respiratory distress syndrome in China: a meta-analysis of randomized controlled trials. BMC pulmonary medicine 2019, 19(1):196.\u003c/li\u003e\n \u003cli\u003eXu CE, Zou CW, Zhang MY, et al: Effects of high-dose ulinastatin on inflammatory response and pulmonary function in patients with type-A aortic dissection after cardiopulmonary bypass under deep hypothermic circulatory arrest. Journal of cardiothoracic and vascular anesthesia 2013, 27(3):479-484.\u003c/li\u003e\n \u003cli\u003eJ\u0026ouml;nsson-Berling BM, Ohlsson K: Distribution and elimination of intravenously injected urinary trypsin inhibitor. Scandinavian journal of clinical and laboratory investigation1991, 51(6):549-557.\u003c/li\u003e\n \u003cli\u003eOh SY, Kim JC, Choi YS, et al: Effects of ulinastatin treatment on myocardial and renal injury in patients undergoing aortic valve replacement with cardiopulmonary bypass.Korean journal of anesthesiology 2012, 62(2):148-153.\u003c/li\u003e\n \u003cli\u003eEnzan K, Mitsuhata H, Masaki Y, et al: [Effects of ulinastatin on granulocyte elastase and fibronectin in patients undergoing cardiopulmonary bypass]. Masui The Japanese journal of anesthesiology 1991, 40(11):1625-1631.\u003c/li\u003e\n \u003cli\u003eJi M, Chen T, Wang B, et al: Effects of ulinastatin combined with mechanical ventilation on oxygen metabolism, inflammation and stress response and antioxidant capacity ofARDS. Experimental and therapeutic medicine 2018, 15(6):4665-4670.\u003c/li\u003e\n \u003cli\u003eHe QL, Zhong F, Ye F, et al: Does intraoperative ulinastatin improve postoperative clinical outcomes in patients undergoing cardiac surgery: a meta-analysis of randomized controlled trials. BioMed research international 2014, 2014:630835.\u003c/li\u003e\n \u003cli\u003eMyles PS, Smith JA, Forbes A, et al: Tranexamic Acid in Patients Undergoing Coronary-Artery Surgery. The New England journal of medicine 2017, 376(2):136-148.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"ulinastatin, acute kidney injury, cardiac surgical procedures, cardiopulmonary bypass","lastPublishedDoi":"10.21203/rs.3.rs-1049165/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1049165/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eBackground\u003c/em\u003e: \u003c/strong\u003eUlinastatin is a serine protease inhibitor with anti-inflammatory effects. Evidence for the effects of ulinastatin on renal outcomes remains sparse in patients receiving cardiac surgery with cardiopulmonary bypass (CPB).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eMethods\u003c/em\u003e\u003c/strong\u003e\u003cem\u003e: \u003c/em\u003eThis prospective cohort study evaluated 413 patients aged 18–70 years who underwent cardiac surgery with CPB, from Aug 2008 to Jul 2019 in Fuwai Hospital, Beijing ,China. The ulinastatin group included 135 patients who received intravenous ulinastatin (1×106 U) after induction of anesthesia. The remaining 278 patients without ulinastatin served as the control group. The primary outcome was the rate of new-onset postoperative acute kidney injury (AKI). The secondary outcome was renal replacement therapy(RRT). Serum creatinine, plasma NGAL, and serum IL-6 levels were evaluated and the CSANGAL Score was calculated. In addition, in-hospital mortality, morbidity, adverse outcomes and 10-year follow-up the survival rate was analyzed.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eResults:\u003c/em\u003e\u003c/strong\u003e Rate of new-onset AKI was significantly lower in the ulinastatin group than in the control group (20.00% vs. 32.40%, p=0.009). There was no significant difference of RRT between the two groups (0.00% vs. 2.16%, p=0.09). In-hospital mortality, morbidity, and adverse outcomes were comparable between the two groups except for a significantly lower incidence of respiratory failure in the ulinastatin group compared with the control group (0.76% vs. 5.40%, p=0.02). The 10-year follow-up survival rates did not differ significantly between the two groups.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConclusions:\u003c/em\u003e\u003c/strong\u003e Ulinastatin significantly reduced postope rative AKI and respiratory failure in patients receiving cardiac surgery with CPB. But ulinastatin did not reduce ICU and hospital stay and mortality.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eClinical trial registration: \u003c/em\u003e\u003c/strong\u003eNCT01060189\u003c/p\u003e","manuscriptTitle":"Effects of Ulinastatin on Postoperative Renal Function in Patients Undergoing Cardiac Surgery With Cardiopulmonary Bypass: a Prospective Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-11-16 15:28:49","doi":"10.21203/rs.3.rs-1049165/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"14dbb4fd-460a-4645-b6d5-305a47b70154","owner":[],"postedDate":"November 16th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":8547271,"name":"Cardiothoracic Surgery"}],"tags":[],"updatedAt":"2022-04-20T19:21:48+00:00","versionOfRecord":[],"versionCreatedAt":"2021-11-16 15:28:49","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1049165","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1049165","identity":"rs-1049165","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}