Measuring The Concentration of Serum Syndecan-1 To Assess Vascular Endothelial Glycocalyx Injury During Hemodialysis

Measuring The Concentration of Serum Syndecan-1 To Assess Vascular Endothelial Glycocalyx Injury During Hemodialysis | 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 Measuring The Concentration of Serum Syndecan-1 To Assess Vascular Endothelial Glycocalyx Injury During Hemodialysis Keigo Kusuzawa, Keiko Suzuki, Hideshi Okada, Kodai Suzuki, Chihiro Takada, and 28 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-846591/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 23 Dec, 2021 Read the published version in Frontiers in Medicine → Version 1 posted You are reading this latest preprint version Abstract Glycocalyx is present on the surface of healthy endothelium, and the concentration of serum syndecan-1 can serve as an injury marker. This study aimed to evaluate the hemodialysis-associated changes in the serum syndecan-1 concentration. This was a single-center, retrospective, observational study. Between March 2017 and December 2019, 145 patients who underwent hemodialysis at the Gifu University Hospital were enrolled. The median dialysis period and dialysis time were 63 months and 3.7 hours, respectively. The serum syndecan-1 concentration increased from 124.6 ± 107.8 ng/mL before hemodialysis to 229.0 ± 138.1 ng/mL after hemolysis ( P < 0.001). Treatment with anticoagulant nafamostat mesylate inhibited hemodialysis-induced increase in the levels of serum syndecan-1 in comparison to unfractionated heparin. Dialysis time and the change in concentration of syndecan-1 were positively correlated, whereas the amount of body fluid removed and changes in the concentration of syndecan-1 were not correlated. The reduction in amount of body fluid removed and dialysis time inhibited the change in of syndecan-1 levels before and after hemodialysis. In conclusion, quantitative assessment of the endothelial glycocalyx injury during hemodialysis can be done by measuring the concentration of serum syndecan-1 which may aid in the selection of appropriate anticoagulants, hemodialysis time, and the amount of body fluid removed. Urology & Nephrology Mathematical Physics Computational Physics Laboratory Diagnostics Hemodialysis Glycocalyx Syndecan-1 Body fluid removal Nafamostat mesylate Figures Figure 1 Figure 2 Introduction Malnutrition, inflammation, and atherosclerosis are strongly associated in chronic kidney disease 1 . and both a malnourished state and atherosclerosis can be caused by inflammation. Moreover, chronic microinflammation is observed in patients who undergo hemodialysis 2 . Several factors, such as uremia, activation of free radicals and adhesion molecules, and hemodialysis membrane, lead to microinflammation in patients who undergo hemodialysis 3 – 5 . Uremic substances and the hemodialysis membrane promote the production of free radicals and cytokines by stimulating neutrophils, and the resulting inflammation further causes endothelial injury. However, there is no method to quantitatively assess endothelial cells injury. The vascular endothelium is composed of a thin monolayer of endothelial cells, and this lines the entire circulatory system, particularly those parts that are exposed to the circulating blood. The healthy endothelium is covered by a sugar-protein called glycocalyx 6 – 10 that plays pivotal roles in vascular homeostasis 11 , 12 . The endothelial glycocalyx is degraded by several factors, such as sepsis, major surgery, trauma, ischemia/reperfusion, and prolonged hyperglycemia. Persistent and diffuse alterations in the glycocalyx are associated with widespread endothelial dysfunction, changed permeability, and impaired oxygen and nutrient delivery to the cells 11 , 13 , 14 . Several studies have revealed the relationship between endothelial glycocalyx injury and serious diseases, such as cardiovascular disease, acute kidney injury, and chronic kidney disease 15 , 16 . Moreover, the structure of the endothelial glycocalyx is degraded in chronic diseases, such as aging 17 , diabetes 18 , and hypertriglyceridemia 19 . The glycocalyx comprises cell-bound proteoglycans, glycosaminoglycan side chains, and sialoproteins 13 , 20 . The proteoglycans consist of a core protein, such as a member of the syndecan protein family, to which glycosaminoglycan molecules are linked 21 . Syndecan-1 is the core protein in heparan sulfate proteoglycan that is found in the glycocalyx. Syndecan-1 is released from the endothelium when the glycocalyx is injured, causing an increase in its concentration in circulation 22 . Moreover, serum syndecan-1 has been used as an endothelial injury marker in recent clinical studies in critically ill patients 23 – 26 . Therefore, the present study aimed to assess endothelial injury using serum syndecan-1 as a marker of endothelial glycocalyx injury in patients who underwent hemodialysis. Additionally, the present study examined the medication type and factors that influence the concentration of syndecan-1. Results Characteristics of patients We finally enrolled 145 patients with a median age of 66 years (Fig. 1 , Table 1 ). The median dialysis period and dialysis time were 63 months and 3.7 hours, respectively. The most common primary illness was diabetic nephropathy which was observed in 37 patients (25.5%). Table 1 Patient demographics. Characteristics Median (range) or number Number of cases, n 145 Age (years), mean (IQR) 68 (60–77) Sex (female/male), n (%) 44 (30.3) / 101 (69.7) Dialysis period (months), median (IQR) 20.0 (1.0, 87.0) Dialysis time (hours), median (IQR) 4.0 (3.0, 4.0) Primary illness, n (%) Chronic glomerulonephritis 29 (20.0) Rapidly progressive glomerulonephritis 4 (2.8) Polycystic kidney disease 8 (5.5) Nephrosclerosis 8 (5.5) Diabetic nephropathy 37 (25.5) Nephritis with autoimmune disease 6 (4.1) Renal/urological tumor 5 (3.4) Obstructive urinary tract/urination disorders 1 (0.7) Paraproteinemia (myeloma) 1 (0.7) Acute kidney injury 10 (6.9) Congenital anomalies of the kidney and urinary tract 1 (0.7) Unknown 33 (22.8) Others 2 (1.4) Hemodialysis type, n (%) HD 133 (91.7) HDF 12 (8.3) Dialysis efficiency Kt/V 1.20 (0.06–1.86) Medication, n (%) Unfractionated heparin 101 (69.7) Low-molecular-weight heparin 24 (16.6) Nafamostat mesylate 20 (13.8) Dialysis membrane, n (%) Polyethersulfone 110 (75.9) Polysulfone 34 (23.4) Asymmetric triacetate 1 (0.7) HD hemodialysis, HDF hemodiafiltration, IQR interquartile range. The number of patients who underwent hemodialysis and hemodiafiltration was 133 (91.7%) and 12 (8.3%), respectively. Anticoagulation agents, such as unfractionated heparin, low-molecular-weight heparin, and nafamostat mesylate, were administered to 101, 24, and 20 patients, respectively. Median Kt/V, an index of dialysis efficiency, was 1.20. Concentration Of Serum Syndecan-1 And Hemodialysis The concentration of serum syndecan-1 before and after hemodialysis was 124.6 ± 107.8 ng/mL and 229.0 ± 138.1 ng/mL, respectively; this indicates that the concentration of serum syndecan-1 had significantly increased ( P < 0.001) after hemodialysis (Table 2 ). Table 2 Serum SDC-1 concentration before and after hemodialysis. Status SDC-1 concentration (ng/mL) P -value Before HD 124.6 ± 107.8 < 0.001 After HD 229.0 ± 138.1 SDC-1 syndecan-1, HD hemodialysis. P -values were obtained from a mixed-effects model. The concentration of serum syndecan-1 significantly increased after hemodialysis in patients who received unfractionated heparin and low-molecular-weight heparin; however, the concentration of syndecan-1 was not significantly different before and after hemodialysis in those who received nafamostat mesylate (Table 3 ). Table 3 Serum SDC-1 concentration and anticoagulants. Anticoagulants Before HD (ng/mL) After HD (ng/mL) P -value Unfractionated heparin 112.0 ± 79.8 235.4 ± 126.8* < 0.001 Low-molecular-weight heparin 144.1 ± 135.8 248.5 ± 174.1* < 0.001 Nafamostat mesylate 164.2 ± 171.1 173.3 ± 141.3 0.459 SDC-1 syndecan-1, HD hemodialysis. Additionally, according to the multivariable regression analysis after adjusting for age, sex, dry weight, and dialysis period, treatment with nafamostat mesylate inhibited the increase in the concentration of serum syndecan-1 during hemodialysis compared to treatment with unfractionated heparin and low-molecular-weight heparin (Table 4 ). Table 4 Results of multivariable regression analysis between anticoagulants. Anticoagulants Coefficient* 95% LCL 95% UCL P -value Low-molecular-weight heparin vs. unfractionated heparin -18.07 -56.776 20.637 0.358 Nafamostat mesylate vs. unfractionated heparin -116.473 -158.442 -74.504 < 0.001 Nafamostat mesylate vs. low-molecular-weight heparin -98.403 -150.482 -45.324 < 0.001 *Coefficients from the multivariable linear regression model adjusted for age, sex, dry weight, and dialysis period, shown as differences in serum syndecan-1 concentration for low-molecular-weight heparin vs. unfractionated heparin, nafamostat mesylate vs. unfractionated heparin, and nafamostat mesylate vs. low-molecular-weight heparin, respectively. LCL lower confidence limit, UCL upper confidence limit. Association of concentration of serum syndecan-1 with dialysis time and body fluid removal The relationship between the concentration variability of syndecan-1 and the dialysis condition, including the dialysis time and the amount of body fluid removed, was confirmed. The amount of body fluid removal was corrected by dry weight. The dialysis time and change in concentration of syndecan-1 showed positive correlation ( P = 0.033), but there was no significant association ( P = 0.111) between the amount of body fluid removed and changes in the concentration of syndecan-1 (Table 5 ). Table 5 Relationship between syndecan-1 concentration variability and dialysis conditions. Factors Coefficient* 95% LCL 95% UCL P -value Body fluid removed/dry weight (per 0.01 L/Kg increase) 9.107 0.144 18.07 0.111 Dialysis time (per 1 minute increase) 23.349 -8.836 55.533 0.033 *Coefficients from the multivariable linear regression model adjusted for age, sex, and dialysis period, shown as increment in serum syndecan-1 concentration for a unit change in factors. LCL lower confidence limit, UCL upper confidence limit. Next, we examined the association between changes in the concentration of syndecan-1 and dialysis parameters, including dialysis time and the amount of body fluid removed. The change in the concentration of syndecan-1 before and after hemodialysis increased with respect to enhanced removal of body fluids and prolonged dialysis time ( P for interaction = 0.063, Fig. 2 ). However, the amount of change in the concentration of syndecan-1 before and after hemodialysis decreased with respect to a decrease in the amount of body fluid removed and shortened dialysis time. Discussion The present study revealed that a) the endothelial glycocalyx is injured during hemodialysis; b) endothelial glycocalyx injury is attenuated by administering nafamostat mesylate as an anticoagulant; and c) endothelial glycocalyx injury is aggravated by an increase in the amount of body fluid removed and prolonged dialysis time. The endothelial glycocalyx is injured in patients with chronic kidney disease and by plasma volume expansion 27 . Therefore, we hypothesized that the serum syndecan-1 levels would increase in patients who undergo hemodialysis. A previous study indicated that the concentration of serum syndecan-1 was approximately 20 ng/mL in healthy people 19 ; in contrast, in the present study, it was 124.6 ± 107.8 ng/mL in patients who underwent hemodialysis. This result confirmed that the endothelial glycocalyx sustained injuries in patients who undergo hemodialysis. Endothelial glycocalyx injury may be attenuated by a decrease in fluid volume after hemodialysis. However, the levels of serum syndecan-1 increased after hemodialysis than those before hemodialysis. This finding suggests that the endothelial glycocalyx is injured during hemodialysis due to neutrophils and inflammation via the production of free radicals and cytokines. During hemodialysis, unfractionated heparin, low-molecular-weight heparin, and nafamostat mesylate were used as anticoagulating agents. Low-molecular-weight heparin and nafamostat were administered in patients that had any disease which was associated with bleeding tendencies. The results of the present study suggest that an increase in the concentration of syndecan-1 is attenuated in patients who receive nafamostat mesylate. Nafamostat mesylate, a synthetic serine protease inhibitor, is a short-acting anticoagulant 28 , and is also used during hemodialysis to prevent proteolysis of fibrinogen into fibrin 29 . It is a slow, tight-binding substrate that traps the target protein in the acyl-enzyme intermediate form, and inhibits enzyme activity 30 , 31 . Nafamostat has been recently identified as a potential therapy against COVID-19 32 . Infection with SARS-CoV-2 induces endotheliitis due to viral involvement and inflammatory response of the host, and thus, it is associated with endothelial glycocalyx injury 21 . Therefore, nafamostat mesylate may have a beneficial effect on the endothelial glycocalyx, although it is supported by only circumstantial evidence. Extension of dialysis time is a strategy to improve prognosis 33 ; however, it remains controversial 33 , 34 . The present study identified that changes in the levels of serum syndecan-1 are small in patients who have prolonged dialysis time and slow removal of body fluid. Therefore, these two strategies could prevent endothelial glycocalyx injury. Several reports have also revealed that prolonged hemodialysis was associated with improved blood pressure and fluid management 35 – 37 . Additionally, rapid removal of body fluid is associated with a greater risk of mortality and cardiovascular events 38 . Moreover, hypotension during hemodialysis is also associated with higher mortality 39 . These mechanisms may explain how lower ultrafiltration rates with prolonged hemodialysis and slow removal of body fluids may ameliorate endothelial vascular permeability via attenuation of endothelial glycocalyx injury. Therefore, we propose that slow removal of body fluids with prolonged hemodialysis can reduce hypotension during hemodialysis. This study has some limitations. First, the hemodialysis time in most patients was less than 4 h. Therefore, an accurate examination of prolonged hemodialysis could not be performed. Second, less type of dialyzer was used in the present study. Although further studies are required, measuring the concentration of serum syndecan-1 may help in the assessment of endothelial injury under low blood flow (e.g., chronic hemodiafiltration), and of membrane compatibility by using a different type of dialyzer. Moreover, serum syndecan-1 is proposed to be a useful biomarker for daily monitoring of organ dysfunction, and may be an important risk factor for mortality in critically ill patients 25 . In conclusion, the study presented a method for the quantitative assessment of endothelial glycocalyx injury by measuring the concentration of serum syndecan-1 during hemodialysis. Although hemodialysis causes endothelial glycocalyx injury, it may be mitigated by maintenance of hemodialysis duration and by modulation of the amount of body fluid removed via the quantitative assessment of the serum syndecan-1. Methods Patients This was a single-center, retrospective, observational study conducted at the Gifu University Hospital, affiliated to Gifu University, Gifu, Japan. Patients who underwent hemodialysis at the Gifu University Hospital between March 2017 and December 2019 were enrolled in the study. Patients aged <20 years, who underwent plasma apheresis, plasma exchange, and double filtration plasma therapy, and who had not maintained their dry weight were excluded from the analysis. Finally, data from 145 patients were used for the final analyses in this study (Fig. 1). Ethics approval and consent to participate The study conformed to the principles outlined in the Declaration of Helsinki 40 . Ethics approval was obtained from the Medical Ethics Committee of the Gifu University Graduate School of Medicine, Gifu, Japan (record no.: 2021-A005). The need for informed consent from participants was waived by the medical ethics committee due to the retrospective nature of the study. Before initiation, the study was registered in the UMIN Clinical Trials Registry (registry number: UMIN000051415). Data collection and study design Blood was routinely sampled before and after hemodialysis from eligible patients at the time of last hemodialysis before being discharged from Gifu University Hospital, and data from these blood samples were used in the present study. All laboratory data (except serum syndecan-1), dry weight, and other patient demographics were extracted from the hospital’s electronic medical records. The concentration of serum syndecan-1 was measured using an enzyme-linked immunosorbent assay (950.640.192; Diaclone, Besancon, Cedex, France). The data were retrospectively analyzed. As an index of the efficiency of dialysis, Kt/V was calculated as described previously 41 . Statistical analysis Patients’ baseline characteristics are presented as median and interquartile range (IQR) for continuous variables, and frequency and proportion for categorical variables. For the primary analysis, a mixed effect model was used to assess the change in syndecan-1 levels with hemodialysis. The difference in syndecan-1 levels before and after hemodialysis in the anticoagulant subgroup was confirmed using paired t -test. A multivariable linear regression analysis was performed to compare the change in syndecan-1 levels before/after hemodialysis and treatment with anticoagulants. The covariates in the regression model were age, sex, dry weight, and dialysis period 42 . These variables were selected a priori on the basis of previous studies. In another model, dry weight and dialysis period were simultaneously incorporated into the linear regression model to evaluate the effect of factors during dialysis on the levels of syndecan-1. An interaction term was included in the model to confirm the effect of modification of dry weight and dialysis period on changes in the levels of syndecan-1. If the interaction term was statistically significant, the effect of the dialysis period (or dry weight) on syndecan-1 was determined to be modified by dry weight (or the dialysis period). There were no missing values in the data used in the analyses. A two-sided P <0.05 was considered to be statistically significant. The study is exploratory and there were concerns about low statistical power; therefore, the interaction was evaluated with a two-sided P <0.1. R version 4.1.0 was used for statistical analyses ( www.r-project.org ). Data availability The data that support the findings of this study are available from the corresponding author (HO) upon reasonable request. Declarations Acknowledgements The authors would like to thank the paramedical crew that shared the data obtained by them with us and allowed us to use the data for the writing of this report. The authors thank Editage (www.editage.com) for English language editing. Author contributions K.K. and H. Okada wrote the manuscript. K.K., Kodai S., S.N., H. Okamoto, G.Y., R.K., and T. Miura collected the blood samples. Y. Keiko S., C.T., Y. Kawasaki, T. Minamiyama., A.N., H.F., T.S., Y.T., Tomoki Y., and Y.N. measured the syndecan-1 concentration using ELISA. Keiko S. and R.Y. created a database. T.I. performed statistical analysis. Y.M., T. Miyake, Y. Kitagawa, T.F., T.D., and Takahiro Y. treated the patients. H.T., S.Y., and S.O. supervised the study. H. Okada and A.S. revised and edited the manuscript. The final manuscript was reviewed and approved by all authors. Competing interests All authors declare no competing interests. Funding This work was supported by the Ministry of Education, Science and Culture of Japan grants-in-aid for scientific research [grant numbers 19H03756, 19K18347, 19K09410, 18K16511]. References Stenvinkel, P. et al. Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure. Kidney Int , 55 , 1899–1911 https://doi.org/10.1046/j.1523-1755.1999.00422.x (1999). Zimmermann, J., Herrlinger, S., Pruy, A., Metzger, T. & Wanner, C. Inflammation enhances cardiovascular risk and mortality in hemodialysis patients. Kidney Int , 55 , 648–658 https://doi.org/10.1046/j.1523-1755.1999.00273.x (1999). Kultz, D. Hyperosmolality triggers oxidative damage in kidney cells. Proc Natl Acad Sci U S A , 101 , 9177–9178 https://doi.org/10.1073/pnas.0403241101 (2004). Rashid, G., Benchetrit, S., Fishman, D. & Bernheim, J. 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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-846591","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":49135741,"identity":"43b9623f-0df7-49fe-9c28-69f9f9dda859","order_by":0,"name":"Keigo Kusuzawa","email":"","orcid":"","institution":"Gifu University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Keigo","middleName":"","lastName":"Kusuzawa","suffix":""},{"id":49135742,"identity":"2bcd1167-3728-48dd-8c11-b2fbc3ec523f","order_by":1,"name":"Keiko Suzuki","email":"","orcid":"","institution":"Gifu University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Keiko","middleName":"","lastName":"Suzuki","suffix":""},{"id":49135743,"identity":"2a7dc0f2-9071-4e32-8bff-2b590503e8f4","order_by":2,"name":"Hideshi Okada","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4UlEQVRIie3PvQrCMBSG4S8cqIviGiiYW2gR/AHF0dtQhHZyEhylUIiL0LWbt2A3RyHgJLo61sXdsYNgsahbzSiYd0k48HASwGT6wRyCAxbwBoilr+FIizRB5GgSPAnGAT6kvHaFkku27fjrIVmcSYh6gGtaRrqhNWvWDnyaqIK48Q5+6T5HVVs2kzkJ63v7LsE2gMe/kHaWSe67YbFloENaqEk+ElSQsQaxZnZO3A0RdXDkk1h9+8tJJbdMLoSIFDtj3utHy5WXlpGP3T2P/ElU9bQERPC+VvZ6xGQymf6lB6FpPRq0SxKzAAAAAElFTkSuQmCC","orcid":"","institution":"Gifu University Graduate School of Medicine","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Hideshi","middleName":"","lastName":"Okada","suffix":""},{"id":49135744,"identity":"d472840a-3210-45e6-8ba5-896d08fa3f90","order_by":3,"name":"Kodai Suzuki","email":"","orcid":"","institution":"Gifu University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kodai","middleName":"","lastName":"Suzuki","suffix":""},{"id":49135745,"identity":"c78cb151-cf0e-4832-8343-4d2b919d6380","order_by":4,"name":"Chihiro Takada","email":"","orcid":"","institution":"Gifu University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Chihiro","middleName":"","lastName":"Takada","suffix":""},{"id":49135746,"identity":"0d59a4fb-b429-4a15-bcd9-b56399a7700c","order_by":5,"name":"Soichiro Nagaya","email":"","orcid":"","institution":"Gifu University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Soichiro","middleName":"","lastName":"Nagaya","suffix":""},{"id":49135747,"identity":"7b8ad584-289b-45ca-a55e-a478cfd7b277","order_by":6,"name":"Ryu Yasuda","email":"","orcid":"","institution":"Gifu University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ryu","middleName":"","lastName":"Yasuda","suffix":""},{"id":49135748,"identity":"0d489059-8d6f-43cb-a329-86f3731f3205","order_by":7,"name":"Haruka Okamoto","email":"","orcid":"","institution":"Gifu University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Haruka","middleName":"","lastName":"Okamoto","suffix":""},{"id":49135749,"identity":"3f9e09bc-4463-44d0-a0b8-10bd1188e115","order_by":8,"name":"Takuma Ishihara","email":"","orcid":"","institution":"Gifu University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Takuma","middleName":"","lastName":"Ishihara","suffix":""},{"id":49135750,"identity":"e3c066bb-ad9f-45cc-8c1c-5732826232e7","order_by":9,"name":"Hiroyuki Tomita","email":"","orcid":"","institution":"Gifu University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hiroyuki","middleName":"","lastName":"Tomita","suffix":""},{"id":49135751,"identity":"99c0da02-a1b3-48ec-ad30-02bcf81f54c7","order_by":10,"name":"Yuki Kawasaki","email":"","orcid":"","institution":"Gifu University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yuki","middleName":"","lastName":"Kawasaki","suffix":""},{"id":49135752,"identity":"2bcd6032-f200-49a6-ad99-33d26c8abba4","order_by":11,"name":"Toru Minamiyama","email":"","orcid":"","institution":"Gifu University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Toru","middleName":"","lastName":"Minamiyama","suffix":""},{"id":49135753,"identity":"296392a8-7895-4d0b-9f53-da72fe47f33b","order_by":12,"name":"Ayane Nishio","email":"","orcid":"","institution":"Gifu University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ayane","middleName":"","lastName":"Nishio","suffix":""},{"id":49135754,"identity":"490d8744-9a8b-4f2c-b2d8-702959c556b2","order_by":13,"name":"Hirotsugu Fukuda","email":"","orcid":"","institution":"Gifu University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hirotsugu","middleName":"","lastName":"Fukuda","suffix":""},{"id":49135755,"identity":"3947b567-b734-4cce-b374-c6e55b3e248a","order_by":14,"name":"Takuto Shimada","email":"","orcid":"","institution":"Gifu University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Takuto","middleName":"","lastName":"Shimada","suffix":""},{"id":49135756,"identity":"18f31926-f5e5-4710-bb5f-e52f356db610","order_by":15,"name":"Yuto Tamaoki","email":"","orcid":"","institution":"Gifu University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yuto","middleName":"","lastName":"Tamaoki","suffix":""},{"id":49135757,"identity":"da599d54-1f13-4e38-80ea-4ab228afe044","order_by":16,"name":"Tomoki Yoshida","email":"","orcid":"","institution":"Gifu University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Tomoki","middleName":"","lastName":"Yoshida","suffix":""},{"id":49135758,"identity":"5e39f61b-d494-43f3-a627-223062a85436","order_by":17,"name":"Yusuke Nakashima","email":"","orcid":"","institution":"Gifu University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yusuke","middleName":"","lastName":"Nakashima","suffix":""},{"id":49135759,"identity":"1a097a1b-3704-4052-85cf-f513f41a844d","order_by":18,"name":"Genki Yoshimura","email":"","orcid":"","institution":"Gifu University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Genki","middleName":"","lastName":"Yoshimura","suffix":""},{"id":49135760,"identity":"188f1f43-8158-4515-8ee4-98bfc8ed3af3","order_by":19,"name":"Ryo Kamidani","email":"","orcid":"","institution":"Gifu University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ryo","middleName":"","lastName":"Kamidani","suffix":""},{"id":49135761,"identity":"cb9e8339-e71e-4a64-90d6-5c34524e83ee","order_by":20,"name":"Tomotaka Miura","email":"","orcid":"","institution":"Gifu University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Tomotaka","middleName":"","lastName":"Miura","suffix":""},{"id":49135762,"identity":"dbacd6f7-0c1d-4d1e-9acc-b562ed2c36be","order_by":21,"name":"Hideaki Oiwa","email":"","orcid":"","institution":"Gifu University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hideaki","middleName":"","lastName":"Oiwa","suffix":""},{"id":49135763,"identity":"85749846-f40b-450d-b7d9-7dccd2a5d0dd","order_by":22,"name":"Fuminori Yamaji","email":"","orcid":"","institution":"Gifu University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Fuminori","middleName":"","lastName":"Yamaji","suffix":""},{"id":49135764,"identity":"8af4f5fc-417e-4a01-8aaf-68ce24c2733b","order_by":23,"name":"Yosuke Mizuno","email":"","orcid":"","institution":"Gifu University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yosuke","middleName":"","lastName":"Mizuno","suffix":""},{"id":49135765,"identity":"ce5f689f-8760-4243-b39d-b394db63131c","order_by":24,"name":"Takahito Miyake","email":"","orcid":"","institution":"Gifu University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Takahito","middleName":"","lastName":"Miyake","suffix":""},{"id":49135766,"identity":"f0d1ffe0-4794-4e32-b09a-82b98bd0e40f","order_by":25,"name":"Yuichiro Kitagawa","email":"","orcid":"","institution":"Gifu University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yuichiro","middleName":"","lastName":"Kitagawa","suffix":""},{"id":49135767,"identity":"692c1ad5-cb78-4c13-8c54-a6f4f3a4d261","order_by":26,"name":"Tetsuya Fukuta","email":"","orcid":"","institution":"Gifu University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Tetsuya","middleName":"","lastName":"Fukuta","suffix":""},{"id":49135768,"identity":"7d6bf8e1-d49f-4120-91c9-b87326206ea9","order_by":27,"name":"Tomoaki Doi","email":"","orcid":"","institution":"Gifu University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Tomoaki","middleName":"","lastName":"Doi","suffix":""},{"id":49135769,"identity":"ec0a5753-b83d-40e4-aa33-9d57f5dc9c03","order_by":28,"name":"Akio Suzuki","email":"","orcid":"","institution":"Gifu University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Akio","middleName":"","lastName":"Suzuki","suffix":""},{"id":49135770,"identity":"9af31601-f9c0-400d-856a-1df0162de2e7","order_by":29,"name":"Takahiro Yoshida","email":"","orcid":"","institution":"Gifu University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Takahiro","middleName":"","lastName":"Yoshida","suffix":""},{"id":49135771,"identity":"d3ba70f2-fe1c-4eb3-942d-c9d215087c7e","order_by":30,"name":"Nobuyuki Tetsuka","email":"","orcid":"","institution":"Gifu University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Nobuyuki","middleName":"","lastName":"Tetsuka","suffix":""},{"id":49135772,"identity":"ecad71aa-086f-4161-82b0-86c51c77f9e4","order_by":31,"name":"Shozo Yoshida","email":"","orcid":"","institution":"Gifu University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shozo","middleName":"","lastName":"Yoshida","suffix":""},{"id":49135773,"identity":"38b38944-46b5-4ca3-b749-f4abee96e5ce","order_by":32,"name":"Shinji Ogura","email":"","orcid":"","institution":"Gifu University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shinji","middleName":"","lastName":"Ogura","suffix":""}],"badges":[],"createdAt":"2021-08-26 05:29:02","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-846591/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-846591/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.3389/fmed.2021.791309","type":"published","date":"2021-12-23T15:16:47+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":13018087,"identity":"7c1ed635-1ac1-4373-96ff-21c4c5ce456c","added_by":"auto","created_at":"2021-09-02 15:27:28","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":43353,"visible":true,"origin":"","legend":"Flow diagram for the selection of study participants for data analysis.","description":"","filename":"OnlineFigure1.png","url":"https://assets-eu.researchsquare.com/files/rs-846591/v1/46df9b761087871ed399a3f7.png"},{"id":13018088,"identity":"7833942a-8167-4a34-8778-436e3c71ffba","added_by":"auto","created_at":"2021-09-02 15:27:28","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":60258,"visible":true,"origin":"","legend":"Effect of dialysis time and the amount of body fluid removed on the change in the serum syndecan-1 concentration. The change in the concentration of syndecan-1 before and after hemodialysis increased with respect to the enhanced body fluid removal and prolonged dialysis time. However, the change in the concentration of syndecan-1 before and after hemodialysis decreased with respect to the decreased amount of body fluid removal and the shortened dialysis time.","description":"","filename":"OnlineFigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-846591/v1/f597f84a774f26da9aea45a2.png"},{"id":16721981,"identity":"dfe8461e-ecf5-4e97-a21e-0757262a9215","added_by":"auto","created_at":"2021-12-23 15:16:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":755112,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-846591/v1/8efde6f8-3dc3-476c-8d1f-43554b903c5d.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eMeasuring The Concentration of Serum Syndecan-1 To Assess Vascular Endothelial Glycocalyx Injury During Hemodialysis\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMalnutrition, inflammation, and atherosclerosis are strongly associated in chronic kidney disease\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. and both a malnourished state and atherosclerosis can be caused by inflammation. Moreover, chronic microinflammation is observed in patients who undergo hemodialysis\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Several factors, such as uremia, activation of free radicals and adhesion molecules, and hemodialysis membrane, lead to microinflammation in patients who undergo hemodialysis\u003csup\u003e\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Uremic substances and the hemodialysis membrane promote the production of free radicals and cytokines by stimulating neutrophils, and the resulting inflammation further causes endothelial injury. However, there is no method to quantitatively assess endothelial cells injury.\u003c/p\u003e \u003cp\u003eThe vascular endothelium is composed of a thin monolayer of endothelial cells, and this lines the entire circulatory system, particularly those parts that are exposed to the circulating blood. The healthy endothelium is covered by a sugar-protein called glycocalyx\u003csup\u003e\u003cspan additionalcitationids=\"CR7 CR8 CR9\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e that plays pivotal roles in vascular homeostasis\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. The endothelial glycocalyx is degraded by several factors, such as sepsis, major surgery, trauma, ischemia/reperfusion, and prolonged hyperglycemia. Persistent and diffuse alterations in the glycocalyx are associated with widespread endothelial dysfunction, changed permeability, and impaired oxygen and nutrient delivery to the cells\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Several studies have revealed the relationship between endothelial glycocalyx injury and serious diseases, such as cardiovascular disease, acute kidney injury, and chronic kidney disease\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Moreover, the structure of the endothelial glycocalyx is degraded in chronic diseases, such as aging\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e, diabetes\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e, and hypertriglyceridemia\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe glycocalyx comprises cell-bound proteoglycans, glycosaminoglycan side chains, and sialoproteins\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. The proteoglycans consist of a core protein, such as a member of the syndecan protein family, to which glycosaminoglycan molecules are linked\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. Syndecan-1 is the core protein in heparan sulfate proteoglycan that is found in the glycocalyx. Syndecan-1 is released from the endothelium when the glycocalyx is injured, causing an increase in its concentration in circulation\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. Moreover, serum syndecan-1 has been used as an endothelial injury marker in recent clinical studies in critically ill patients\u003csup\u003e\u003cspan additionalcitationids=\"CR24 CR25\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTherefore, the present study aimed to assess endothelial injury using serum syndecan-1 as a marker of endothelial glycocalyx injury in patients who underwent hemodialysis. Additionally, the present study examined the medication type and factors that influence the concentration of syndecan-1.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics of patients\u003c/h2\u003e \u003cp\u003eWe finally enrolled 145 patients with a median age of 66 years (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The median dialysis period and dialysis time were 63 months and 3.7 hours, respectively. The most common primary illness was diabetic nephropathy which was observed in 37 patients (25.5%).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient demographics.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMedian (range) or number\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of cases, n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e145\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years), mean (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e68 (60\u0026ndash;77)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (female/male), n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44 (30.3) / 101 (69.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDialysis period (months), median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20.0 (1.0, 87.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDialysis time (hours), median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.0 (3.0, 4.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary illness, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic glomerulonephritis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (20.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRapidly progressive glomerulonephritis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (2.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePolycystic kidney disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (5.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNephrosclerosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (5.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetic nephropathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37 (25.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNephritis with autoimmune disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (4.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenal/urological tumor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (3.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eObstructive urinary tract/urination disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParaproteinemia (myeloma)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcute kidney injury\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (6.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCongenital anomalies of the kidney and urinary tract\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (22.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOthers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (1.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemodialysis type, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e133 (91.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHDF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (8.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDialysis efficiency\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKt/V\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.20 (0.06\u0026ndash;1.86)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedication, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnfractionated heparin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e101 (69.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLow-molecular-weight heparin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (16.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNafamostat mesylate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (13.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDialysis membrane, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePolyethersulfone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e110 (75.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePolysulfone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34 (23.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAsymmetric triacetate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u003cem\u003eHD\u003c/em\u003e hemodialysis, \u003cem\u003eHDF\u003c/em\u003e hemodiafiltration, \u003cem\u003eIQR\u003c/em\u003e interquartile range.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe number of patients who underwent hemodialysis and hemodiafiltration was 133 (91.7%) and 12 (8.3%), respectively. Anticoagulation agents, such as unfractionated heparin, low-molecular-weight heparin, and nafamostat mesylate, were administered to 101, 24, and 20 patients, respectively. Median Kt/V, an index of dialysis efficiency, was 1.20.\u003c/p\u003e \u003c/div\u003e\n\u003ch2\u003eConcentration Of Serum Syndecan-1 And Hemodialysis\u003c/h2\u003e\n\u003cp\u003eThe concentration of serum syndecan-1 before and after hemodialysis was 124.6\u0026thinsp;\u0026plusmn;\u0026thinsp;107.8 ng/mL and 229.0\u0026thinsp;\u0026plusmn;\u0026thinsp;138.1 ng/mL, respectively; this indicates that the concentration of serum syndecan-1 had significantly increased (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) after hemodialysis (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSerum SDC-1 concentration before and after hemodialysis.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStatus\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSDC-1 concentration (ng/mL)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBefore HD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e124.6\u0026thinsp;\u0026plusmn;\u0026thinsp;107.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAfter HD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e229.0\u0026thinsp;\u0026plusmn;\u0026thinsp;138.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003cem\u003eSDC-1\u003c/em\u003e syndecan-1, \u003cem\u003eHD\u003c/em\u003e hemodialysis.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003cem\u003eP\u003c/em\u003e-values were obtained from a mixed-effects model.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe concentration of serum syndecan-1 significantly increased after hemodialysis in patients who received unfractionated heparin and low-molecular-weight heparin; however, the concentration of syndecan-1 was not significantly different before and after hemodialysis in those who received nafamostat mesylate (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSerum SDC-1 concentration and anticoagulants.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnticoagulants\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBefore HD (ng/mL)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAfter HD (ng/mL)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnfractionated heparin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e112.0\u0026thinsp;\u0026plusmn;\u0026thinsp;79.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e235.4\u0026thinsp;\u0026plusmn;\u0026thinsp;126.8*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLow-molecular-weight heparin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e144.1\u0026thinsp;\u0026plusmn;\u0026thinsp;135.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e248.5\u0026thinsp;\u0026plusmn;\u0026thinsp;174.1*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNafamostat mesylate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e164.2\u0026thinsp;\u0026plusmn;\u0026thinsp;171.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e173.3\u0026thinsp;\u0026plusmn;\u0026thinsp;141.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.459\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003cem\u003eSDC-1\u003c/em\u003e syndecan-1, \u003cem\u003eHD\u003c/em\u003e hemodialysis.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAdditionally, according to the multivariable regression analysis after adjusting for age, sex, dry weight, and dialysis period, treatment with nafamostat mesylate inhibited the increase in the concentration of serum syndecan-1 during hemodialysis compared to treatment with unfractionated heparin and low-molecular-weight heparin (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eResults of multivariable regression analysis between anticoagulants.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnticoagulants\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCoefficient*\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% LCL\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e95% UCL\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLow-molecular-weight heparin vs. unfractionated heparin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-18.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-56.776\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e20.637\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.358\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNafamostat mesylate vs. unfractionated heparin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-116.473\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-158.442\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-74.504\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNafamostat mesylate vs. low-molecular-weight heparin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-98.403\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-150.482\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-45.324\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e*Coefficients from the multivariable linear regression model adjusted for age, sex, dry weight, and dialysis period, shown as differences in serum syndecan-1 concentration for low-molecular-weight heparin vs. unfractionated heparin, nafamostat mesylate vs. unfractionated heparin, and nafamostat mesylate vs. low-molecular-weight heparin, respectively.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cem\u003eLCL\u003c/em\u003e lower confidence limit, \u003cem\u003eUCL\u003c/em\u003e upper confidence limit.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eAssociation of concentration of serum syndecan-1 with dialysis time and body fluid removal\u003c/h2\u003e \u003cp\u003eThe relationship between the concentration variability of syndecan-1 and the dialysis condition, including the dialysis time and the amount of body fluid removed, was confirmed. The amount of body fluid removal was corrected by dry weight. The dialysis time and change in concentration of syndecan-1 showed positive correlation (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.033), but there was no significant association (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.111) between the amount of body fluid removed and changes in the concentration of syndecan-1 (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRelationship between syndecan-1 concentration variability and dialysis conditions.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFactors\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCoefficient*\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% LCL\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e95% UCL\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody fluid removed/dry weight (per 0.01 L/Kg increase)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9.107\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.144\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e18.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.111\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDialysis time\u003c/p\u003e \u003cp\u003e(per 1 minute increase)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23.349\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-8.836\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e55.533\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.033\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e*Coefficients from the multivariable linear regression model adjusted for age, sex, and dialysis period, shown as increment in serum syndecan-1 concentration for a unit change in factors.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cem\u003eLCL\u003c/em\u003e lower confidence limit, \u003cem\u003eUCL\u003c/em\u003e upper confidence limit.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eNext, we examined the association between changes in the concentration of syndecan-1 and dialysis parameters, including dialysis time and the amount of body fluid removed. The change in the concentration of syndecan-1 before and after hemodialysis increased with respect to enhanced removal of body fluids and prolonged dialysis time (\u003cem\u003eP\u003c/em\u003e for interaction\u0026thinsp;=\u0026thinsp;0.063, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). However, the amount of change in the concentration of syndecan-1 before and after hemodialysis decreased with respect to a decrease in the amount of body fluid removed and shortened dialysis time.\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe present study revealed that a) the endothelial glycocalyx is injured during hemodialysis; b) endothelial glycocalyx injury is attenuated by administering nafamostat mesylate as an anticoagulant; and c) endothelial glycocalyx injury is aggravated by an increase in the amount of body fluid removed and prolonged dialysis time.\u003c/p\u003e \u003cp\u003eThe endothelial glycocalyx is injured in patients with chronic kidney disease and by plasma volume expansion\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. Therefore, we hypothesized that the serum syndecan-1 levels would increase in patients who undergo hemodialysis. A previous study indicated that the concentration of serum syndecan-1 was approximately 20 ng/mL in healthy people\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e; in contrast, in the present study, it was 124.6\u0026thinsp;\u0026plusmn;\u0026thinsp;107.8 ng/mL in patients who underwent hemodialysis. This result confirmed that the endothelial glycocalyx sustained injuries in patients who undergo hemodialysis.\u003c/p\u003e \u003cp\u003eEndothelial glycocalyx injury may be attenuated by a decrease in fluid volume after hemodialysis. However, the levels of serum syndecan-1 increased after hemodialysis than those before hemodialysis. This finding suggests that the endothelial glycocalyx is injured during hemodialysis due to neutrophils and inflammation via the production of free radicals and cytokines.\u003c/p\u003e \u003cp\u003eDuring hemodialysis, unfractionated heparin, low-molecular-weight heparin, and nafamostat mesylate were used as anticoagulating agents. Low-molecular-weight heparin and nafamostat were administered in patients that had any disease which was associated with bleeding tendencies. The results of the present study suggest that an increase in the concentration of syndecan-1 is attenuated in patients who receive nafamostat mesylate.\u003c/p\u003e \u003cp\u003eNafamostat mesylate, a synthetic serine protease inhibitor, is a short-acting anticoagulant\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e, and is also used during hemodialysis to prevent proteolysis of fibrinogen into fibrin\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. It is a slow, tight-binding substrate that traps the target protein in the acyl-enzyme intermediate form, and inhibits enzyme activity\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. Nafamostat has been recently identified as a potential therapy against COVID-19\u003csup\u003e32\u003c/sup\u003e. Infection with SARS-CoV-2 induces endotheliitis due to viral involvement and inflammatory response of the host, and thus, it is associated with endothelial glycocalyx injury\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. Therefore, nafamostat mesylate may have a beneficial effect on the endothelial glycocalyx, although it is supported by only circumstantial evidence.\u003c/p\u003e \u003cp\u003eExtension of dialysis time is a strategy to improve prognosis\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e; however, it remains controversial\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e,\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. The present study identified that changes in the levels of serum syndecan-1 are small in patients who have prolonged dialysis time and slow removal of body fluid. Therefore, these two strategies could prevent endothelial glycocalyx injury. Several reports have also revealed that prolonged hemodialysis was associated with improved blood pressure and fluid management\u003csup\u003e\u003cspan additionalcitationids=\"CR36\" citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e. Additionally, rapid removal of body fluid is associated with a greater risk of mortality and cardiovascular events\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. Moreover, hypotension during hemodialysis is also associated with higher mortality\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThese mechanisms may explain how lower ultrafiltration rates with prolonged hemodialysis and slow removal of body fluids may ameliorate endothelial vascular permeability via attenuation of endothelial glycocalyx injury. Therefore, we propose that slow removal of body fluids with prolonged hemodialysis can reduce hypotension during hemodialysis.\u003c/p\u003e \u003cp\u003eThis study has some limitations. First, the hemodialysis time in most patients was less than 4 h. Therefore, an accurate examination of prolonged hemodialysis could not be performed. Second, less type of dialyzer was used in the present study. Although further studies are required, measuring the concentration of serum syndecan-1 may help in the assessment of endothelial injury under low blood flow (e.g., chronic hemodiafiltration), and of membrane compatibility by using a different type of dialyzer. Moreover, serum syndecan-1 is proposed to be a useful biomarker for daily monitoring of organ dysfunction, and may be an important risk factor for mortality in critically ill patients\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn conclusion, the study presented a method for the quantitative assessment of endothelial glycocalyx injury by measuring the concentration of serum syndecan-1 during hemodialysis. Although hemodialysis causes endothelial glycocalyx injury, it may be mitigated by maintenance of hemodialysis duration and by modulation of the amount of body fluid removed via the quantitative assessment of the serum syndecan-1.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003ePatients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis was a single-center, retrospective, observational study conducted at the Gifu University Hospital, affiliated to Gifu University, Gifu, Japan. Patients who underwent hemodialysis at the Gifu University Hospital between March 2017 and December 2019 were enrolled in the study. Patients aged \u0026lt;20 years, who underwent plasma apheresis, plasma exchange, and double filtration plasma therapy, and who had not maintained their dry weight were excluded from the analysis. Finally, data from 145 patients were used for the final analyses in this study (Fig. 1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study conformed to the principles outlined in the Declaration of Helsinki\u003csup\u003e40\u003c/sup\u003e. Ethics approval was obtained from the Medical Ethics Committee of the Gifu University Graduate School of Medicine, Gifu, Japan (record no.: 2021-A005). The need for informed consent from participants was waived by the medical ethics committee due to the retrospective nature of the study. Before initiation, the study was registered in the UMIN Clinical Trials Registry (registry number: UMIN000051415).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection and study design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBlood was routinely sampled before and after hemodialysis from eligible patients at the time of last hemodialysis before being discharged from Gifu University Hospital, and data from these blood samples were used in the present study. All laboratory data (except serum syndecan-1), dry weight, and other patient demographics were extracted from the hospital\u0026rsquo;s electronic medical records. The concentration of serum syndecan-1 was measured using an enzyme-linked immunosorbent assay (950.640.192; Diaclone, Besancon, Cedex, France). The data were retrospectively analyzed. As an index of the efficiency of dialysis, Kt/V was calculated as described previously\u003csup\u003e41\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients\u0026rsquo; baseline characteristics are presented as median and interquartile range (IQR) for continuous variables, and frequency and proportion for categorical variables. For the primary analysis, a mixed effect model was used to assess the change in syndecan-1 levels with hemodialysis. The difference in syndecan-1 levels before and after hemodialysis in the anticoagulant subgroup was confirmed using paired \u003cem\u003et\u003c/em\u003e-test. A multivariable linear regression analysis was performed to compare the change in syndecan-1 levels before/after hemodialysis and treatment with anticoagulants. The covariates in the regression model were age, sex, dry weight, and dialysis period\u003csup\u003e42\u003c/sup\u003e. These variables were selected a priori on the basis of previous studies. In another model, dry weight and dialysis period were simultaneously incorporated into the linear regression model to evaluate the effect of factors during dialysis on the levels of syndecan-1. An interaction term was included in the model to confirm the effect of modification of dry weight and dialysis period on changes in the levels of syndecan-1. If the interaction term was statistically significant, the effect of the dialysis period (or dry weight) on syndecan-1 was determined to be modified by dry weight (or the dialysis period). There were no missing values in the data used in the analyses. A two-sided \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05 was considered to be statistically significant. The study is exploratory and there were concerns about low statistical power; therefore, the interaction was evaluated with a two-sided \u003cem\u003eP\u003c/em\u003e\u0026lt;0.1. R version 4.1.0 was used for statistical analyses (\u003ca href=\"http://www.r-project.org\"\u003ewww.r-project.org\u003c/a\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author (HO) upon reasonable request.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank the paramedical crew that shared the data obtained by them with us and allowed us to use the data for the writing of this report. The authors thank Editage (www.editage.com) for English language editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eK.K. and H. Okada wrote the manuscript. K.K., Kodai S., S.N., H. Okamoto, G.Y., R.K., and T. Miura collected the blood samples. Y. Keiko S., C.T., Y. Kawasaki, T. Minamiyama., A.N., H.F., T.S., Y.T., Tomoki Y., and Y.N. measured the syndecan-1 concentration using ELISA. Keiko S. and R.Y. created a database. T.I. performed statistical analysis. Y.M., T. Miyake, Y. Kitagawa, T.F., T.D., and Takahiro Y. treated the patients. H.T., S.Y., and S.O. supervised the study. H. Okada and A.S. revised and edited the manuscript. The final manuscript was reviewed and approved by all authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Ministry of Education, Science and Culture of Japan grants-in-aid for scientific research [grant numbers 19H03756, 19K18347, 19K09410, 18K16511].\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eStenvinkel, P. \u003cem\u003eet al.\u003c/em\u003e Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure. \u003cem\u003eKidney Int\u003c/em\u003e, \u003cb\u003e55\u003c/b\u003e, 1899\u0026ndash;1911 \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1046/j.1523-1755.1999.00422.x\u003c/span\u003e\u003c/span\u003e (1999).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZimmermann, J., Herrlinger, S., Pruy, A., Metzger, T. \u0026amp; Wanner, C. 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Second generation logarithmic estimates of single-pool variable volume Kt/V: an analysis of error. \u003cem\u003eJ Am Soc Nephrol\u003c/em\u003e, \u003cb\u003e4\u003c/b\u003e, 1205\u0026ndash;1213 \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1681/ASN.V451205\u003c/span\u003e\u003c/span\u003e (1993).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKoch, J. \u003cem\u003eet al.\u003c/em\u003e An acute rise of plasma Na(+) concentration associates with syndecan-1 shedding during hemodialysis. \u003cem\u003eAm J Physiol Renal Physiol\u003c/em\u003e, \u003cb\u003e319\u003c/b\u003e, F171\u0026ndash;F177 \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1152/ajprenal.00005.2020\u003c/span\u003e\u003c/span\u003e (2020).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"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":"Hemodialysis, Glycocalyx, Syndecan-1, Body fluid removal, Nafamostat mesylate","lastPublishedDoi":"10.21203/rs.3.rs-846591/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-846591/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eGlycocalyx is present on the surface of healthy endothelium, and the concentration of serum syndecan-1 can serve as an injury marker. This study aimed to evaluate the hemodialysis-associated changes in the serum syndecan-1 concentration. This was a single-center, retrospective, observational study. Between March 2017 and December 2019, 145 patients who underwent hemodialysis at the Gifu University Hospital were enrolled. The median dialysis period and dialysis time were 63 months and 3.7 hours, respectively. The serum syndecan-1 concentration increased from 124.6\u0026thinsp;\u0026plusmn;\u0026thinsp;107.8 ng/mL before hemodialysis to 229.0\u0026thinsp;\u0026plusmn;\u0026thinsp;138.1 ng/mL after hemolysis (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Treatment with anticoagulant nafamostat mesylate inhibited hemodialysis-induced increase in the levels of serum syndecan-1 in comparison to unfractionated heparin. Dialysis time and the change in concentration of syndecan-1 were positively correlated, whereas the amount of body fluid removed and changes in the concentration of syndecan-1 were not correlated. The reduction in amount of body fluid removed and dialysis time inhibited the change in of syndecan-1 levels before and after hemodialysis. In conclusion, quantitative assessment of the endothelial glycocalyx injury during hemodialysis can be done by measuring the concentration of serum syndecan-1 which may aid in the selection of appropriate anticoagulants, hemodialysis time, and the amount of body fluid removed.\u003c/p\u003e","manuscriptTitle":"Measuring The Concentration of Serum Syndecan-1 To Assess Vascular Endothelial Glycocalyx Injury During Hemodialysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-09-02 15:27:27","doi":"10.21203/rs.3.rs-846591/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":"73069ec7-4b7c-49e2-9d4f-36aaa059500e","owner":[],"postedDate":"September 2nd, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":6901373,"name":"Urology \u0026 Nephrology"},{"id":6901374,"name":"Mathematical Physics"},{"id":6901375,"name":"Computational Physics"},{"id":6901376,"name":"Laboratory Diagnostics"}],"tags":[],"updatedAt":"2021-12-23T15:16:47+00:00","versionOfRecord":{"articleIdentity":"rs-846591","link":"https://doi.org/10.3389/fmed.2021.791309","journal":{"identity":"frontiers-in-medicine","isVorOnly":true,"title":"Frontiers in Medicine"},"publishedOn":"2021-12-23 15:16:47","publishedOnDateReadable":"December 23rd, 2021"},"versionCreatedAt":"2021-09-02 15:27:27","video":"","vorDoi":"10.3389/fmed.2021.791309","vorDoiUrl":"https://doi.org/10.3389/fmed.2021.791309","workflowStages":[]},"version":"v1","identity":"rs-846591","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-846591","identity":"rs-846591","version":["v1"]},"buildId":"cBFmMYwuxLRRLfASyISRj","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}