Evaluation of serum syndecan-1 levels in patients with diabetic retinopathy

Evaluation of serum syndecan-1 levels in patients with diabetic retinopathy | 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 Evaluation of serum syndecan-1 levels in patients with diabetic retinopathy Murat Okutucu, Medeni Arpa This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9258120/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 23 You are reading this latest preprint version Abstract Purpose This study aimed to evaluate vascular endothelial cell health through serum Syndecan-1 (SDC-1) level measurement in patients with diabetic retinopathy undergoing intravitreal anti-VEGF therapy and to increase the awareness of clinicians about the systemic side effects of this treatment. Methods This prospective case-control study included 144 patients divided into the DME with NPDR ( n = 44), DME with PDR ( n = 46), and control groups ( n = 54). Anterior and posterior eye segments were evaluated with biomicroscopic and funduscopic examination, macula with optical coherence tomography, and serum SDC-1 levels were analyzed using an enzyme-linked immunosorbent assay. Results There was no significant difference among the three groups in terms of age, sex, or the presence of hypertension (HT) (all p > 0.05). The serum SDC-1 level of the DME with PDR group was significantly higher than that of the DME with NPDR and control groups (all p < 0.001). There was no statistically significant difference between the DME with NPDR group and the control groups in terms of serum SDC-1 level. The SDC-1 level of the hypertension (+) group was significantly higher than that of the hypertension (-) group (p < 0.001). Conclusions The fact that the SDC-1 level in the DME with PDR group was significantly higher than that in the DME with NPDR and control groups indicates that the vascular endothelial cell health of this group was impaired. Ophthalmologists who administer intravitreal anti-VEGF treatment should be more alert in terms of systemic side effects in all patients, especially in patients with DME with PDR. Diabetic Retinopathy Syndecan-1 vascular Endothelium Bevacizumab Ranibizumab Aflibercept Figures Figure 1 Figure 2 INTRODUCTION Diabetic retinopathy refers to microvascular end-organ damage that occurs as a result of diabetes. 1 It ranges from nonproliferative diabetic retinopathy and its stages to proliferative diabetic retinopathy. 1 As the disease progresses, associated diabetic macular edema (DME) may also develop. Vascular endothelial growth factor (VEGF) is secreted by ischemic retina. VEGF causes increased vascular permeability, leading to retinal swelling/edema and angiogenesis or new blood vessel formation. 1 Fluorescence angiography (FA) can be used to determine the degree of ischemia or the presence of retinal vascular abnormalities. 1 Optical coherence tomography (OCT) is useful in determining the presence and location of intra- and/or sub-retinal fluid and in measuring retinal thickness. 1 Diabetic patients are at an increased risk of developing venous thromboembolism, a type of disease that includes not only atherothrombotic events but also pulmonary embolism and deep vein thrombosis. 2 Various mechanisms, such as endothelial dysfunction, coagulative activation, and platelet hyperreactivity, contribute to the diabetic prothrombotic state. 2 Diabetic platelets, in particular, are characterized by the irregularity of various signaling pathways, leading to increased adhesion, activation, and aggregation. 2 These changes stem from the interaction between hyperglycemia, insulin resistance, inflammation, and oxidative stress. 2 Syndecan-1 (SDC-1) is the main component of the endothelial glycocalyx, which is a layer of membrane-encircled macromolecules on the luminal surface of the vascular endothelium. 3 SDC-1, a 33 kDa single-pass type I transmembrane proteoglycan, consists of a core protein and ≥ 1 glycosaminoglycan chain covalently bound to the protein. 3 The ectodomain of the SDC-1 protein nucleus carries 3 heparan sulfate chains and 2 chondroitin sulfate chains. 3 In some pathological conditions, such as acute inflammation, hyperglycemia, and ischemia-reperfusion damage, ectodomains of SDC-1 are degraded by leukocyte-derived proteases, metalloproteinases, and heparinase. 4 – 6 Therefore, an increase in plasma SDC-1 levels has been observed in patients with inflammation, traumatic brain injury, hemorrhagic shock, and diffuse intravascular coagulation (DIC). 7 , 8 Lu et al. reported that in thrombotic thrombocytopenic purpura, SDC-1 plasma level increased, indicating vascular endothelial damage. 9 Intravitreal anti-VEGF agents are used in the treatment of DME and proliferative diabetic retinopathy (PDR). 1 , 10 Avery et al. 11 and Hirano et al. 12 observed a significant decrease in plasma VEGF levels after intravitreal bevacizumab and aflibercept injections for diabetic macular edema, but no such effect was observed after intravitreal ranibizumab injection. From clinical experience in oncology, it is understood that there are adverse effects, such as cardiovascular and arterial thromboembolic events, by blocking VEGF in the systemic circulation. 13 Studies have reported that all three intravitreal anti-VEGF drugs increase the risk of thromboembolic events at different rates. 14 , 15 In this study, we aimed to evaluate the vascular endothelial health status over serum SDC-1 levels in patients with diabetic retinopathy who need IV anti-VEGF treatment, and to increase the awareness of clinicians about the side effects that may occur in patients after treatment. MATERIALS AND METHODS Study participants This case-control study was conducted between May 2024 and June 2025 in the ophthalmology clinic of the Recep Tayyip Erdogan Training and Research Hospital, affiliated with Recep Tayyip Erdogan University. The study protocol was approved by the Ethics Committee of Recep Tayyip Erdogan University (Approval No 2024/81). The principles of the Declaration of Helsinki were followed throughout this study. Written consent was obtained from all participants prior to participation. The study consisted of three groups of 114 participants, including 44 individuals with DME and nonproliferative diabetic retinopathy (NPDR), 46 individuals with DME and PDR, and 54 individuals with no disorders but controlled hypertension, matched in terms of age and sex, as the control group. The patients were diagnosed with PDR, NPDR, and DME according to the criteria of international clinical DR and DME disease severity scales. 16 Exclusion criteria included a history of cardiovascular and cerebrovascular disease, chronic inflammatory diseases (rheumatoid arthritis, systemic sclerosis, psoriasis, ulcerative colitis, and Crohn's disease), hematological diseases, malignancies, kidney and liver diseases, and diseases that could alter serum SDC-1 concentrations, such as vasculitis. In addition, patients who had received intravitreal anti-VEGF treatment for at least 6 months were excluded from the study. The study group comprised patients with type 2 diabetes. Patients with concomitant hypertension were also included in the study if their blood pressure was controlled. Individuals who did not have a history of any systemic disease other than hypertension and were scheduled for elective phacoemulsification cataract surgery constituted the control group. All patients underwent detailed ophthalmological examinations, including best-corrected visual acuity (BCVA), biomicroscopic examination, tonometry, dilated fundus examination, and optical coherence tomography evaluation. Fundus fluorescein angiography was performed in individuals with suspected PDR, even though no visible neovascularization was detected via funduscopic examination. In both the study and control groups, the examination of participants whose funduscopic examination could not be evaluated due to cataract was performed again when the optical media was transparent after cataract surgery. Collection of blood samples Venous blood samples (5 mL) were collected from the participants in the experimental groups immediately before intravitreal anti-VEGF injection, and the samples were stored in serum-separating tubes. Venous blood samples were collected from the control group before cataract surgery. Venous blood samples (5 mL) were collected from all participants after 8-h of overnight fasting between 9:00 and 12:00 to avoid diurnal changes. The coagulated blood samples were centrifuged at 3000×g for 10 min to obtain sera, which were stored at − 20°C until quantification of SDC-1 concentrations was performed. Quantification of SDC-1 concentrations Serum SDC-1 concentrations were determined using enzyme-linked immunosorbent assay (ELISA) kits (Elabscience, Texas, Catalogue No: E-EL-H1298) according to the manufacturer’s instructions. STATISTICAL ANALYSIS Statistical analyses were performed using SPSS Statistics for Windows, Version 29.0 (IBM Corp., Armonk, NY, USA). The distribution characteristics of continuous variables were evaluated using normality tests. One-way analysis of variance (One-way ANOVA) was applied in multiple group comparisons with a normal distribution, and the Kruskal-Wallis test was applied in those without a normal distribution. In cases where significant differences were detected, Bonferroni-corrected post hoc tests were used for pairwise comparisons. The distribution of categorical variables between the groups was examined using the chi-squared test. Spearman’s correlation analysis was performed to evaluate the relationship between age and serum syndecan levels. In all analyses, statistical significance was set at p < 0.05. RESULTS Baseline demographic and clinical characteristics of the participants are presented in Table 1 . There was no significant difference among the three groups in terms of age, sex, or the presence of hypertension (HT) (all p > 0.05). The serum SDC-1 level of the DME with PDR group was significantly higher than that of the DME with NPDR and the control groups (all p < 0.001) (Table 1 ) (Fig. 1 ). There was no statistically significant difference between the DME with NPDR group and the control groups in terms of serum SDC-1 level (Table 1 ) (Fig. 1 ). No significant difference was found between the hypertension (+) and hypertension (−) groups in terms of age and sex (all p > 0.05). The SDC-1 level in the hypertension (+) group [2.09 (0.71–4.11)] ng/ml was significantly higher than that in the hypertension (-) group [1.02 (0.30–4.31)] ng/ml (p < 0.001) (Fig. 2 ). Table 1 Demographic and clinical data of the study group Control NPDR PDR p value a Mean ± SD; Median (min-max) Mean ± SD; Median (min-max) Mean ± SD; Median (min-max) Age (years) 67 ± 8 68 ± 8 69 ± 7 0,385 Syndecan-1 level (ng/ml) 0,9 (0,3 − 2,32) 1,08 (0,65 − 3,23) c 1,8 (0,73 − 4,31) b < 0,001 Female n (%) 30 (55,6 ) 22 (50) 27 (58,7) 0,703 Male n (%) 24 (44,4) 22 (50) 19 (41,3) Hypertensive group n (%) 45 (83,3) 33 (75) 33 (71,7) 0,360 Normotensive group n (%) 9 (16,7) 11 (25) 13 (28,3) PDR proliferative diabetic retinopathy NPDR nonproliferative diabetic retinopathy a : Obtained by One-way ANOVA, Kruskal Wallis or Chi-Square tests; b :Significant vs control (p < 0.001); c :Significant vs PDR (p = 0.003) DISCUSSION Chronic hyperglycemia causes both micro- and macrovascular complications that affect various organs such as the skin, muscles, heart, brain, eyes, and kidneys. Microvascular complications included retinopathy, nephropathy, and neuropathy. The role of suspected endothelial glycocalyx (EG) damage in the pathophysiology of diabetes has only recently been demonstrated. In patients with type 2 diabetes, a decrease in EG volume was detected in the sublingual and retinal vessels. 17 In terms of functional outcomes, EG impairment during diabetes mellitus is clearly associated with many typical micro- and macrovascular complication phenomena, such as decreased arterial vasodilation (a typical step in endothelial dysfunction), increased endothelial permeability to macromolecules, fluid leakage, loss of pericytes, and neovascularization in retinal vessels. 18 – 20 EG damage in diabetes mellitus is also associated with activation of coagulation and increased leukocyte adhesion. 21 , 22 High circulating SDC-1 level is an indicator of endothelial glycocalyx damage. 23 In the present study, the serum SDC-1 level in the DME with PDR group was significantly higher than that in the control group. Consistent with the literature, the high level of SDC-1, which is an indicator of EG damage, caused microvascular complications in the retina observed in this patient group. There were no significant differences between the DME with NPDR group and control groups. Svennevig et al. reported that serum SDC-1 concentrations were significantly increased in patients with microalbuminuric type 1 diabetes compared to normoalbuminuric type 1 diabetic patients and healthy controls. 24 According to the results of the study conducted by Manaviat et al., there is a high positive correlation between diabetic retinopathy and renal involvement, and microalbuminuria is associated with diabetic retinopathy in type 2 diabetic patients and is a reliable marker of retinopathy. 25 While the rate of microalbuminuria is low in low-stage diabetic retinopathy stages, it is observed at a much higher rate in advanced stages, such as proliferative diabetic retinopathy. 25 The common conclusion derived from the studies conducted by Svennevig et al., Manaviat et al., and the present study is that serum SDC-1 levels increase in stages of diabetes mellitus with severe microvascular damage, such as proliferative diabetic retinopathy. 24 , 25 Chen et al. reported that the SDC-1 level was high in patients with nephrotic syndrome, which accelerated the hypercoagulability status through endothelial damage, and that it may be vital in the formation and progression of thrombosis in this group of patients. 26 Lu et al. reported that high plasma SDC-1 levels increased the severity of vascular thrombosis-mediated organ damage and disease in the thrombotic thrombocytopenic purpura patient group. 9 Harahsheh et al. associated high levels of SDC-1, a biomarker of endothelial function, with the risk of developing thromboembolism in critically acquired coagulopathy patients with an impaired clotting profile. 27 To raise awareness about the systemic side effects of intravitreal anti-VEGF drugs administered for diabetic macular edema, retinal vein occlusion, and neovascular age-related macular degeneration, many studies have been conducted to investigate serum and plasma VEGF levels after administering these drugs. Hirano et al. reported that basal plasma VEGF levels did not correlate with diabetic retinopathy or DME severity, that single-dose bevacizumab or intravitreal injection of aflibercept significantly reduced plasma VEGF levels up to 4 weeks, while ranibizumab did not cause such effects. 12 Since there was no relationship between systemic VEGF levels and disease severity, the authors pointed out the unnecessary suppression of systemic VEGF, as well as the risk of the patient being unnecessarily exposed to systemic side effects. 12 Zehetner et al. reported that after intravitreal aflibercept injection, systemic VEGF levels decreased significantly over the 4-week observation period, whereas intravitreal ranibizumab did not show a significant systemic effect on plasma VEGF. 28 As the VEGF pathway is critical not only for normal growth and development, but also for physiological response and homeostasis in many organs and functions in adulthood, various side effects are expected with pharmacological blocking of this pathway. 28 Indeed, the clinical side effect profiles are quite extensive. The side effects attributed to VEGF inhibition include hypertension, arterial thromboembolic events (AT), proteinuria or renal dysfunction, wound complications, bleeding, and reversible posterior leukoencephalopathy syndrome. 28 Hypertension is the best-documented cardiovascular side effect of VEGF inhibitors. 29 The VEGF signal produces nitric oxide and prostaglandin I2. 30 This causes endothelial cell-dependent vasodilation in arterioles and venules. 30 This is the vascular component that has the most impact on blood pressure. 30 Blocking VEGF leads to vasoconstriction. 11 In the present study, it was determined that serum SDC-1 levels were higher in individuals with hypertension than in those without hypertension. According to this result, a higher rate of side effects is expected after IV anti-VEGF injections in individuals with diabetic retinopathy and hypertension. The pathogenesis underlying venous and arterial thrombosis is differently related to certain distinctive features, although some mechanisms are partially overlapping. 30 For example, the clotting cascade, which is mainly regulated by tissue factor, plays a role in venous thrombosis, while arterial thrombosis is mainly regulated by platelets. 30 The importance of VEGF in vascular endothelial cell-platelet homeostasis may explain the tendency of VEGF inhibitors to increase the risk of arterial thromboembolism. 11 Under normal physiological conditions, secretory factors such as VEGF from vascular endothelial cells and platelets have an important role in preventing blood cells from adhering to the vascular system and ensuring the survival and regeneration of vascular endothelial cells in response to vascular damage. 11 When VEGF signaling is inhibited by VEGF inhibitors, this may compromise the integrity of vascular endothelial cells and promote platelet aggregation. 11 According to the results of the present study, there may be an increase in the likelihood of arterial and venous thromboembolic side effects after IV anti-VEGF injection in patients with DME with PDR with high SDC-1 levels compared to the control group and DME with NPDR patient group. The filtration barrier of renal glomeruli is formed by vascular endothelial cells, podocytes, and basement membrane components. 31 , 32 The interaction of VEGF produced by podocytes with VEGFr2 in glomerular vascular endothelial cells is critical for normal function and repair of the system. 31 , 32 In preclinical rat models, heterozygous deletion of VEGF in podocytes leads to loss of fenestration, podocyte loss, mesangiolysis, and proteinuria in vascular endothelial cells. 31 , 32 More importantly, VEGF has been shown to have a critical protective role in the pathogenesis of the microangiopathic process. 33 Clinically, renal side effects may occur as asymptomatic proteinuria following anti-VEGF treatment, and acute renal failure, nephrotic syndrome, or microangiopathy may rarely develop. 34 – 36 According to the results of the present study, there may be an increase in the likelihood of renal side effects after IV anti-VEGF injection in patients with DME with PDR with high SDC-1 levels compared to the control group and DME with NPDR patient group. In conclusion, this study demonstrated that the SDC-1 level was higher in patients with DME with PDR than in the control and DME with NPDR groups. Elevated SDC-1, which is an indicator of vascular endothelial damage and is observed in the DME with NPDR patient group, may cause a further increase in the side effects of IV anti-VEGF treatment related to vascular endothelial damage in this patient group. Ophthalmologists who administer IV anti-VEGF treatment for DME should be careful in terms of side effects, especially in the proliferative diabetic retinopathy patient group, inform the patient in this direction, and follow up closely. Declarations Ethics declarations Ethics approval and consent to participate Ethical approval was obtained from the Ethics Committee of Recep Tayyip Erdogan University (Approval ID: 2024/81). The tenets of the Declaration of Helsinki were followed throughout this study. Written informed consent was obtained from all the participants before participation. Consent for publication Not applicable. Competing interests The authors declare no competing interests. Data availability The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request. Funding No funding was received for the study. Author’s contributions MO designed the study and collected blood samples and data, MA analyzed the serum SDC-1 levels with ELISA kits and performed the statistical analysis, MO and MA interpreted the data and wrote the original draft; all authors reviewed, edited, and approved the final manuscript. Acknowledgements None Conflicts of Interest Statement There is no conflict of interest to disclose References Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial. Ophthalmology. 2016;123(6):1351–9. 10.1016/j.ophtha.2016.02.022 . 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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-9258120","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":629889600,"identity":"3cc63f0d-05ac-4344-bf11-5bdc1ce08a67","order_by":0,"name":"Murat Okutucu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEElEQVRIiWNgGAWjYBADAwhVAcQHIEzGBnzqD4C0sIFYZ1C0MBOhhbGNCC26M3Iffv7AYGNscL/H8DPvPJt8vuPtFz8XMNjIbjjAf+wDFi1mN9KNJQ4wpJkZHOMxlubdlmY588yZYukZDGnGGw4wM8/AqiWNAajlsA1Qixkz77bDBgY3chKkeRgOJ4K0YHMYUAvzD4SWOf9BWpJ/8zD8x6eFDWSLGURLwwGglvRjQFsO4NZy5hmbxRmDNGPJY2nFknOOJRtInjnDZs1jkGw88zCzMVYtx9OYb1RU2Bj2HT688cObGjsDYIg9vs1TYSfbd7zxMdZQBgMDFB6PAUQET0yiA/YHxKsdBaNgFIyCkQAA6+BjBriI4BYAAAAASUVORK5CYII=","orcid":"","institution":"Recep Tayyip Erdoğan University","correspondingAuthor":true,"prefix":"","firstName":"Murat","middleName":"","lastName":"Okutucu","suffix":""},{"id":629889602,"identity":"4b8f42b6-a270-4532-a3ad-ab3e4433ebe1","order_by":1,"name":"Medeni Arpa","email":"","orcid":"","institution":"Recep Tayyip Erdoğan University","correspondingAuthor":false,"prefix":"","firstName":"Medeni","middleName":"","lastName":"Arpa","suffix":""}],"badges":[],"createdAt":"2026-03-29 10:39:06","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9258120/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9258120/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108406480,"identity":"b0304dca-2e20-4bb6-bcde-3ccefa888ce2","added_by":"auto","created_at":"2026-05-04 09:43:23","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":10004,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of serum syndecan-1 levels of the control group and the study group. The syndecan-1 level of the proliferative diabetic retinopathygroup [1,8 (0,73-4,31) ng/mL] was statistically significantly higher than the nonproliferative diabetic retinopathy and control group [0,9 (0,3-2,32)pg/mL and 1,08 (0,65-3,23) ng/mL, respectively]\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-9258120/v1/4aba2cde4f769999b49197ae.png"},{"id":108492556,"identity":"b2fb27c0-ea52-40ee-9b2b-6fb810858f6e","added_by":"auto","created_at":"2026-05-05 09:58:03","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":10781,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of serum syndecan-1 levels of the hypertensive and the normotensive \u0026nbsp;group. The syndecan-1 level of the hypertensive group [2.09 (0.71-4.11)] ng/ml was statistically significantly higher than the normotensive group [1.02 (0.30-4.31)] ng/ml.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-9258120/v1/83b6eaf3fe82ca5c7945853b.png"},{"id":109067474,"identity":"c90867ee-a384-48f9-8998-9924d935328f","added_by":"auto","created_at":"2026-05-12 09:54:02","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":255042,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9258120/v1/776b9915-5baa-433c-b553-275a395515df.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Evaluation of serum syndecan-1 levels in patients with diabetic retinopathy","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eDiabetic retinopathy refers to microvascular end-organ damage that occurs as a result of diabetes.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e It ranges from nonproliferative diabetic retinopathy and its stages to proliferative diabetic retinopathy.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e As the disease progresses, associated diabetic macular edema (DME) may also develop. Vascular endothelial growth factor (VEGF) is secreted by ischemic retina. VEGF causes increased vascular permeability, leading to retinal swelling/edema and angiogenesis or new blood vessel formation.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Fluorescence angiography (FA) can be used to determine the degree of ischemia or the presence of retinal vascular abnormalities.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Optical coherence tomography (OCT) is useful in determining the presence and location of intra- and/or sub-retinal fluid and in measuring retinal thickness.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eDiabetic patients are at an increased risk of developing venous thromboembolism, a type of disease that includes not only atherothrombotic events but also pulmonary embolism and deep vein thrombosis.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Various mechanisms, such as endothelial dysfunction, coagulative activation, and platelet hyperreactivity, contribute to the diabetic prothrombotic state.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Diabetic platelets, in particular, are characterized by the irregularity of various signaling pathways, leading to increased adhesion, activation, and aggregation.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e These changes stem from the interaction between hyperglycemia, insulin resistance, inflammation, and oxidative stress.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eSyndecan-1 (SDC-1) is the main component of the endothelial glycocalyx, which is a layer of membrane-encircled macromolecules on the luminal surface of the vascular endothelium.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e SDC-1, a 33 kDa single-pass type I transmembrane proteoglycan, consists of a core protein and \u0026ge;\u0026thinsp;1 glycosaminoglycan chain covalently bound to the protein.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e The ectodomain of the SDC-1 protein nucleus carries 3 heparan sulfate chains and 2 chondroitin sulfate chains.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e In some pathological conditions, such as acute inflammation, hyperglycemia, and ischemia-reperfusion damage, ectodomains of SDC-1 are degraded by leukocyte-derived proteases, metalloproteinases, and heparinase.\u003csup\u003e\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Therefore, an increase in plasma SDC-1 levels has been observed in patients with inflammation, traumatic brain injury, hemorrhagic shock, and diffuse intravascular coagulation (DIC).\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Lu et al. reported that in thrombotic thrombocytopenic purpura, SDC-1 plasma level increased, indicating vascular endothelial damage.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIntravitreal anti-VEGF agents are used in the treatment of DME and proliferative diabetic retinopathy (PDR).\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e Avery et al.\u003csup\u003e11\u003c/sup\u003e and Hirano et al.\u003csup\u003e12\u003c/sup\u003e observed a significant decrease in plasma VEGF levels after intravitreal bevacizumab and aflibercept injections for diabetic macular edema, but no such effect was observed after intravitreal ranibizumab injection. From clinical experience in oncology, it is understood that there are adverse effects, such as cardiovascular and arterial thromboembolic events, by blocking VEGF in the systemic circulation.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e Studies have reported that all three intravitreal anti-VEGF drugs increase the risk of thromboembolic events at different rates.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e In this study, we aimed to evaluate the vascular endothelial health status over serum SDC-1 levels in patients with diabetic retinopathy who need IV anti-VEGF treatment, and to increase the awareness of clinicians about the side effects that may occur in patients after treatment.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy participants\u003c/h2\u003e \u003cp\u003eThis case-control study was conducted between May 2024 and June 2025 in the ophthalmology clinic of the Recep Tayyip Erdogan Training and Research Hospital, affiliated with Recep Tayyip Erdogan University. The study protocol was approved by the Ethics Committee of Recep Tayyip Erdogan University (Approval No 2024/81). The principles of the Declaration of Helsinki were followed throughout this study. Written consent was obtained from all participants prior to participation. The study consisted of three groups of 114 participants, including 44 individuals with DME and nonproliferative diabetic retinopathy (NPDR), 46 individuals with DME and PDR, and 54 individuals with no disorders but controlled hypertension, matched in terms of age and sex, as the control group. The patients were diagnosed with PDR, NPDR, and DME according to the criteria of international clinical DR and DME disease severity scales.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e Exclusion criteria included a history of cardiovascular and cerebrovascular disease, chronic inflammatory diseases (rheumatoid arthritis, systemic sclerosis, psoriasis, ulcerative colitis, and Crohn's disease), hematological diseases, malignancies, kidney and liver diseases, and diseases that could alter serum SDC-1 concentrations, such as vasculitis. In addition, patients who had received intravitreal anti-VEGF treatment for at least 6 months were excluded from the study.\u003c/p\u003e \u003cp\u003eThe study group comprised patients with type 2 diabetes. Patients with concomitant hypertension were also included in the study if their blood pressure was controlled. Individuals who did not have a history of any systemic disease other than hypertension and were scheduled for elective phacoemulsification cataract surgery constituted the control group. All patients underwent detailed ophthalmological examinations, including best-corrected visual acuity (BCVA), biomicroscopic examination, tonometry, dilated fundus examination, and optical coherence tomography evaluation. Fundus fluorescein angiography was performed in individuals with suspected PDR, even though no visible neovascularization was detected via funduscopic examination. In both the study and control groups, the examination of participants whose funduscopic examination could not be evaluated due to cataract was performed again when the optical media was transparent after cataract surgery.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eCollection of blood samples\u003c/h3\u003e\n\u003cp\u003eVenous blood samples (5 mL) were collected from the participants in the experimental groups immediately before intravitreal anti-VEGF injection, and the samples were stored in serum-separating tubes. Venous blood samples were collected from the control group before cataract surgery. Venous blood samples (5 mL) were collected from all participants after 8-h of overnight fasting between 9:00 and 12:00 to avoid diurnal changes. The coagulated blood samples were centrifuged at 3000\u0026times;g for 10 min to obtain sera, which were stored at \u0026minus;\u0026thinsp;20\u0026deg;C until quantification of SDC-1 concentrations was performed.\u003c/p\u003e\n\u003ch3\u003eQuantification of SDC-1 concentrations\u003c/h3\u003e\n\u003cp\u003eSerum SDC-1 concentrations were determined using enzyme-linked immunosorbent assay (ELISA) kits (Elabscience, Texas, Catalogue No: E-EL-H1298) according to the manufacturer\u0026rsquo;s instructions.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eSTATISTICAL ANALYSIS\u003c/h2\u003e \u003cp\u003eStatistical analyses were performed using SPSS Statistics for Windows, Version 29.0 (IBM Corp., Armonk, NY, USA). The distribution characteristics of continuous variables were evaluated using normality tests. One-way analysis of variance (One-way ANOVA) was applied in multiple group comparisons with a normal distribution, and the Kruskal-Wallis test was applied in those without a normal distribution. In cases where significant differences were detected, Bonferroni-corrected post hoc tests were used for pairwise comparisons.\u003c/p\u003e \u003cp\u003eThe distribution of categorical variables between the groups was examined using the chi-squared test. Spearman\u0026rsquo;s correlation analysis was performed to evaluate the relationship between age and serum syndecan levels. In all analyses, statistical significance was set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eBaseline demographic and clinical characteristics of the participants are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. There was no significant difference among the three groups in terms of age, sex, or the presence of hypertension (HT) (all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). The serum SDC-1 level of the DME with PDR group was significantly higher than that of the DME with NPDR and the control groups (all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). There was no statistically significant difference between the DME with NPDR group and the control groups in terms of serum SDC-1 level (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). No significant difference was found between the hypertension (+) and hypertension (\u0026minus;) groups in terms of age and sex (all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). The SDC-1 level in the hypertension (+) group [2.09 (0.71\u0026ndash;4.11)] ng/ml was significantly higher than that in the hypertension (-) group [1.02 (0.30\u0026ndash;4.31)] ng/ml (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\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\u003eDemographic and clinical data of the study group\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNPDR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePDR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ep value\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD; Median (min-max)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD; Median (min-max)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD; Median (min-max)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge (years)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e67\u0026thinsp;\u0026plusmn;\u0026thinsp;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68\u0026thinsp;\u0026plusmn;\u0026thinsp;8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e69\u0026thinsp;\u0026plusmn;\u0026thinsp;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0,385\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSyndecan-1 level (ng/ml)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0,9 (0,3\u0026thinsp;\u0026minus;\u0026thinsp;2,32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1,08 (0,65\u0026thinsp;\u0026minus;\u0026thinsp;3,23)\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1,8 (0,73\u0026thinsp;\u0026minus;\u0026thinsp;4,31)\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" 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\u003e\u003cb\u003eFemale n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (55,6 )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27 (58,7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0,703\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMale n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (44,4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19 (41,3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHypertensive group\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003en (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45 (83,3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33 (75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33 (71,7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0,360\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNormotensive group\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003en (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (16,7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (28,3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cem\u003ePDR\u003c/em\u003e proliferative diabetic retinopathy \u003cem\u003eNPDR\u003c/em\u003e nonproliferative diabetic retinopathy\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003ea\u003c/sup\u003e: Obtained by One-way ANOVA, Kruskal Wallis or Chi-Square tests; \u003csup\u003eb\u003c/sup\u003e:Significant vs control (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001); \u003csup\u003ec\u003c/sup\u003e:Significant vs PDR (p\u0026thinsp;=\u0026thinsp;0.003)\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eChronic hyperglycemia causes both micro- and macrovascular complications that affect various organs such as the skin, muscles, heart, brain, eyes, and kidneys. Microvascular complications included retinopathy, nephropathy, and neuropathy. The role of suspected endothelial glycocalyx (EG) damage in the pathophysiology of diabetes has only recently been demonstrated. In patients with type 2 diabetes, a decrease in EG volume was detected in the sublingual and retinal vessels.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e In terms of functional outcomes, EG impairment during diabetes mellitus is clearly associated with many typical micro- and macrovascular complication phenomena, such as decreased arterial vasodilation (a typical step in endothelial dysfunction), increased endothelial permeability to macromolecules, fluid leakage, loss of pericytes, and neovascularization in retinal vessels.\u003csup\u003e\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e EG damage in diabetes mellitus is also associated with activation of coagulation and increased leukocyte adhesion.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e High circulating SDC-1 level is an indicator of endothelial glycocalyx damage.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn the present study, the serum SDC-1 level in the DME with PDR group was significantly higher than that in the control group. Consistent with the literature, the high level of SDC-1, which is an indicator of EG damage, caused microvascular complications in the retina observed in this patient group. There were no significant differences between the DME with NPDR group and control groups. Svennevig et al. reported that serum SDC-1 concentrations were significantly increased in patients with microalbuminuric type 1 diabetes compared to normoalbuminuric type 1 diabetic patients and healthy controls.\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e According to the results of the study conducted by Manaviat et al., there is a high positive correlation between diabetic retinopathy and renal involvement, and microalbuminuria is associated with diabetic retinopathy in type 2 diabetic patients and is a reliable marker of retinopathy.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e While the rate of microalbuminuria is low in low-stage diabetic retinopathy stages, it is observed at a much higher rate in advanced stages, such as proliferative diabetic retinopathy.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e The common conclusion derived from the studies conducted by Svennevig et al., Manaviat et al., and the present study is that serum SDC-1 levels increase in stages of diabetes mellitus with severe microvascular damage, such as proliferative diabetic retinopathy.\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eChen et al. reported that the SDC-1 level was high in patients with nephrotic syndrome, which accelerated the hypercoagulability status through endothelial damage, and that it may be vital in the formation and progression of thrombosis in this group of patients.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e Lu et al. reported that high plasma SDC-1 levels increased the severity of vascular thrombosis-mediated organ damage and disease in the thrombotic thrombocytopenic purpura patient group.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e Harahsheh et al. associated high levels of SDC-1, a biomarker of endothelial function, with the risk of developing thromboembolism in critically acquired coagulopathy patients with an impaired clotting profile.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eTo raise awareness about the systemic side effects of intravitreal anti-VEGF drugs administered for diabetic macular edema, retinal vein occlusion, and neovascular age-related macular degeneration, many studies have been conducted to investigate serum and plasma VEGF levels after administering these drugs. Hirano et al. reported that basal plasma VEGF levels did not correlate with diabetic retinopathy or DME severity, that single-dose bevacizumab or intravitreal injection of aflibercept significantly reduced plasma VEGF levels up to 4 weeks, while ranibizumab did not cause such effects.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e Since there was no relationship between systemic VEGF levels and disease severity, the authors pointed out the unnecessary suppression of systemic VEGF, as well as the risk of the patient being unnecessarily exposed to systemic side effects.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e Zehetner et al. reported that after intravitreal aflibercept injection, systemic VEGF levels decreased significantly over the 4-week observation period, whereas intravitreal ranibizumab did not show a significant systemic effect on plasma VEGF.\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAs the VEGF pathway is critical not only for normal growth and development, but also for physiological response and homeostasis in many organs and functions in adulthood, various side effects are expected with pharmacological blocking of this pathway.\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e Indeed, the clinical side effect profiles are quite extensive. The side effects attributed to VEGF inhibition include hypertension, arterial thromboembolic events (AT), proteinuria or renal dysfunction, wound complications, bleeding, and reversible posterior leukoencephalopathy syndrome.\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eHypertension is the best-documented cardiovascular side effect of VEGF inhibitors.\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e The VEGF signal produces nitric oxide and prostaglandin I2.\u003csup\u003e30\u003c/sup\u003e This causes endothelial cell-dependent vasodilation in arterioles and venules.\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e This is the vascular component that has the most impact on blood pressure.\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e Blocking VEGF leads to vasoconstriction.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e In the present study, it was determined that serum SDC-1 levels were higher in individuals with hypertension than in those without hypertension. According to this result, a higher rate of side effects is expected after IV anti-VEGF injections in individuals with diabetic retinopathy and hypertension.\u003c/p\u003e \u003cp\u003eThe pathogenesis underlying venous and arterial thrombosis is differently related to certain distinctive features, although some mechanisms are partially overlapping.\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e For example, the clotting cascade, which is mainly regulated by tissue factor, plays a role in venous thrombosis, while arterial thrombosis is mainly regulated by platelets.\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e The importance of VEGF in vascular endothelial cell-platelet homeostasis may explain the tendency of VEGF inhibitors to increase the risk of arterial thromboembolism.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e Under normal physiological conditions, secretory factors such as VEGF from vascular endothelial cells and platelets have an important role in preventing blood cells from adhering to the vascular system and ensuring the survival and regeneration of vascular endothelial cells in response to vascular damage.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e When VEGF signaling is inhibited by VEGF inhibitors, this may compromise the integrity of vascular endothelial cells and promote platelet aggregation.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e According to the results of the present study, there may be an increase in the likelihood of arterial and venous thromboembolic side effects after IV anti-VEGF injection in patients with DME with PDR with high SDC-1 levels compared to the control group and DME with NPDR patient group.\u003c/p\u003e \u003cp\u003eThe filtration barrier of renal glomeruli is formed by vascular endothelial cells, podocytes, and basement membrane components.\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e,\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e The interaction of VEGF produced by podocytes with VEGFr2 in glomerular vascular endothelial cells is critical for normal function and repair of the system.\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e,\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e In preclinical rat models, heterozygous deletion of VEGF in podocytes leads to loss of fenestration, podocyte loss, mesangiolysis, and proteinuria in vascular endothelial cells.\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e,\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e More importantly, VEGF has been shown to have a critical protective role in the pathogenesis of the microangiopathic process.\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e Clinically, renal side effects may occur as asymptomatic proteinuria following anti-VEGF treatment, and acute renal failure, nephrotic syndrome, or microangiopathy may rarely develop.\u003csup\u003e\u003cspan additionalcitationids=\"CR35\" citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e According to the results of the present study, there may be an increase in the likelihood of renal side effects after IV anti-VEGF injection in patients with DME with PDR with high SDC-1 levels compared to the control group and DME with NPDR patient group.\u003c/p\u003e \u003cp\u003eIn conclusion, this study demonstrated that the SDC-1 level was higher in patients with DME with PDR than in the control and DME with NPDR groups. Elevated SDC-1, which is an indicator of vascular endothelial damage and is observed in the DME with NPDR patient group, may cause a further increase in the side effects of IV anti-VEGF treatment related to vascular endothelial damage in this patient group. Ophthalmologists who administer IV anti-VEGF treatment for DME should be careful in terms of side effects, especially in the proliferative diabetic retinopathy patient group, inform the patient in this direction, and follow up closely.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics declarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval was obtained from the Ethics Committee of Recep Tayyip Erdogan University (Approval ID: 2024/81). The tenets of the Declaration of Helsinki were followed throughout this study. Written informed consent was obtained from all the participants before participation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding was received for the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMO designed the study and collected blood samples and data, MA analyzed the serum SDC-1 levels with ELISA kits and performed the statistical analysis, MO and MA interpreted the data and wrote the original draft; all authors reviewed, edited, and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere is no conflict of interest to disclose\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWells JA, Glassman AR, Ayala AR, et al. 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Lancet Oncol. 2007;8:177\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRoncone D, satoskar A, Nadasdy T, Monk JP. rovin BH. Proteinuria in a patient receiving anti-veGF therapy for metastatic renal cell carcinoma. Nat Clin Pract Nephrol. 2007;3:287\u0026ndash;93.\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":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Diabetic Retinopathy, Syndecan-1, vascular Endothelium, Bevacizumab, Ranibizumab, Aflibercept","lastPublishedDoi":"10.21203/rs.3.rs-9258120/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9258120/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eThis study aimed to evaluate vascular endothelial cell health through serum Syndecan-1 (SDC-1) level measurement in patients with diabetic retinopathy undergoing intravitreal anti-VEGF therapy and to increase the awareness of clinicians about the systemic side effects of this treatment.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis prospective case-control study included 144 patients divided into the DME with NPDR (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;44), DME with PDR (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;46), and control groups (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;54). Anterior and posterior eye segments were evaluated with biomicroscopic and funduscopic examination, macula with optical coherence tomography, and serum SDC-1 levels were analyzed using an enzyme-linked immunosorbent assay.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThere was no significant difference among the three groups in terms of age, sex, or the presence of hypertension (HT) (all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). The serum SDC-1 level of the DME with PDR group was significantly higher than that of the DME with NPDR and control groups (all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). There was no statistically significant difference between the DME with NPDR group and the control groups in terms of serum SDC-1 level. The SDC-1 level of the hypertension (+) group was significantly higher than that of the hypertension (-) group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThe fact that the SDC-1 level in the DME with PDR group was significantly higher than that in the DME with NPDR and control groups indicates that the vascular endothelial cell health of this group was impaired. Ophthalmologists who administer intravitreal anti-VEGF treatment should be more alert in terms of systemic side effects in all patients, especially in patients with DME with PDR.\u003c/p\u003e","manuscriptTitle":"Evaluation of serum syndecan-1 levels in patients with diabetic retinopathy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-04 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