Association between Systemic Immune-inflammation Index and Decreased Kidney Function in Patients with Early Chronic Kidney Disease: A Retrospective Study

Association between Systemic Immune-inflammation Index and Decreased Kidney Function in Patients with Early Chronic Kidney Disease: A Retrospective Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Association between Systemic Immune-inflammation Index and Decreased Kidney Function in Patients with Early Chronic Kidney Disease: A Retrospective Study Jinshi Zhang, Yueming Liu, Baihui Xu, Bin Zhu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4782517/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract The systemic immune-inflammation index (SII) is a newly developed biomarker to assess inflammation, which plays a crucial role in chronic kidney disease (CKD). The objective of the investigation was to examine the connection between SII and early CKD. Retrospective clinical data from patients admitted to the Zhejiang Provincial People’s Hospital between 1996 and 2022 were analyzed. SII was calculated as platelet count × neutrophil count/lymphocyte count and estimated glomerular filtration rate (eGFR) slope as the difference between the first and last observed eGFR divided by the year interval. The independent connection between Sll and eGFR slope was explored employing the curves of Kaplan – Meier survival, Multivariable regression analysis, and subgroup analysis. This study included 3,419 patients who were separated into four groups depending on SII quartiles, with early decreased kidney function defined as eGFR slope ≥ 1. After adjustment for covariates, the adjusted HR (95%CIs) for the second, third, fourth quartiles were 1.36(1.18,1.56), 1.28(1.11,1.47) and 1.30(1.13,1.51), respectively. Subgroup analyses showed elevated SII levels were related to early CKD in patients aged ≤ 65, male, with no history of diabetes mellitus, and with or without hypertension. Kaplan–Meier survival curves showed that with increasing SII levels, the cumulative renal survival rate (eGFR slope < 1) significantly decreased. Our findings suggest that SII may act as a valuable novel marker for anticipating prognosis in individuals with early-stage CKD. Health sciences/Nephrology Health sciences/Nephrology/Kidney diseases Biological sciences/Immunology/Inflammation/Chronic inflammation SII eGFR slope early chronic kidney disease kidney function biomarker prognosis Figures Figure 1 Introduction Chronic kidney disease (CKD) is an important health concern characterized by a high occurrence rate, poor prognosis, and long disease course. Research on CKD, which employs kidney failure and doubling of serum creatinine levels as clinical endpoints, often requires substantial follow-up periods [ 1 ], leading to medical expenditure and irreversible morbidity. Therefore, in order to prevent the progress of CKD, it is necessary to possess a thorough comprehension of the prospective elements linked to the early development of CKD. Considering that observing the outcome variables in clinical trials takes a long time, recent research has suggested that the estimated glomerular filtration rate (eGFR) slope can serve as a surrogate endpoint [ 2 ]. Inflammation has an important function in the development and progression of CKD [ 3 ]. Investigations have shown that the kidney gets 25% of the total blood volume but lacks the detoxifying, antioxidant, and anti-inflammatory defensive systems seen in other highly vascularized organs like the liver. Hence, the kidneys are easily damaged by inflammation. Studies have indicated that inflammatory markers like neutrophil count, C-reactive protein (CRP), the ratio of procalcitonin, monocyte-lymphocyte, and the ratio of platelet-to-lymphocyte can anticipate the progression of CKD [ 4 – 6 ]. The systemic immune-inflammation index (SII) has become an accurate measure of inflammation and immunological state across the whole human body [ 7 ]. It is detected as platelet count × neutrophil count/lymphocyte count and has been widely investigated. This comprehensive parameter can comprehensively reflect the body's inflammatory status compared with a single inflammatory indicator. Its role in predicting the clinical outcomes of tumors, end-stage kidney disease, acute renal injury (AKI), and diabetic kidney disease has been demonstrated [ 7 – 11 ]. Additionally, it is connected with an elevated risk of kidney stones [ 12 ], chronic heart failure [ 13 ], osteoporosis in postmenopausal women [ 14 ], and peripheral arterial diseases [ 15 ]. In this study, we aim to assess whether the SII has predictive value for the progression of early CKD. Methods Study population This was a retrospective study using the medical information of patients admitted to the Zhejiang Provincial People’s Hospital between 1996 and 2022. The criteria for inclusion were as follows: (1) The patient has been diagnosed with CKD, chronic kidney failure, renal insufficiency, increased blood creatinine, nephritis, or kidney disease. (2) Imaging results indicate bilateral renal atrophy; (3) urine protein ≥ 0.3g/24h, urine protein/ urine creatinine ≥ 0.3g/24h, urine microalbumin/ urine creatinine ≥ 30 mg/g lasting for more than 3 months; (4)eGFR < 60 mL/min/1.73 m 2 lasting for more than 3 months. The criteria for exclusion were as follows: (1) Patients < 18 years; (2) eGFR < 30 mL/min/1.73 m 2 ; (3) lost platelet count or neutrophil or lymphocyte levels; and (4) reflux nephropathy, obstructive nephropathy, urinary system tumors, and chronic pyelonephritis. Finally, 3419 patients were included in the study. Te study was approved by the local ethics committee of Zhejiang Provincial People's Hospital, and informed consent was obtained from all study participants. Te study was performed in conformity with the Helsinki Declaration-based ethical principles for medical research involving human subjects. Definition of variables SII = platelets × neutrophils/lymphocytes [ 7 ]. eGFR slope = (first eGFR - last eGFR)/year interval. eGFR scores were detected utilizing the C K D Epidemiology Collaboration algorithm. Hypertension was characterized as having a systolic blood pressure (SBP) of 140 mmHg or greater and a diastolic blood pressure (DBP) of 90 mmHg or higher, either via multiple investigations or a previous diagnosis of hypertension. Diabetes mellitus was characterized as having a fasting blood glucose level of ≥ 7.0 mmol/l, and/or a 2-hour postprandial blood glucose level of ≥ 11.1 mmol/l, and/or a HbA1c level of ≥ 6.5%, or a previous diagnosis of diabetes mellitus. Outcome variable Decreased kidney function was defined as eGFR slope ≥ 1. Statistical analyses The initial features of every participant were categorized based on the SII quartile. Continuous variables were represented employing medians and interquartile ranges. The Kruskal-Wallis test was used to determine differences between them, whereas categorical variables were presented as frequencies or percentages and compared employing the Chi-square test. The study utilized Cox proportional hazard models to ascertain the correlation between the SII and reduced kidney function in individuals diagnosed with early-stage CKD. Stratification studies were conducted to ascertain the correlation between the SII and the decline in renal function across different subgroups categorized by age (≤ 60 or > 65 years), gender (male or female), hypertension (yes or no), and diabetes (yes or no). Moreover, the Kaplan-Meier analysis was used to determine the cumulative incidence of results, graphically illustrating the association between the SII and decreased renal function. All statistical analyses were performed using SPSS software (version 27). A two-tailed p-value < 0.05 was considered statistically significant. Results Baseline features of participants grouped according to SII quartiles The investigation included an overall of 3419 individuals suffering from early CKD who met the inclusion and exclusion criteria(Table 1). Among them, 1886 (55.2%) were males and 1533 (44.8%) were females. The median age and SII level were 61.78 (46.84, 76.19) years and 447.7 × 109/L (296.79–726.53), respectively. Table 1 provides a summary of the features of the investigation, organized by the quartile of the SII. Prevalence of hypertension, drinking status, low-density lipoprotein cholesterol (LDL-C), age, SBP, serum uric acid, DBP, albuminuria, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), CRP Showed statistical differences across SII quartiles. eGFR was not statistically different among the groups. Association between SII and outcomes We used the models of Cox proportional hazards regression to detect the connection between SII and declined renal function (Table 2). In Model 1, the HR (95% CIs) for the second, third, and fourth quartiles were 1.250 (1.089, 1.435), 1.188 (1.033, 1.367), and 1.302 (1.142, 1.485), respectively. In Model 2, following the adjustment of age and sex, the adjusted HR (with 95% CIs) for the second, third, and fourth quartiles were 1.252 (1.090, 1.437), 1.190 (1.034, 1.369), and 1.270 (1.103, 1.461), respectively. In Model 3, we adjusted for diabetes mellitus, hypertension, drinking， smoking, SBP, DBP, eGFR, albumin, uric acid, TC, LDL, HDL, ALT, AST, CRP, hemoglobin and albuminuria in addition to the variables in Model 2. The adjusted HR (95% CIs) for the second, third, and fourth quartiles were 1.359 (1.181, 1.564), 1.278 (1.108, 1.474), and 1.304 (1.127, 1.508), respectively. Subgroup analysis The subgroup study revealed inconsistent connections between SII and decreased renal function. Table 3 shows that an increase in SII levels was related to decreased kidney function in patients aged ≤65, male, with no history of diabetes mellitus, and with or without hypertension. Furthermore, factors like age and history of diabetes mellitus and hypertension did not have an impact on the relationship between SII and decreased kidney function, except for a significant interaction identified only in men (P= 0.038). Kaplan–Meier survival analysis Figure 1 illustrates the Kaplan–Meier survival analysis. With the increasing of SII level, the cumulative renal survival rate （eGFR slope ＜1 ）significantly decreased ( P=0.0028). Discussion In this investigation, we observed that SII was significantly connected with a decrease in kidney function in patients with early CKD. The SII has the potential to serve as a valuable novel marker for prognosticating the outcome of individuals with early CKD. Traditional clinical trials often used urinary protein and eGFR as outcome variables. Proteinuria mainly reflects the permeability of glomerular filtration membranes. In the pathogenesis of many CKD, an increase in urine protein levels usually occurs before a decrease in eGFR. However, due to the influence of multiple factors on the production of urine proteins, the relationship between the progression rate of CKD and proteinuria is not the same for different etiologies, and an increase in urine protein may not necessarily lead to renal failure. Therefore, the value of urinary protein as a renal endpoint in clinical trials remains controversial [ 16 ]. eGFR is an indicator reflecting overall renal function, and end-stage renal disease is defined as eGFR < 15 mLl/min · 1.73 ㎡. However, the progression from chronic glomerulonephritis to end-stage renal disease is relatively long. This imposes high requirements for both the scale and cost of drug research. The eGFR slope refers to the rate of change in the glomerular filtration rate. The larger the slope of the eGFR, the faster the decrease in the glomerular filtration rate, indicating accelerated deterioration of renal function [ 2 ]. Therefore, this study selected the eGFR slope as the outcome variable. The inflammation role in patients with CKD has been extensively analyzed and discussed [ 17 ]. Xiang et al. reported a gradual decrease in lymphocytes with the progression of kidney disease [ 18 ]. Fathabad et al. discovered that neutrophils had a significant impact on the development of renal damage. Nevertheless, there exists a negative correlation between lymphocytes and inflammation. When lymphocytes are decreased, it results in aberrant immunological function, hence facilitating the progression of renal damage [ 19 ]. A separate investigation revealed that the neutrophil count emerged as the most reliable independent risk factor for CKD [ 6 ]. The platelet count, which is an unusual inflammatory marker for first diagnosis, was also shown to have a correlation with CKD. Individuals diagnosed with CKD have higher levels of the platelet activity indicator CD40L in comparison to those who are in good health [ 20 ]. Several studies have shown that platelet count is associated with CKD development [ 21 , 22 ]. SII is a new and stable marker of inflammation that reflects local immune and systemic inflammatory responses. The SII, which is determined by the levels of lymphocytes, neutrophils, and platelets, offers a greater depth of clinical data compared to relying on only one or two types of peripheral blood cells. Multiple investigations have shown that the SII has a notable capacity for predicting AKI, DKD, and hemodialysis [ 8 – 10 ]. Our study successfully proved that the SII level was associated with a decrease in kidney function in patients with early CKD. There were a few restrictions in this investigation: Initially, the investigation was conducted at a single location and had a retrospective design, making it vulnerable to selection bias. Furthermore, since the data was gathered retrospectively, it is possible that some crucial factors were excluded owing to inadequate data. Lastly, despite our efforts to control for several potential confounding variables, it is likely that our findings were influenced by unidentified factors. Consequently, conducting additional investigations with a greater number of participants is essential in order to establish the cause-and-effect correlations. Conclusion In our investigation, we showed that a higher SII level was associated with decreased kidney function in patients with early CKD. Additional wide prospective investigations are necessary to validate these findings. Declarations Funding This research was supported by the Zhejiang Provincial Medical and Health Science and Technology Program (2024KY665), the Zhejiang Provincial Traditional Chinese Medicine Science and Technology Project (2024ZL287), the Basic Scientific Research Funds of Department of Education of Zhejiang Province (KYQN2023009), and the Zhejiang Provincial Traditional Chinese Medicine Science and Technology Project (2024ZL019). Author Contribution B.X. and B.Z. designed the study. J.Z. wrote the manuscript. J.Z. , and Y.L. analyzed the data and visualized the figures. All authors contributed to the article and approved the submitted version. Data Availability The data that support the findings of this study are available on request from the corresponding author, upon reasonable request. References Andrew S, L. et al. GFR decline as an end point for clinical trials in CKD: a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration. 64, doi: 10.1053/j.ajkd.2014.07.030 (2014). Lesley A, I. et al. GFR Slope as a Surrogate End Point for Kidney Disease Progression in Clinical Trials: A Meta-Analysis of Treatment Effects of Randomized Controlled Trials. 30, doi: 10.1681/asn.2019010007 (2019). Saurav Prashant, K., Matthew, S., Michael, M., Kai, M. & Rupesh, R. J. C. The Role of Inflammation in CKD. 12, doi: 10.3390/cells12121581 (2023). Ramsés, D.-C., Oscar, J.-D., Andrés, S.-V., Mai Anh, N. & J Luis, E. J. J. P. M. Elevated Monocyte to Lymphocyte Ratio and Increased Mortality among Patients with Chronic Kidney Disease Hospitalized for COVID-19. 11, doi: 10.3390/jpm11030224 (2021). Zeng, M. et al. J-shaped association of platelet-to-lymphocyte ratio with 5-year mortality among patients with chronic kidney disease in a prospective cohort study. 52, - (2020). Rui, Z. et al. Increased neutrophil count Is associated with the development of chronic kidney disease in patients with diabetes. 14, doi: 10.1111/1753-0407.13292 (2022). Bo, H. et al. Systemic immune-inflammation index predicts prognosis of patients after curative resection for hepatocellular carcinoma. 20, doi: 10.1158/1078-0432.Ccr-14-0442 (2014). Wencong, G. et al. Systemic immune-inflammation index is associated with diabetic kidney disease in Type 2 diabetes mellitus patients: Evidence from NHANES 2011–2018. 13, doi: 10.3389/fendo.2022.1071465 (2022). Anna, K. et al. Systemic Immune Inflammation Index as a Key Predictor of Dialysis in Pediatric Chronic Kidney Disease with the Use of Random Forest Classifier. 12, doi: 10.3390/jcm12216911 (2023). Lan, J. et al. Prognostic Value of Systemic Immune-Inflammation Index among Critically Ill Patients with Acute Kidney Injury: A Retrospective Cohort Study. 11, doi: 10.3390/jcm11143978 (2022). Xing, L. et al. Systemic immune-inflammation index is a promising non-invasive biomarker for predicting the survival of urinary system cancers: a systematic review and meta-analysis. 53, doi: 10.1080/07853890.2021.1991591 (2021). Xingpeng, D., Shaozhuang, L., Liyuan, X. & Xi, J. J. F. I. Association between the systemic immune-inflammation index and kidney stone: A cross-sectional study of NHANES 2007–2018. 14, doi: 10.3389/fimmu.2023.1116224 (2023). Zeyu, W. et al. Systemic immune-inflammation index as a prognostic marker for advanced chronic heart failure with renal dysfunction. 10, doi: 10.1002/ehf2.14217 (2022). Y N, D., Y J, C., H Y, Z., X, W. & Z F, Z. J. G. E. Inverse association between systemic immune-inflammation index and bone mineral density in postmenopausal women. 37, doi: 10.1080/09513590.2021.1885642 (2021). Zheng, Z. & Zhong, C. J. A. V. S. Higher Systemic Immune-Inflammation Index is Associated With Higher Likelihood of Peripheral Arterial Disease. 84, doi: 10.1016/j.avsg.2021.12.011 (2021). Andrew S, L. et al. Change in Albuminuria and GFR as End Points for Clinical Trials in Early Stages of CKD: A Scientific Workshop Sponsored by the National Kidney Foundation in Collaboration With the US Food and Drug Administration and European Medicines Agency. 75, doi: 10.1053/j.ajkd.2019.06.009 (2019). Simona, M. et al. Inflammation-Related Mechanisms in Chronic Kidney Disease Prediction, Progression, and Outcome. 2018, doi: 10.1155/2018/2180373 (2018). Fang-fang, X. et al. Lymphocyte depletion and subset alteration correlate to renal function in chronic kidney disease patients. 38, doi: 10.3109/0886022x.2015.1106871 (2015). Somayeh, G. F. et al. T Lymphocytes in Acute Kidney Injury and Repair. 40, doi: 10.1016/j.semnephrol.2020.01.003 (2020). Jeffrey X, X. et al. Circulating CD40 and sCD40L Predict Changes in Renal Function in Subjects with Chronic Kidney Disease. 7, doi: 10.1038/s41598-017-08426-8 (2017). Juxiang, L. et al. The association of neutrophil to lymphocyte ratio, mean platelet volume, and platelet distribution width with diabetic retinopathy and nephropathy: a meta-analysis. 38, doi: 10.1042/bsr20180172 (2018). Ksenija, S. et al. Elevation of Platelet and Monocyte Activity Markers of Atherosclerosis in Haemodialysis Patients Compared to Peritoneal Dialysis Patients. 2017, doi: 10.1155/2017/8506072 (2017). Tables Table 1 to 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Tables13.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-4782517","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":343427120,"identity":"f54c8e6c-6637-46d5-b698-a0e237ecbc2d","order_by":0,"name":"Jinshi Zhang","email":"","orcid":"","institution":"Urology \u0026 Nephrology Center, Department of Nephrology, Zhejiang Provincial People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jinshi","middleName":"","lastName":"Zhang","suffix":""},{"id":343427121,"identity":"5a994a49-2f0a-481e-9a23-c78990ef5c7e","order_by":1,"name":"Yueming Liu","email":"","orcid":"","institution":"Urology \u0026 Nephrology Center, Department of Nephrology, Zhejiang Provincial People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yueming","middleName":"","lastName":"Liu","suffix":""},{"id":343427122,"identity":"ef7fceaf-5eef-4c87-bf00-89025ea02ff7","order_by":2,"name":"Baihui Xu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA00lEQVRIiWNgGAWjYJACCQaGAwxsIPKDgY0daVoOzihISyZeC4hk5vlwiLGBkHJ59+aDt3nb7sjzSfcYHrYxOMDMwH746AZ8WgzPHEu2nNn2zLBN5ozB4RyDO3wMPGlpN/BqmZFjJvGx7TBjm0QOSMszZgYJHjPCWhLbDtuDtVgYHGZsIKRFXgJiSyJYCwMxWgx4gH6Zce5ZcptEWsHBHoO0ZDZCfpFvB4YYT9kd2/kzkjd/+PHHxo6f/fAx/LYcQBdhw6ccbEsDIRWjYBSMglEwCgB3dU4draommgAAAABJRU5ErkJggg==","orcid":"","institution":"Urology \u0026 Nephrology Center, Department of Nephrology, Zhejiang Provincial People's Hospital","correspondingAuthor":true,"prefix":"","firstName":"Baihui","middleName":"","lastName":"Xu","suffix":""},{"id":343427123,"identity":"f068e178-859f-4fc4-ba73-bf1e9ff455be","order_by":3,"name":"Bin Zhu","email":"","orcid":"","institution":"Urology \u0026 Nephrology Center, Department of Nephrology, Zhejiang Provincial People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Bin","middleName":"","lastName":"Zhu","suffix":""}],"badges":[],"createdAt":"2024-07-22 14:21:46","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4782517/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4782517/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":63486584,"identity":"4921a12b-11ad-48ef-a90c-8a88c79ad8da","added_by":"auto","created_at":"2024-08-28 16:07:37","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":495986,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier survival curves for the development reduced kidney function.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4782517/v1/018dc77fa1d8402ee56c28f3.jpeg"},{"id":69226726,"identity":"a045dc6d-f520-4a5b-859a-a6ff2031b3a8","added_by":"auto","created_at":"2024-11-18 08:10:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":803893,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4782517/v1/3781b6f7-fc8e-47ef-9b47-f3c967728b6f.pdf"},{"id":63486583,"identity":"145fd552-fdad-4b9b-b8d8-a72b00291505","added_by":"auto","created_at":"2024-08-28 16:07:37","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":36684,"visible":true,"origin":"","legend":"","description":"","filename":"Tables13.docx","url":"https://assets-eu.researchsquare.com/files/rs-4782517/v1/ecf48bd13c32d5f79e8ddefd.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Association between Systemic Immune-inflammation Index and Decreased Kidney Function in Patients with Early Chronic Kidney Disease: A Retrospective Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eChronic kidney disease (CKD) is an important health concern characterized by a high occurrence rate, poor prognosis, and long disease course. Research on CKD, which employs kidney failure and doubling of serum creatinine levels as clinical endpoints, often requires substantial follow-up periods [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], leading to medical expenditure and irreversible morbidity. Therefore, in order to prevent the progress of CKD, it is necessary to possess a thorough comprehension of the prospective elements linked to the early development of CKD. Considering that observing the outcome variables in clinical trials takes a long time, recent research has suggested that the estimated glomerular filtration rate (eGFR) slope can serve as a surrogate endpoint [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eInflammation has an important function in the development and progression of CKD [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Investigations have shown that the kidney gets 25% of the total blood volume but lacks the detoxifying, antioxidant, and anti-inflammatory defensive systems seen in other highly vascularized organs like the liver. Hence, the kidneys are easily damaged by inflammation. Studies have indicated that inflammatory markers like neutrophil count, C-reactive protein (CRP), the ratio of procalcitonin, monocyte-lymphocyte, and the ratio of platelet-to-lymphocyte can anticipate the progression of CKD [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe systemic immune-inflammation index (SII) has become an accurate measure of inflammation and immunological state across the whole human body [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. It is detected as platelet count \u0026times; neutrophil count/lymphocyte count and has been widely investigated. This comprehensive parameter can comprehensively reflect the body's inflammatory status compared with a single inflammatory indicator. Its role in predicting the clinical outcomes of tumors, end-stage kidney disease, acute renal injury (AKI), and diabetic kidney disease has been demonstrated [\u003cspan additionalcitationids=\"CR8 CR9 CR10\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Additionally, it is connected with an elevated risk of kidney stones [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], chronic heart failure [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], osteoporosis in postmenopausal women [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], and peripheral arterial diseases [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In this study, we aim to assess whether the SII has predictive value for the progression of early CKD.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cp\u003eThis was a retrospective study using the medical information of patients admitted to the Zhejiang Provincial People\u0026rsquo;s Hospital between 1996 and 2022. The criteria for inclusion were as follows: (1) The patient has been diagnosed with CKD, chronic kidney failure, renal insufficiency, increased blood creatinine, nephritis, or kidney disease. (2) Imaging results indicate bilateral renal atrophy; (3) urine protein\u0026thinsp;\u0026ge;\u0026thinsp;0.3g/24h, urine protein/ urine creatinine\u0026thinsp;\u0026ge;\u0026thinsp;0.3g/24h, urine microalbumin/ urine creatinine\u0026thinsp;\u0026ge;\u0026thinsp;30 mg/g lasting for more than 3 months; (4)eGFR\u0026thinsp;\u0026lt;\u0026thinsp;60 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e lasting for more than 3 months. The criteria for exclusion were as follows: (1) Patients\u0026thinsp;\u0026lt;\u0026thinsp;18 years; (2) eGFR\u0026thinsp;\u0026lt;\u0026thinsp;30 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e; (3) lost platelet count or neutrophil or lymphocyte levels; and (4) reflux nephropathy, obstructive nephropathy, urinary system tumors, and chronic pyelonephritis. Finally, 3419 patients were included in the study. Te study was approved by the local ethics committee of Zhejiang Provincial People's Hospital, and informed consent was obtained from all study participants. Te study was performed in conformity with the Helsinki Declaration-based ethical principles for medical research involving human subjects.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eDefinition of variables\u003c/strong\u003e \u003cp\u003eSII\u0026thinsp;=\u0026thinsp;platelets \u0026times; neutrophils/lymphocytes [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. eGFR slope = (first eGFR - last eGFR)/year interval. eGFR scores were detected utilizing the C K D Epidemiology Collaboration algorithm. Hypertension was characterized as having a systolic blood pressure (SBP) of 140 mmHg or greater and a diastolic blood pressure (DBP) of 90 mmHg or higher, either via multiple investigations or a previous diagnosis of hypertension. Diabetes mellitus was characterized as having a fasting blood glucose level of \u0026ge;\u0026thinsp;7.0 mmol/l, and/or a 2-hour postprandial blood glucose level of \u0026ge;\u0026thinsp;11.1 mmol/l, and/or a HbA1c level of \u0026ge;\u0026thinsp;6.5%, or a previous diagnosis of diabetes mellitus.\u003c/p\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eOutcome variable\u003c/h2\u003e \u003cp\u003eDecreased kidney function was defined as eGFR slope\u0026thinsp;\u0026ge;\u0026thinsp;1.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses\u003c/h2\u003e \u003cp\u003eThe initial features of every participant were categorized based on the SII quartile. Continuous variables were represented employing medians and interquartile ranges. The Kruskal-Wallis test was used to determine differences between them, whereas categorical variables were presented as frequencies or percentages and compared employing the Chi-square test. The study utilized Cox proportional hazard models to ascertain the correlation between the SII and reduced kidney function in individuals diagnosed with early-stage CKD. Stratification studies were conducted to ascertain the correlation between the SII and the decline in renal function across different subgroups categorized by age (\u0026le;\u0026thinsp;60 or \u0026gt; 65 years), gender (male or female), hypertension (yes or no), and diabetes (yes or no). Moreover, the Kaplan-Meier analysis was used to determine the cumulative incidence of results, graphically illustrating the association between the SII and decreased renal function.\u003c/p\u003e \u003cp\u003eAll statistical analyses were performed using SPSS software (version 27). A two-tailed p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eBaseline features of participants grouped according to SII quartiles\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe investigation included an overall of 3419 individuals suffering from early CKD who met the inclusion and exclusion criteria(Table 1). Among them, 1886 (55.2%) were males and 1533 (44.8%) were females. The median age and SII level were 61.78 (46.84, 76.19) years and 447.7 \u0026times; 109/L (296.79\u0026ndash;726.53), respectively. Table 1 provides a summary of the features of the investigation, organized by the quartile of the SII.\u0026nbsp;Prevalence of hypertension, drinking status,\u0026nbsp;low-density lipoprotein\u0026nbsp;cholesterol (LDL-C), age, SBP, serum uric acid, DBP, albuminuria, total cholesterol (TC),\u0026nbsp;high-density lipoprotein\u0026nbsp;cholesterol (HDL-C), triglycerides (TG), CRP Showed statistical differences across SII quartiles. eGFR was not statistically different among the groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssociation between SII and outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe used the models of Cox proportional hazards regression to detect the connection\u0026nbsp;between\u0026nbsp;SII and declined renal function (Table 2). In Model 1, the HR (95% CIs) for the second, third, and fourth quartiles were 1.250 (1.089, 1.435), 1.188 (1.033, 1.367), and 1.302 (1.142, 1.485), respectively. In Model 2, following the adjustment of age and sex, the adjusted HR (with 95% CIs) for the second, third, and fourth quartiles were 1.252 (1.090, 1.437), 1.190 (1.034, 1.369), and 1.270 (1.103, 1.461), respectively. In Model 3, we adjusted for diabetes mellitus,\u0026nbsp;hypertension, drinking，\u0026nbsp;smoking,\u0026nbsp;SBP, DBP, eGFR, albumin, uric acid,\u0026nbsp;TC, LDL, HDL, ALT, AST, CRP, hemoglobin\u0026nbsp;and\u0026nbsp;albuminuria in addition to the variables in Model 2. The adjusted HR (95% CIs) for the second, third,\u0026nbsp;and fourth quartiles were 1.359 (1.181, 1.564), 1.278 (1.108, 1.474), and 1.304 (1.127, 1.508), respectively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSubgroup analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe subgroup study revealed inconsistent connections between SII and decreased renal function. Table 3 shows that an increase in SII levels was related to decreased kidney function in patients aged \u0026le;65, male, with no history of diabetes mellitus, and with or without hypertension. Furthermore, factors like age and history of\u0026nbsp;diabetes mellitus\u0026nbsp;and hypertension did not have an impact on the relationship between SII and decreased kidney function, except for a significant interaction identified only in men (P= 0.038).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eKaplan\u0026ndash;Meier survival analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFigure 1 illustrates the Kaplan\u0026ndash;Meier survival analysis. With the increasing of SII level, the cumulative renal survival rate （eGFR slope ＜1 ）significantly decreased \u0026nbsp;( P=0.0028).\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this investigation, we observed that SII was significantly connected with a decrease in kidney function in patients with early CKD. The SII has the potential to serve as a valuable novel marker for prognosticating the outcome of individuals with early CKD.\u003c/p\u003e \u003cp\u003eTraditional clinical trials often used urinary protein and eGFR as outcome variables. Proteinuria mainly reflects the permeability of glomerular filtration membranes. In the pathogenesis of many CKD, an increase in urine protein levels usually occurs before a decrease in eGFR. However, due to the influence of multiple factors on the production of urine proteins, the relationship between the progression rate of CKD and proteinuria is not the same for different etiologies, and an increase in urine protein may not necessarily lead to renal failure. Therefore, the value of urinary protein as a renal endpoint in clinical trials remains controversial [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. eGFR is an indicator reflecting overall renal function, and end-stage renal disease is defined as eGFR\u0026thinsp;\u0026lt;\u0026thinsp;15 mLl/min \u0026middot; 1.73 ㎡. However, the progression from chronic glomerulonephritis to end-stage renal disease is relatively long. This imposes high requirements for both the scale and cost of drug research. The eGFR slope refers to the rate of change in the glomerular filtration rate. The larger the slope of the eGFR, the faster the decrease in the glomerular filtration rate, indicating accelerated deterioration of renal function [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Therefore, this study selected the eGFR slope as the outcome variable.\u003c/p\u003e \u003cp\u003eThe inflammation role in patients with CKD has been extensively analyzed and discussed [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Xiang et al. reported a gradual decrease in lymphocytes with the progression of kidney disease [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Fathabad et al. discovered that neutrophils had a significant impact on the development of renal damage. Nevertheless, there exists a negative correlation between lymphocytes and inflammation. When lymphocytes are decreased, it results in aberrant immunological function, hence facilitating the progression of renal damage [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. A separate investigation revealed that the neutrophil count emerged as the most reliable independent risk factor for CKD [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The platelet count, which is an unusual inflammatory marker for first diagnosis, was also shown to have a correlation with CKD. Individuals diagnosed with CKD have higher levels of the platelet activity indicator CD40L in comparison to those who are in good health [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Several studies have shown that platelet count is associated with CKD development [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSII is a new and stable marker of inflammation that reflects local immune and systemic inflammatory responses. The SII, which is determined by the levels of lymphocytes, neutrophils, and platelets, offers a greater depth of clinical data compared to relying on only one or two types of peripheral blood cells. Multiple investigations have shown that the SII has a notable capacity for predicting AKI, DKD, and hemodialysis [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Our study successfully proved that the SII level was associated with a decrease in kidney function in patients with early CKD.\u003c/p\u003e \u003cp\u003eThere were a few restrictions in this investigation: Initially, the investigation was conducted at a single location and had a retrospective design, making it vulnerable to selection bias. Furthermore, since the data was gathered retrospectively, it is possible that some crucial factors were excluded owing to inadequate data. Lastly, despite our efforts to control for several potential confounding variables, it is likely that our findings were influenced by unidentified factors. Consequently, conducting additional investigations with a greater number of participants is essential in order to establish the cause-and-effect correlations.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn our investigation, we showed that a higher SII level was associated with decreased kidney function in patients with early CKD. Additional wide prospective investigations are necessary to validate these findings.\u003c/p\u003e "},{"header":"Declarations","content":"\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis research was supported by the Zhejiang Provincial Medical and Health Science and Technology Program (2024KY665), the Zhejiang Provincial Traditional Chinese Medicine Science and Technology Project (2024ZL287), the Basic Scientific Research Funds of Department of Education of Zhejiang Province (KYQN2023009), and the Zhejiang Provincial Traditional Chinese Medicine Science and Technology Project (2024ZL019).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eB.X. and B.Z. designed the study. J.Z. wrote the manuscript. J.Z. , and Y.L. analyzed the data and visualized the figures. All authors contributed to the article and approved the submitted version.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe data that support the findings of this study are available on request from the corresponding author, upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAndrew S, L. \u003cem\u003eet al.\u003c/em\u003e GFR decline as an end point for clinical trials in CKD: a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration. 64, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1053/j.ajkd.2014.07.030\u003c/span\u003e\u003cspan address=\"10.1053/j.ajkd.2014.07.030\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2014).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLesley A, I. \u003cem\u003eet al.\u003c/em\u003e GFR Slope as a Surrogate End Point for Kidney Disease Progression in Clinical Trials: A Meta-Analysis of Treatment Effects of Randomized Controlled Trials. 30, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1681/asn.2019010007\u003c/span\u003e\u003cspan address=\"10.1681/asn.2019010007\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaurav Prashant, K., Matthew, S., Michael, M., Kai, M. \u0026amp; Rupesh, R. 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The objective of the investigation was to examine the connection between SII and early CKD. Retrospective clinical data from patients admitted to the Zhejiang\u003c/p\u003e \u003cp\u003eProvincial People\u0026rsquo;s Hospital between 1996 and 2022 were analyzed. SII was calculated as platelet count \u0026times; neutrophil count/lymphocyte count and estimated glomerular filtration rate (eGFR) slope as the difference between the first and last observed eGFR divided by the year interval. The independent connection between Sll and eGFR slope was explored employing the curves of Kaplan\u003cb\u003e\u0026ndash;\u003c/b\u003eMeier survival, Multivariable regression analysis, and subgroup analysis. This study included 3,419 patients who were separated into four groups depending on SII quartiles, with early decreased kidney function defined as eGFR slope\u0026thinsp;\u0026ge;\u0026thinsp;1. After adjustment for covariates, the adjusted HR (95%CIs) for the second, third, fourth quartiles were 1.36(1.18,1.56), 1.28(1.11,1.47) and 1.30(1.13,1.51), respectively. Subgroup analyses showed elevated SII levels were related to early CKD in patients aged\u0026thinsp;\u0026le;\u0026thinsp;65, male, with no history of diabetes mellitus, and with or without hypertension. Kaplan\u0026ndash;Meier survival curves showed that with increasing SII levels, the cumulative renal survival rate (eGFR slope\u0026thinsp;\u0026lt;\u0026thinsp;1) significantly decreased. Our findings suggest that SII may act as a valuable novel marker for anticipating prognosis in individuals with early-stage CKD.\u003c/p\u003e","manuscriptTitle":"Association between Systemic Immune-inflammation Index and Decreased Kidney Function in Patients with Early Chronic Kidney Disease: A Retrospective Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-28 16:07:32","doi":"10.21203/rs.3.rs-4782517/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":"6d57b34c-c68c-4b10-a5e7-fb5c2c8af443","owner":[],"postedDate":"August 28th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":36389397,"name":"Health sciences/Nephrology"},{"id":36389398,"name":"Health sciences/Nephrology/Kidney diseases"},{"id":36389399,"name":"Biological sciences/Immunology/Inflammation/Chronic inflammation"}],"tags":[],"updatedAt":"2024-11-18T08:09:54+00:00","versionOfRecord":[],"versionCreatedAt":"2024-08-28 16:07:32","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4782517","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4782517","identity":"rs-4782517","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}