Elements contributing to the risk of stroke in individuals on maintenance hemodialysis

Elements contributing to the risk of stroke in individuals on maintenance hemodialysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Elements contributing to the risk of stroke in individuals on maintenance hemodialysis Weiwei hu, Xiaochun Zhou, wenjun Zhang, yingying Wang, Yuke Kong This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6337092/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 OBJECTIVE Both stroke and CKD have high morbidity and mortality rates, these two disease pose a serious threat to patient’s lives. To investigate the risk factors for stroke in patients undergoing maintenance hemodialysis (MHD), aiming to propose targeted preventive and therapeutic strategies. Additionally, our study seeks to explore the mechanisms underlying stroke in MHD patients. RESULTS The study included 70 patients in the MHD group who had experienced a stroke, with 48 males and 22 females, and an average age of 59.34 ± 11.56 years. In the non-stroke MHD group, 69 patients were included, with 45 males and 24 females, and an average age of 59.01 ± 8.42 years. Univariate logistic analysis showed that a history of hypertension, hemoglobin, albumin, and blood calcium levels were significantly associated with the occurrence of stroke in MHD patients. However, there were no statistically significant differences between the stroke and non-stroke groups in terms of history of diabetes mellitus, the presence of atrial fibrillation, serum levels of parathyroid hormone, blood phosphorus, triglycerides, and total cholesterol. Further multifactorial logistic regression analysis revealed that higher blood calcium levels [0.187, (0.040, 0.864), p = 0.032] was a protective factor against stroke. CONCLUSION History of hypertension, anemia, albumin and serum calcium levels were identified as risk factors for stroke in MHD patients compared to non-stroke MHD patients, and further multivariate logistic regression analysis showed that higher calcium levels [0.187, (0.040, 0.864), p = 0.032] were protective factor for stroke. maintenance hemodialysis(MHD) stroke hypertension anemia albumin calcium platelet lymphocyte ratio (PLR) risk factors Figures Figure 1 Introduction Chronic kidney failure (CKD) is a global public health problem that is characterized by high morbidity and mortality and places an enormous economic burden on healthcare systems and families around the world[ 1 ]. Stroke is a leading cause of chronic neurological deficits and ranks as the second leading cause of disability and death worldwide. The two main subtypes of stroke, ischemic stroke (IS) and hemorrhagic stroke (HS), are both associated with high rates of morbidity, mortality, recurrence, and disability. Both stroke and CKD are major global health concerns that are often discussed separately. Stroke and CKD share several common risk factors, including hypertension, smoking, high cholesterol, and diabetes.[ 1 ]. Importantly, CKD is not only a comorbid condition but also an independent risk factor for stroke, it plays a significant role in increasing stroke-related morbidity and mortality. The incidence of stroke in CKD patients is notably high, with dialysis patients facing an even greater risk, reaching up to 25.3 cases per 1,000 person-years, and a mortality rate of up to 90% [ 2 ]. Stroke is a critical complication for those on long-term MHD patients, where the prevalence and incidence rates surpass those of the general population[ 3 ]. In addition, the incidence of stroke remains high in dialysis patients even after renal transplantation, amounting to 6.0 cases per 1,000 person-years. The risk of stroke appears to be higher in patients on hemodialysis compared with those on peritoneal dialysis. Although it has been reported that patients with end-stage renal disease (ESRD) have a 4- to 10-fold increased risk of ischemic or hemorrhagic stroke, respectively, compared with non- ESRD patients, little is known about the potential risk factors for stroke in patients with ESRD in developing countries, including China, and the presence of CKD complicates stroke risk prediction, diagnosis, management, and prevention. Therefore, effective prevention of stroke in patients with CKD is of great clinical importance. In this study, we intend to retrospectively analyze the risk factors associated with stroke in patients on MHD in order to provide a reference for clinical prevention and treatment. Materials and methods Study design and data sources for analysis Study subjects: The retrospective study ultimately included 139 patients on maintenance hemodialysis who were hospitalized for various reasons and were diagnosed with stroke during the course of their hospitalization when cranial CT scan was completed.The cohort was divided into two groups by if the patients accompany with stroke, 70 patients were assigned to the stroke group, while the remaining 69 were categorized in the non-stroke group. 1.2 Inclusion criteria: (1) Older than 18 years; (2) Undergoing regular hemodialysis for at least 3 months, with treatments scheduled 3 times every week; (3) Diagnosed with stroke in accordance with the criteria outlined in the 2014 Chinese Guidelines for the Diagnosis and Treatment of Acute Ischemic Stroke, with confirmation via cranial CT scans; (4) complete clinical data. 1.3 Exclusion criteria: (1) Combination of serious infections and hematologic diseases; (2) Combination of cerebral injury; (3) Combination of psychiatric diseases; (4) Incomplete clinical data. Informed consent was obtained orally through a telephone interview with the subject or his/her legal representative, including an explanation of data collection, use, and protection procedures. 1.4 Research Methods and Observation Indexes: The general data and laboratory-related indexes of the two groups were retrospectively data to analyze the clinical characteristics of patients with stroke complicated by maintenance hemodialysis. General data included: gender, age, history of basic diseases (hypertension and/or diabetes mellitus), and age on dialysis. Laboratory-related parameters included: total cholesterol, triglycerides, calcium, phosphorus, parathyroid hormone, serum albumin level, and platelet lymphocyte ratio (PLR). Statistical analyses The study was statistically analyzed by using SPSS 23.0. Normally distributed measures were expressed as mean ± standard deviation, and independent samples t-test was used for comparison between groups, while non-normally distributed measures were expressed as median (interquartile spacing), and independent samples t-test was used for comparison between groups. The categorical variables were represented by numbers and percentages. Categorical variables were summarized as frequencies and percentages. Prognostic risk factors were examined using univariate and multivariate logistic regression analysis. p < 0.05 was considered statistically significant. Definition of terms Stroke was defined as an acute episode of neurological dysfunction, with etiology presumed to be either ischemic or hemorrhagic, as diagnosed by a physician using non-contrast computed tomography (CT). Ischemic stroke(IS) was diagnosed from a CT image showing reduced density in a specific vascular territory or when the CT image showed no abnormalities. Hemorrhagic stroke(HS) was diagnosed based on a non-contrast CT image showing a region of high density (white) that usually was rounded and space occupying. Hemodialysis treatment All patients received conventional thrice-weekly hemodialysis treatment. Each hemodialysis session was conducted for 3 to 4 h by using a dialyzer with blood flow rates ranging 250–300 mL/min and a dialysate flow rate of 500 mL/min. Results Demographics of Enrolled Patients The time period was restricted to January 2019 to June 2021, and a total of 331 patients matched the search criteria by searching the hospital information system for the key words: chronic kidney disease or chronic kidney failure and dialysis and stroke. A total of 289 patients remained after removing repeat hospitalizations. These included 86 non-dialysis patients with chronic kidney disease(CKD) and a total of 203 dialysis patients. After excluding repeat hospitalizations, 289 unique patients remained in the dataset. These patients included 86 non-dialysis patients with chronic kidney failure and 203 dialysis patients. Following the exclusion of those with incomplete clinical data, 139 dialysis patients were ultimately included in the study, all of whom received hemodialysis. In the stroke group, there were 14 cases of hemorrhagic stroke and 56 cases of ischemic stroke. The detailed inclusion and exclusion process is illustrated in Figure 1. Figure 1. Flowchart demonstrates the creation of the study cohort. Study population The baseline clinical characteristics of MHD patients listed in table 1.A total of 70 patients on MHD who had experienced a stroke were included in the study, comprising 48 men and 22 women, with an average age of 59.34 ± 11.56 years. In the control group, which consisted of patients on MHD who had not experienced a stroke, there were 69 individuals, including 45 men and 24 women, with an average age of 59.01 ± 8.42 years. Univariate logistic analysis revealed that a history of hypertension, hemoglobin levels, albumin levels, and blood calcium levels were associated with stroke in patients on MHS. However, no significant associations were found between stroke occurrence and factors such as a history of diabetes mellitus, the presence of atrial fibrillation, or serum levels of parathyroid hormone, blood phosphorus, triglycerides, and total cholesterol. In a binary logistic regression analysis, blood calcium [0.187 (95% CI: 0.040, 0.864), p = 0.032] was identified as a protective factor against stroke. Table 1 As the data in Table 2 illustrate, Univariate analysis demonstrated that hypertension, hemoglobin (HGB), serum albumin (ALB), and calcium (CA) had p-values less than 0.05, indicating a statistically significant difference in stroke occurrence between the stroke and non-stroke groups. In contrast, diabetes, atrial fibrillation (AF), parathyroid hormone (PTH), phosphorus (P), triglycerides (TG), total cholesterol (CHO), and the platelet-to-lymphocyte ratio (PLR) all had p-values greater than 0.05, suggesting no statistically significant association with stroke in these patients. Table 2. The binary logistic regression analysis (Table 3) included hypertension, hemoglobin (HGB), serum albumin (ALB), and calcium (CA) as independent variables, with stroke occurrence as the dependent variable. The analysis showed no statistically significant differences in hypertension, HGB, or ALB between the stroke and non-stroke groups. However, calcium levels were significantly different between the two groups (p = 0.032, which is less than 0.05), with an odds ratio (OR) of 0.187. This indicates that calcium is a protective factor against stroke. Table 3 Abbreviations: CI: confidence interval; OR: odds ratio. Measurement data are presented as mean ±sd. and enumeration data are presented as number (percent). Discussion A hemodialysis treatment is currently the primary treatment for patients with uremia. The global rise of uremia is notable for its high incidence, mortality, treatment expenses and morbidity rates. The cerebrovascular disease such as stroke is very common in all stages of chronic kidney disease, especially in the patients diagnosed with uremia. In 2006, the American Academy of Neurology first proposed a strong link between kidney disease and cerebrovascular disease and that chronic kidney disease (CKD) is an important risk factor for stroke and cognitive impairment, leading to the concept of reno-cerebrovascular disease, uremia is the end of the CKD stage. CKD and stroke share common risk factors, such as advanced age, diabetes and hypertension. The 5-year survival rate for hemodialysis patients is only 39.8%-60.2% [4]. In the Global Burden of Disease epidemiological statistics, stroke is the second leading cause of death and physical disability worldwide [5], and the overall burden of stroke has increased dramatically [6], particularly in low- and middle-income developing countries [7]. The United States Renal Data System (USRDS) analyzed the causes of death in long-term dialysis patients from 2009 to 2011 and found that the proportion of deaths caused by heart disease in long-term hemodialysis patients was up to 40% and that deaths caused by cerebrovascular events were the third largest cause of death after cardiovascular events and infections. In China, the incidence of stroke is approximately 274/100,000 per year. Although the mortality rate of patients in the acute phase of stroke has decreased significantly in recent years, 75% of patients will still be left with varying degrees of limb dysfunction after acute treatment, of which about 40% will cause severe disability, which not only causes great pain and inconvenience to patients, but also imposes a heavy economic burden on their families [5-6]. According to a study by Soneye MA and colleagues, dialysis patients have a tenfold increased risk for hemorrhagic stroke and a two-fold increased risk for ischemic stroke compared to the general population [8]. This study showed that dialysis patients have a high risk of hemorrhagic stroke compared with the general population, mainly because of the high prevalence of hypertension, impaired erythrocyte deformability and vascular endothelial dysfunction in this group, each of which can increase the risk of hemorrhagic stroke. In addition, the increased risk of hemorrhagic stroke may be associated with the routine administration of heparin during hemodialysis, as shown by Junzhou Fu et al. The results of a multifactorial regression model corrected for age and sex showed that the relative risk of ischemic stroke in hemodialysis patients was 2.88, the relative risk of hemorrhagic stroke was 6.83, and the relative risk of ischemic stroke in peritoneal dialysis patients was 3.5 compared with the general population. The relative risk of ischemic stroke was 2.88 and hemorrhagic stroke 6.83 in hemodialysis patients, and the relative risk of ischemic stroke 3.21 and hemorrhagic stroke 6.15 in peritoneal dialysis patients, compared with the general population. Mark D et al. showed that hemorrhagic strokes were more common than ischemic strokes, with 7-day, 28-day and 365-day mortality rates for hemorrhagic strokes being 62.5, 87.5 and 100% respectively, compared with ischemic stroke rates of 16.4, 23.7, 53.9 and 53.9% respectively. When patients with previous cerebrovascular disease were excluded, the mortality rates were even higher, with 7-, 28- and 365-day rates of 24 percent, 34 percent and 72 percent, respectively [9]. It is well known that stroke have the characteristics of high morbidity, disability, and mortality. Furthermore, in recent years, with the aging of China's population, the incidence of cerebrovascular diseases has shown a trend of low age, and effective prevention and treatment of stroke is imminent. In dialysis patients, the increased risk of stroke can be attributed to many factors, including common traditional risk factors (e.g. hypertension and diabetes mellitus) [8], and non-traditional risk factors associated with dialysis (e.g. oxidative stress and abnormalities in calcium and phosphorus metabolism) and dialysis-related factors (e.g. cerebral underperfusion and structural changes in the heart) [8]. In addition, factors such as a history of smoking, elevated cholesterol levels, overweight, low serum albumin levels and dialysis-induced hypercoagulable state increase the risk of stroke. Simultaneously, stroke risk factors are closely related to cardiac and peripheral vascular disease risk factors [9]. Our study shows that compared with dialysis patients without stroke, history of hypertension, anemia, albumin, blood calcium were risk factors for stroke in MHD patients. Furthermore, both unifactorial and multifactorial retrospective logistic analyses in our study showed that a history of hypertension was a risk factor for stroke in MHD patients, which was confirmed by many previous studies. The study by Mark D et al. found that advanced age, hypertension, diabetes mellitus, history of previous cerebrovascular disease, and post dialysis hyperkalemia were significantly associated with stroke in hemodialysis patients [10]. The study by Chun-Yu Lin et al found that the incidence of intracerebral hemorrhage (ICH) was high in chronic dialysis patients, that middle age, hypertension and history of stroke were independent risk factors for ICH, and that diabetes mellitus and malignancy were significant predictors of mortality after ICH [11]. The long-term prognosis of patients with cerebral hemorrhage who have a history of stroke tends to be worse,this study also found that hypertension and being a man were independent risk factors for hemorrhagic stroke in long-term dialysis patients. These observations are consistent with a recent study by Yoo et al, which also found that diabetes was an independent risk factor for cerebral hemorrhage mortality in the general population [12]. However, the exact reason for the association of diabetes with the risk of death after cerebral hemorrhage is unclear and may be related to diabetes-induced changes in the structure and function of the microvasculature, leading to fibrinoid necrosis of the vessel wall and microaneurysm formation. Our findings also conclude that anemia is a risk factor for the development of stroke. Desai, A. et al. found that anemia prolonged hospital stay in patients with acute cerebrovascular disease by an average of 1.7 days and that one-year mortality in these patients was 15.2% higher on average [13]. Anemia in CKD is a complex process involving relative erythropoietin deficiency, erythropoietin resistance and iron homeostasis disorders [14]. Thus, standardized management of anemia in dialysis patients and achievement of outcome standards are clinically important. What’s more, our study found that albumin is also an important factor affecting stroke. Many scholars have previously indicated that there is a strong relationship between serum albumin levels and cardiovascular disease [15].In Bielewicz J et al’s study, it was found that the lower albumin levels in IS patients in the acute stage, together with the further decline in neurological function, indirectly reflect the intense catabolic processes in the ischemic lesions in the acute stage of IS [16]. Babu MS and colleagues found that low serum albumin levels were associated with higher mortality and greater likelihood to be disabled [18]. Several animal studies have shown that serum albumin restores neurological function and contributes to a reduction in the extent of cerebral infarction. In addition, serum albumin effectively alleviates the symptoms of cerebral oedema and improves behavioral function in animals [19].Lower albumin levels are associated with higher mortality, which may be due to several mechanisms. Firstly, due to the long circulating metabolic half-life, serum albumin may be a biomarker of certain pre-stroke pathological states, such as malnutrition, which is often combined with stroke [20]. Second, serum albumin deficiency may disrupt the dynamic balance of the coagulation system，serum albumin is involved in the interaction of tissue plasminogen activator, which prevents the oxidation of arachidonic acid and acts as an inhibitor of thromboxane A2 synthesis, which in turn promotes platelet aggregation, and reduced serum albumin may attenuate anticoagulant effects and increase coagulant effects, making intravascular thrombus formation more likely [21]. Thirdly, low albumin levels increase the risk of stroke complications (e.g. pleural effusion, peritoneal effusion), which can severely compromise patient survival and functional recovery. Thus, in clinical practice, the monitoring of serum albumin levels in dialysis patients should be intensified, and if the level is lower than the lower limit of normal, great attention should be given to early correction of hypoalbuminemia by various methods. 在讨论中，请重点说明您推测较高的钙水平对预防中风具有保护作用的机制。 Our study confirms that serum calcium level is an important factor in stroke. A previous study by Kitamura et al had similar findings to ours [22], where serum calcium level was significantly higher in patients with cerebral hemorrhage than in the control group. Mechanisms of cerebral hemorrhage are complex, and serum calcium may play multiple roles at each stage. The most important effect of serum calcium in hemodialysis patients is the calcification of the vessel wall, leading to a decrease in vessel compliance and an increase in vessel fragility, which leads to an increased risk of bleeding. This may occur through several mechanisms: 1. Serum calcium may be associated with hormones that increase blood pressure, such as renin[22, 23] . 2. Serum calcium can affect vascular tone through calcium-sensitive receptors[24] ; 3. Calcium plays an important role in the electrical conduction system of the heart, and higher levels can affect cardiac stability; 4. Hypercalcemia can lead to vascular calcification, which can increase arterial fragility and decrease compliance, leading to hypertension[25]. 5. Altered calcium homeostasis affects the blood-brain barrier, and the interaction of calcium ions with connexins can alter the integrity of the blood-brain barrier. The study by Morotti, A. has shown that hypercalcemia accounts for a significant proportion of the risk factors for cerebral hemorrhage. In addition, changes in serum calcium have been associated with accelerated apoptosis, impaired phagocytosis and weakened oxidative burst of neutrophils in the circulation, which may lead to an increased incidence of infection-related complications in uremic patients. Therefore, it is important to monitor blood calcium levels in regular hemodialysis patients [26]. It is well known that the inflammatory response plays an significant role in the development of stroke in dialysis patients. A large number of studies have confirmed the predictive value of inflammation for morbidity, mortality and cardiovascular outcomes in MHD patients by measuring C-reactive protein and interleukin (IL)-6 [27]. The causes of inflammation may be related to reduced clearance of pro-inflammatory cytokines, accumulation of uremic toxins, increased endotoxin levels, oxidative stress and increased susceptibility to infection, but the more expensive and complex operation of CRP and IL-6 assays has limited their widespread clinical use. The platelet to lymphocyte ratio (PLR) has been proposed as a new marker of inflammation in recent years [28].Platelet to lymphocyte ratio (PLR), as a newly proposed inflammatory marker in recent years [28], is one of the hematocrits, which is obtained by dividing the absolute platelet count by the absolute lymphocyte count, and it is a new type of inflammatory marker that is simple, economical, and highly accessible [29]. Elevation of PLR Correlating with the inflammatory state, elevated PLR indicates an imbalance in the pro-inflammatory and anti-inflammatory response of the organism, and this imbalance in the immune response leads to many organ failures, metabolic disorders and immunodeficiencies, which in turn leads to the occurrence of adverse outcomes in the organism [30]. The study by Tian YS, Ishizuka M et al. confirmed that serum albumin, PLR, is a predictive factor for the occurrence of adverse outcomes in the disease [30]. Caceda-Samame et al. confirmed that elevated PLR is strongly associated with development of atherosclerotic cardiovascular disease and that elevated PLR can provide important information on inflammation and plaque instability . A study by Yun Zhang et al. showed [16] that PLR was closely associated with the occurrence and severity of cerebral hemorrhage in patients with acute ischemic stroke. Wen H et al. reported that high PLR values predicted the likelihood of hemorrhagic transformation in young patients with acute ischemic stroke, with sensitivities and specificities of 0.806 and 0.674, respectively. Zhang JL et al. found that high PLR values were associated with an increased risk of all-cause mortality in hemodialysis patients, and PLR was a risk factor for cardiovascular death in HD patients. Increased PLR emerged as an independent risk factor for predicting cerebral hemorrhage in regular hemodialysis patients, but our study did not reach this conclusion, which may be related to the small number of study participants and needs further investigation. However, the data in this study did not show a significant difference between a history of diabetes, atrial fibrillation, and serum levels of parathyroid hormone, blood phosphorus, triglycerides, PLR, and total cholesterol with and without stroke in patients on MHD patients. Conclusion To the best of our knowledge, this is one of the few clinical studies in China in recent years that has comprehensively analyzed the risk factors for stroke in MHD patients. A major strength of this study, compared to previous ones, is the selection of clinical indicators that are both comprehensive and easy to obtain without incurring additional costs. In particular, we use the platelet-to-lymphocyte ratio (PLR), a newly proposed marker of inflammation, stands out as a simple, economical, and accessible indicator with significant clinical implications. In this study, we finally analyzed clinical data from 139 patients on MHD in our hospital, these patients were hospitalized for various reasons and were diagnosed with stroke during the course of their hospitalization between January 2019 and June 2021. Our analysis revealed that a history of hypertension, anemia, serum albumin levels, and calcium levels were risk factors for stroke in this population, while higher calcium appeared to be a protective factor. Nevertheless, there are several limitations to this study. First, as a retrospective, single-center study, it is susceptible to selection bias. Second, the relatively small sample size means that further studies with larger populations are needed to validate these findings and increase their reliability. Moreover, this study did not address the potential link between ischemic stroke and atrial fibrillation, due to incomplete data on the use and dosage of anticoagulant and antiplatelet medications. This gap will need to be addressed in future research with an expanded sample size. Declarations Acknowledgments We thank the Nephrology and Dialysis Department of Lanzhou University Second Affiliated Hospital for their support. Statement of Ethics The study protocol was approved by the Ethics Review Committee of the Second Hospital of Lanzhou University. All clinical studies were conducted in accordance with the principles of the Declaration of Helsinki. The principles of the Declaration of Helsinki were carried out. All patients and controls consented to the release of their information. Declaration of interest statement The authors declared no potential conflict of interest with respect to the research, authorship, and/or publication of this article. Authors contributions Weiwei hu and Yuke Kong contributed to the research idea and study design; Xiao chun Zhou, Wenjun zhang, Yingying Wang were involved in data acquisition; Weiwei Hu contributed to statistical analysis and manuscript drafting; Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that question spertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. References Saini V, Guada L, Yavagal DR. Global Epidemiology of Stroke and Access to Acute Ischemic Stroke Interventions. Neurology. 2021;97(20 Suppl 2):S6–16. Nakamura H, et al. Current status of stroke in hemodialysis patients on a remote island. PLoS ONE. 2023;18(9):e0288731. Lee M, et al. Low glomerular filtration rate and risk of stroke: meta-analysis. BMJ. 2010;341:c4249. Fu J, et al. Prevalence and Impact on Stroke in Patients Receiving Maintenance Hemodialysis versus Peritoneal Dialysis: A Prospective Observational Study. PLoS ONE. 2015;10(10):e0140887. Collaborators GBDMD. Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Psychiatry. 2022;9(2):137–50. Group G. Global, regional, and national burden of neurological disorders during 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Neurol. 2017;16(11):877–97. O'Donnell MJ, et al. Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study. Lancet. 2010;376(9735):112–23. Soneye MA, et al. Intima-media thickness of femoral arteries and carotids among an adult hypertensive Nigerian population: A case-control study to assess their use as surrogate markers of atherosclerosis. Ann Afr Med. 2019;18(3):158–66. Findlay MD, et al. Risk Factors of Ischemic Stroke and Subsequent Outcome in Patients Receiving Hemodialysis. Stroke. 2015;46(9):2477–81. Murray AM, et al. Incidence of stroke before and after dialysis initiation in older patients. J Am Soc Nephrol. 2013;24(7):1166–73. Sato K, et al. Prognostic factors for acute ischemic stroke in patients undergoing hemodialysis. Clin Exp Nephrol. 2022;26(3):286–93. Lin CY, et al. The impact of comorbidity on survival after hemorrhagic stroke among dialysis patients: a nationwide population-based study. BMC Nephrol. 2014;15:186. Desai A, et al. Impact of anemia on acute ischemic stroke outcomes: A systematic review of the literature. PLoS ONE. 2023;18(1):e0280025. Hung PH, et al. Erythropoietin Use and the Risk of Stroke in Patients on Hemodialysis: A Retrospective Cohort Study in Taiwan. J Am Heart Assoc. 2021;10(14):e019529. Chen B, Wang C, Li W. Serum albumin levels and risk of atrial fibrillation: a Mendelian randomization study. Front Cardiovasc Med. 2024;11:1385223. Bielewicz J, et al. Worse Neurological State During Acute Ischemic Stroke is Associated with a Decrease in Serum Albumin Levels. J Mol Neurosci. 2016;58(4):493–6. Chen F, et al. Stroke mortality attributable to high red meat intake in China and South Korea: An age-period-cohort and joinpoint analysis. Front Nutr. 2022;9:921592. Babu MS, et al. Serum albumin levels in ischemic stroke and its subtypes: correlation with clinical outcome. Nutrition. 2013;29(6):872–5. Belayev L, et al. Albumin treatment reduces neurological deficit and protects blood-brain barrier integrity after acute intracortical hematoma in the rat. Stroke. 2005;36(2):326–31. Soeters PB, Wolfe RR, Shenkin A. Hypoalbuminemia: Pathogenesis and Clinical Significance. JPEN J Parenter Enter Nutr. 2019;43(2):181–93. He H, Guo J. Serum albumin: a risk of stroke? Am J Emerg Med. 2017;35(1):186–7. Kitamura M, et al. Association between serum calcium levels and prognosis, hematoma volume, and onset of cerebral hemorrhage in patients undergoing hemodialysis. BMC Nephrol. 2019;20(1):210. Lee SJ, Lee IK, Jeon JH. Vascular Calcification-New Insights Into Its Mechanism. Int J Mol Sci, 2020. 21(8). Inoue Y, et al. Low serum calcium levels contribute to larger hematoma volume in acute intracerebral hemorrhage. Stroke. 2013;44(7):2004–6. You S, et al. Serum Calcium and Phosphate Levels and Short- and Long-Term Outcomes in Acute Intracerebral Hemorrhage Patients. J Stroke Cerebrovasc Dis. 2016;25(4):914–20. Morotti A, et al. Association Between Serum Calcium Level and Extent of Bleeding in Patients With Intracerebral Hemorrhage. JAMA Neurol. 2016;73(11):1285–90. Li PK, Ng JK, McIntyre CW. Inflammation and Peritoneal Dialysis. Semin Nephrol. 2017;37(1):54–65. Pan L, et al. Platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio associated with disease activity in patients with Takayasu's arteritis: a case-control study. BMJ Open. 2017;7(4):e014451. Balta S, Ozturk C. The platelet-lymphocyte ratio: A simple, inexpensive and rapid prognostic marker for cardiovascular events. Platelets. 2015;26(7):680–1. Wang G et al. Prognostic Value of Platelet to Lymphocyte Ratio in Sepsis: A Systematic Review and Meta-analysis. Biomed Res Int, 2022. 2022: p. 9056363. Tables Tables 1 to 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.jpg Table2.jpg Table3Multivariatelogisticregressionanalysisofriskfactorsforstrokeinhemodialysispatients.pdf 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-6337092","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":441525631,"identity":"4c552954-f019-4106-98b7-431284d404a8","order_by":0,"name":"Weiwei 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University","correspondingAuthor":false,"prefix":"","firstName":"Yuke","middleName":"","lastName":"Kong","suffix":""}],"badges":[],"createdAt":"2025-03-30 06:38:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6337092/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6337092/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":80815411,"identity":"8c46b838-0dd2-4ae9-890d-73645e1bb46d","added_by":"auto","created_at":"2025-04-17 10:59:04","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":101425,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart demonstrates the creation of the study cohort.\u003c/p\u003e","description":"","filename":"figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6337092/v1/839743b6c74ec9442552e419.jpg"},{"id":86627011,"identity":"94b10371-bbba-467d-9995-1de9c1bdc03e","added_by":"auto","created_at":"2025-07-14 05:32:55","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":494644,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6337092/v1/1c6791f3-9525-4133-aee7-8f759824b936.pdf"},{"id":80815407,"identity":"dd8758c8-ba6d-4e0c-a324-3c41413b5fbd","added_by":"auto","created_at":"2025-04-17 10:59:04","extension":"jpg","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":88705,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6337092/v1/9e319ea153167bc949937bc5.jpg"},{"id":80815835,"identity":"e5140cb8-981e-4f4c-b939-8360e20f61bb","added_by":"auto","created_at":"2025-04-17 11:07:04","extension":"jpg","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":115863,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6337092/v1/c9f8e7c0406d91df11d2f0b8.jpg"},{"id":80815408,"identity":"64b91687-b77a-4a08-a7fe-9b78cdd23b2e","added_by":"auto","created_at":"2025-04-17 10:59:04","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":55857,"visible":true,"origin":"","legend":"","description":"","filename":"Table3Multivariatelogisticregressionanalysisofriskfactorsforstrokeinhemodialysispatients.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6337092/v1/33a84a67f21d28429b632ef0.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Elements contributing to the risk of stroke in individuals on maintenance hemodialysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eChronic kidney failure (CKD) is a global public health problem that is characterized by high morbidity and mortality and places an enormous economic burden on healthcare systems and families around the world[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Stroke is a leading cause of chronic neurological deficits and ranks as the second leading cause of disability and death worldwide. The two main subtypes of stroke, ischemic stroke (IS) and hemorrhagic stroke (HS), are both associated with high rates of morbidity, mortality, recurrence, and disability. Both stroke and CKD are major global health concerns that are often discussed separately.\u003c/p\u003e \u003cp\u003eStroke and CKD share several common risk factors, including hypertension, smoking, high cholesterol, and diabetes.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Importantly, CKD is not only a comorbid condition but also an independent risk factor for stroke, it plays a significant role in increasing stroke-related morbidity and mortality. The incidence of stroke in CKD patients is notably high, with dialysis patients facing an even greater risk, reaching up to 25.3 cases per 1,000 person-years, and a mortality rate of up to 90% [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Stroke is a critical complication for those on long-term MHD patients, where the prevalence and incidence rates surpass those of the general population[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In addition, the incidence of stroke remains high in dialysis patients even after renal transplantation, amounting to 6.0 cases per 1,000 person-years. The risk of stroke appears to be higher in patients on hemodialysis compared with those on peritoneal dialysis. Although it has been reported that patients with end-stage renal disease (ESRD) have a 4- to 10-fold increased risk of ischemic or hemorrhagic stroke, respectively, compared with non- ESRD patients, little is known about the potential risk factors for stroke in patients with ESRD in developing countries, including China, and the presence of CKD complicates stroke risk prediction, diagnosis, management, and prevention. Therefore, effective prevention of stroke in patients with CKD is of great clinical importance. In this study, we intend to retrospectively analyze the risk factors associated with stroke in patients on MHD in order to provide a reference for clinical prevention and treatment.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003eStudy design and data sources for analysis\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eStudy subjects: The retrospective study ultimately included 139 patients on maintenance hemodialysis who were hospitalized for various reasons and were diagnosed with stroke during the course of their hospitalization when cranial CT scan was completed.The cohort was divided into two groups by if the patients accompany with stroke, 70 patients were assigned to the stroke group, while the remaining 69 were categorized in the non-stroke group.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003e1.2 Inclusion criteria:\u003c/p\u003e \u003cp\u003e(1) Older than 18 years;\u003c/p\u003e \u003cp\u003e(2) Undergoing regular hemodialysis for at least 3 months, with treatments scheduled 3 times every week;\u003c/p\u003e \u003cp\u003e (3) Diagnosed with stroke in accordance with the criteria outlined in the 2014 Chinese Guidelines for the Diagnosis and Treatment of Acute Ischemic Stroke, with confirmation via cranial CT scans;\u003c/p\u003e \u003cp\u003e(4) complete clinical data.\u003c/p\u003e \u003cp\u003e1.3 Exclusion criteria:\u003c/p\u003e \u003cp\u003e(1) Combination of serious infections and hematologic diseases;\u003c/p\u003e \u003cp\u003e(2) Combination of cerebral injury;\u003c/p\u003e \u003cp\u003e(3) Combination of psychiatric diseases;\u003c/p\u003e \u003cp\u003e(4) Incomplete clinical data. Informed consent was obtained orally through a telephone interview with the subject or his/her legal representative, including an explanation of data collection, use, and protection procedures.\u003c/p\u003e \u003cp\u003e1.4 Research Methods and Observation Indexes:\u003c/p\u003e \u003cp\u003eThe general data and laboratory-related indexes of the two groups were retrospectively data to analyze the clinical characteristics of patients with stroke complicated by maintenance hemodialysis. General data included: gender, age, history of basic diseases (hypertension and/or diabetes mellitus), and age on dialysis. Laboratory-related parameters included: total cholesterol, triglycerides, calcium, phosphorus, parathyroid hormone, serum albumin level, and platelet lymphocyte ratio (PLR).\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses\u003c/h2\u003e \u003cp\u003eThe study was statistically analyzed by using SPSS 23.0. Normally distributed measures were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation, and independent samples t-test was used for comparison between groups, while non-normally distributed measures were expressed as median (interquartile spacing), and independent samples t-test was used for comparison between groups. The categorical variables were represented by numbers and percentages. Categorical variables were summarized as frequencies and percentages. Prognostic risk factors were examined using univariate and multivariate logistic regression analysis. p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eDefinition of terms\u003c/h3\u003e\n\u003cp\u003eStroke was defined as an acute episode of neurological dysfunction, with etiology presumed to be either ischemic or hemorrhagic, as diagnosed by a physician using non-contrast computed tomography (CT).\u003c/p\u003e \u003cp\u003eIschemic stroke(IS) was diagnosed from a CT image showing reduced density in a specific vascular territory or when the CT image showed no abnormalities.\u003c/p\u003e \u003cp\u003eHemorrhagic stroke(HS) was diagnosed based on a non-contrast CT image showing a region of high density (white) that usually was rounded and space occupying.\u003c/p\u003e \u003cp\u003eHemodialysis treatment\u003c/p\u003e \u003cp\u003eAll patients received conventional thrice-weekly hemodialysis treatment. Each hemodialysis session was conducted for 3 to 4 h by using a dialyzer with blood flow rates ranging 250\u0026ndash;300 mL/min and a dialysate flow rate of 500 mL/min.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eDemographics of Enrolled Patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe time period was restricted to January 2019 to June 2021, and a total of 331 patients matched the search criteria by searching the hospital information system for the key words: chronic kidney disease or chronic kidney failure and dialysis and stroke. A total of 289 patients remained after removing repeat hospitalizations. These included 86 non-dialysis patients with chronic kidney disease(CKD) and a total of 203 dialysis patients. After excluding repeat hospitalizations, 289 unique patients remained in the dataset. These patients included 86 non-dialysis patients with chronic kidney failure and 203 dialysis patients. Following the exclusion of those with incomplete clinical data, 139 dialysis patients were ultimately included in the study, all of whom received hemodialysis. In the stroke group, there were 14 cases of hemorrhagic stroke and 56 cases of ischemic stroke. The detailed inclusion and exclusion process is illustrated in Figure 1.\u003c/p\u003e\n\u003cp\u003eFigure 1. Flowchart demonstrates the creation of the study cohort.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe baseline clinical characteristics of MHD patients listed in table 1.A total of 70 patients on MHD who had experienced a stroke were included in the study, comprising 48 men and 22 women, with an average age of 59.34 \u0026plusmn; 11.56 years. In the control group, which consisted of patients on MHD who had not experienced a stroke, there were 69 individuals, including 45 men and 24 women, with an average age of 59.01 \u0026plusmn; 8.42 years. Univariate logistic analysis revealed that a history of hypertension, hemoglobin levels, albumin levels, and blood calcium levels were associated with stroke in patients on MHS. However, no significant associations were found between stroke occurrence and factors such as a history of diabetes mellitus, the presence of atrial fibrillation, or serum levels of parathyroid hormone, blood phosphorus, triglycerides, and total cholesterol. In a binary logistic regression analysis, blood calcium [0.187 (95% CI: 0.040, 0.864), p = 0.032] was identified as a protective factor against stroke.\u003c/p\u003e\n\u003cp\u003eTable 1 \u0026nbsp;\u003cbr\u003e\u0026nbsp;As the data in Table 2 illustrate, Univariate analysis demonstrated that hypertension, hemoglobin (HGB), serum albumin (ALB), and calcium (CA) had p-values less than 0.05, indicating a statistically significant difference in stroke occurrence between the stroke and non-stroke groups. In contrast, diabetes, atrial fibrillation (AF), parathyroid hormone (PTH), phosphorus (P), triglycerides (TG), total cholesterol (CHO), and the platelet-to-lymphocyte ratio (PLR) all had p-values greater than 0.05, suggesting no statistically significant association with stroke in these patients.\u003c/p\u003e\n\u003cp\u003eTable 2.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe binary logistic regression analysis (Table 3) included hypertension, hemoglobin (HGB), serum albumin (ALB), and calcium (CA) as independent variables, with stroke occurrence as the dependent variable. The analysis showed no statistically significant differences in hypertension, HGB, or ALB between the stroke and non-stroke groups. However, calcium levels were significantly different between the two groups (p = 0.032, which is less than 0.05), with an odds ratio (OR) of 0.187. This indicates that calcium is a protective factor against stroke.\u003c/p\u003e\n\u003cp\u003eTable 3\u003c/p\u003e\n\u003cp\u003eAbbreviations: CI: confidence interval; OR: odds ratio.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMeasurement data are presented as mean \u0026plusmn;sd. and enumeration data are presented as number (percent).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eA hemodialysis treatment is currently the primary treatment for patients with uremia. The global rise of uremia is notable for its high incidence, mortality, treatment expenses and morbidity rates. The cerebrovascular disease such as stroke is very common in all stages of chronic kidney disease, especially in the patients diagnosed with uremia. In 2006, the American Academy of Neurology first proposed a strong link between kidney disease and cerebrovascular disease and that chronic kidney disease (CKD) is an important risk factor for stroke and cognitive impairment, leading to the concept of reno-cerebrovascular disease, uremia is the end of the CKD stage. CKD and stroke share common risk factors, such as advanced age, diabetes and hypertension. The 5-year survival rate for hemodialysis patients is only 39.8%-60.2% [4]. In the Global Burden of Disease epidemiological statistics, stroke is the second leading cause of death and physical disability worldwide [5], and the overall burden of stroke has increased dramatically [6], particularly in low- and middle-income developing countries [7].\u003c/p\u003e\n\u003cp\u003eThe United States Renal Data System (USRDS) analyzed the causes of death in long-term dialysis patients from 2009 to 2011 and found that the proportion of deaths caused by heart disease in long-term hemodialysis patients was up to 40% and that deaths caused by cerebrovascular events were the third largest cause of death after cardiovascular events and infections. In China, the incidence of stroke is approximately 274/100,000 per year. Although the mortality rate of patients in the acute phase of stroke has decreased significantly in recent years, 75% of patients will still be left with varying degrees of limb dysfunction after acute treatment, of which about 40% will cause severe disability, which not only causes great pain and inconvenience to patients, but also imposes a heavy economic burden on their families [5-6].\u003c/p\u003e\n\u003cp\u003eAccording to a study by Soneye MA and colleagues, dialysis patients have a tenfold increased risk for hemorrhagic stroke and a two-fold increased risk for ischemic stroke compared to the general population [8]. This study showed that dialysis patients have a high risk of hemorrhagic stroke compared with the general population, mainly because of the high prevalence of hypertension, impaired erythrocyte deformability and vascular endothelial dysfunction in this group, each of which can increase the risk of hemorrhagic stroke. In addition, the increased risk of hemorrhagic stroke may be associated with the routine administration of heparin during hemodialysis, as shown by Junzhou Fu et al. The results of a multifactorial regression model corrected for age and sex showed that the relative risk of ischemic stroke in hemodialysis patients was 2.88, the relative risk of hemorrhagic stroke was 6.83, and the relative risk of ischemic stroke in peritoneal dialysis patients was 3.5 compared with the general population. The relative risk of ischemic stroke was 2.88 and hemorrhagic stroke 6.83 in hemodialysis patients, and the relative risk of ischemic stroke 3.21 and hemorrhagic stroke 6.15 in peritoneal dialysis patients, compared with the general population. Mark D et al. showed that hemorrhagic strokes were more common than ischemic strokes, with 7-day, 28-day and 365-day mortality rates for hemorrhagic strokes being 62.5, 87.5 and 100% respectively, compared with ischemic stroke rates of 16.4, 23.7, 53.9 and 53.9% respectively. When patients with previous cerebrovascular disease were excluded, the mortality rates were even higher, with 7-, 28- and 365-day rates of 24 percent, 34 percent and 72 percent, respectively [9].\u003c/p\u003e\n\u003cp\u003eIt is well known that stroke have the characteristics of high morbidity, disability, and mortality. Furthermore, in recent years, with the aging of China\u0026apos;s population, the incidence of cerebrovascular diseases has shown a trend of low age, and effective prevention and treatment of stroke is imminent. In dialysis patients, the increased risk of stroke can be attributed to many factors, including common traditional risk factors (e.g. hypertension and diabetes mellitus) [8], and non-traditional risk factors associated with dialysis (e.g. oxidative stress and abnormalities in calcium and phosphorus metabolism) and dialysis-related factors (e.g. cerebral underperfusion and structural changes in the heart) [8]. In addition, factors such as a history of smoking, elevated cholesterol levels, overweight, low serum albumin levels and dialysis-induced hypercoagulable state increase the risk of stroke. Simultaneously, stroke risk factors are closely related to cardiac and peripheral vascular disease risk factors [9].\u003c/p\u003e\n\u003cp\u003eOur study shows that compared with dialysis patients without stroke, history of hypertension, anemia, albumin, blood calcium were risk factors for stroke in MHD patients. Furthermore, both unifactorial and multifactorial retrospective logistic analyses in our study showed that a history of hypertension was a risk factor for stroke in MHD patients, which was confirmed by many previous studies. The study by Mark D et al. found that advanced age, hypertension, diabetes mellitus, history of previous cerebrovascular disease, and post dialysis hyperkalemia were significantly associated with stroke in hemodialysis patients [10]. The study by Chun-Yu Lin et al found that the incidence of intracerebral hemorrhage (ICH) was high in chronic dialysis patients, that middle age, hypertension and history of stroke were independent risk factors for ICH, and that diabetes mellitus and malignancy were significant predictors of mortality after ICH [11]. The long-term prognosis of patients with cerebral hemorrhage who have a history of stroke tends to be worse,this study also found that hypertension and being a man were independent risk factors for hemorrhagic stroke in long-term dialysis patients. These observations are consistent with a recent study by Yoo et al, which also found that diabetes was an independent risk factor for cerebral hemorrhage mortality in the general population [12]. However, the exact reason for the association of diabetes with the risk of death after cerebral hemorrhage is unclear and may be related to diabetes-induced changes in the structure and function of the microvasculature, leading to fibrinoid necrosis of the vessel wall and microaneurysm formation.\u003c/p\u003e\n\u003cp\u003eOur findings also conclude that anemia is a risk factor for the development of stroke. Desai, A. et al. found that anemia prolonged hospital stay in patients with acute cerebrovascular disease by an average of 1.7 days and that one-year mortality in these patients was 15.2% higher on average [13]. Anemia in CKD is a complex process involving relative erythropoietin deficiency, erythropoietin resistance and iron homeostasis disorders [14]. Thus, standardized management of anemia in dialysis patients and achievement of outcome standards are clinically important.\u003c/p\u003e\n\u003cp\u003eWhat\u0026rsquo;s more, our study found that albumin is also an important factor affecting stroke. Many scholars have previously indicated that there is a strong relationship between serum albumin levels and cardiovascular disease [15].In Bielewicz J et al\u0026rsquo;s study, it was found that the lower albumin levels in IS patients in the acute stage, together with the further decline in neurological function, indirectly reflect the intense catabolic processes in the ischemic lesions in the acute stage of IS [16]. Babu MS and colleagues found that low serum albumin levels were associated with higher mortality and greater likelihood to be disabled [18]. Several animal studies have shown that serum albumin restores neurological function and contributes to a reduction in the extent of cerebral infarction. In addition, serum albumin effectively alleviates the symptoms of cerebral oedema and improves behavioral function in animals [19].Lower albumin levels are associated with higher mortality, which may be due to several mechanisms. Firstly, due to the long circulating metabolic half-life, serum albumin may be a biomarker of certain pre-stroke pathological states, such as malnutrition, which is often combined with stroke [20]. Second, serum albumin deficiency may disrupt the dynamic balance of the coagulation system，serum albumin is involved in the interaction of tissue plasminogen activator, which prevents the oxidation of arachidonic acid and acts as an inhibitor of thromboxane A2 synthesis, which in turn promotes platelet aggregation, and reduced serum albumin may attenuate anticoagulant effects and increase coagulant effects, making intravascular thrombus formation more likely [21]. Thirdly, low albumin levels increase the risk of stroke complications (e.g. pleural effusion, peritoneal effusion), which can severely compromise patient survival and functional recovery. Thus, in clinical practice, the monitoring of serum albumin levels in dialysis patients should be intensified, and if the level is lower than the lower limit of normal, great attention should be given to early correction of hypoalbuminemia by various methods.\u003c/p\u003e\n\u003cp\u003e在讨论中，请重点说明您推测较高的钙水平对预防中风具有保护作用的机制。\u003c/p\u003e\n\u003cp\u003eOur study confirms that serum calcium level is an important factor in stroke. A previous study by Kitamura et al had similar findings to ours [22], where serum calcium level was significantly higher in patients with cerebral hemorrhage than in the control group. Mechanisms of cerebral hemorrhage are complex, and serum calcium may play multiple roles at each stage. The most important effect of serum calcium in hemodialysis patients is the calcification of the vessel wall, leading to a decrease in vessel compliance and an increase in vessel fragility, which leads to an increased risk of bleeding. This may occur through several mechanisms: 1. Serum calcium may be associated with hormones that increase blood pressure, such as renin[22, 23] . 2. Serum calcium can affect vascular tone through calcium-sensitive receptors[24] ; 3. Calcium plays an important role in the electrical conduction system of the heart, and higher levels can affect cardiac stability; 4. Hypercalcemia can lead to vascular calcification, which can increase arterial fragility and decrease compliance, leading to hypertension[25]. 5. Altered calcium homeostasis affects the blood-brain barrier, and the interaction of calcium ions with connexins can alter the integrity of the blood-brain barrier. The study by Morotti, A. has shown that hypercalcemia accounts for a significant proportion of the risk factors for cerebral hemorrhage. In addition, changes in serum calcium have been associated with accelerated apoptosis, impaired phagocytosis and weakened oxidative burst of neutrophils in the circulation, which may lead to an increased incidence of infection-related complications in uremic patients. Therefore, it is important to monitor blood calcium levels in regular hemodialysis patients [26].\u003c/p\u003e\n\u003cp\u003eIt is well known that the inflammatory response plays an significant role in the development of stroke in dialysis patients. A large number of studies have confirmed the predictive value of inflammation for morbidity, mortality and cardiovascular outcomes in MHD patients by measuring C-reactive protein and interleukin (IL)-6 [27]. The causes of inflammation may be related to reduced clearance of pro-inflammatory cytokines, accumulation of uremic toxins, increased endotoxin levels, oxidative stress and increased susceptibility to infection, but the more expensive and complex operation of CRP and IL-6 assays has limited their widespread clinical use. The platelet to lymphocyte ratio (PLR) has been proposed as a new marker of inflammation in recent years [28].Platelet to lymphocyte ratio (PLR), as a newly proposed inflammatory marker in recent years [28], is one of the hematocrits, which is obtained by dividing the absolute platelet count by the absolute lymphocyte count, and it is a new type of inflammatory marker that is simple, economical, and highly accessible [29]. Elevation of PLR Correlating with the inflammatory state, elevated PLR indicates an imbalance in the pro-inflammatory and anti-inflammatory response of the organism, and this imbalance in the immune response leads to many organ failures, metabolic disorders and immunodeficiencies, which in turn leads to the occurrence of adverse outcomes in the organism [30]. The study by Tian YS, Ishizuka M et al. confirmed that serum albumin, PLR, is a predictive factor for the occurrence of adverse outcomes in the disease [30]. Caceda-Samame et al. confirmed that elevated PLR is strongly associated with development of atherosclerotic cardiovascular disease and that elevated PLR can provide important information on inflammation and plaque instability .\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA study by Yun Zhang et al. showed [16] that PLR was closely associated with the occurrence and severity of cerebral hemorrhage in patients with acute ischemic stroke. Wen H et al. reported that high PLR values predicted the likelihood of hemorrhagic transformation in young patients with acute ischemic stroke, with sensitivities and specificities of 0.806 and 0.674, respectively. Zhang JL et al. found that high PLR values were associated with an increased risk of all-cause mortality in hemodialysis patients, and PLR was a risk factor for cardiovascular death in HD patients. Increased PLR emerged as an independent risk factor for predicting cerebral hemorrhage in regular hemodialysis patients, but our study did not reach this conclusion, which may be related to the small number of study participants and needs further investigation.\u003c/p\u003e\n\u003cp\u003eHowever, the data in this study did not show a significant difference between a history of diabetes, atrial fibrillation, and serum levels of parathyroid hormone, blood phosphorus, triglycerides, PLR, and total cholesterol with and without stroke in patients on MHD patients.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eTo the best of our knowledge, this is one of the few clinical studies in China in recent years that has comprehensively analyzed the risk factors for stroke in MHD patients. A major strength of this study, compared to previous ones, is the selection of clinical indicators that are both comprehensive and easy to obtain without incurring additional costs. In particular, we use the platelet-to-lymphocyte ratio (PLR), a newly proposed marker of inflammation, stands out as a simple, economical, and accessible indicator with significant clinical implications.\u003c/p\u003e\n\u003cp\u003eIn this study, we finally analyzed clinical data from 139 patients on MHD in our hospital, these patients were hospitalized for various reasons and were diagnosed with stroke during the course of their hospitalization between January 2019 and June 2021. Our analysis revealed that a history of hypertension, anemia, serum albumin levels, and calcium levels were risk factors for stroke in this population, while higher calcium appeared to be a protective factor.\u003c/p\u003e\n\u003cp\u003eNevertheless, there are several limitations to this study. First, as a retrospective, single-center study, it is susceptible to selection bias. Second, the relatively small sample size means that further studies with larger populations are needed to validate these findings and increase their reliability. Moreover, this study did not address the potential link between ischemic stroke and atrial fibrillation, due to incomplete data on the use and dosage of anticoagulant and antiplatelet medications. This gap will need to be addressed in future research with an expanded sample size.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the Nephrology and Dialysis Department of Lanzhou University Second Affiliated Hospital for their support.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatement of Ethics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol was approved by the Ethics Review Committee of the Second Hospital of Lanzhou University. All clinical studies were conducted in accordance with the principles of the Declaration of Helsinki. The principles of the Declaration of Helsinki were carried out. All patients and controls consented to the release of their information.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of interest statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declared no potential conflict of interest with respect to the research, authorship, and/or publication of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWeiwei hu and Yuke Kong contributed to the research idea and study design; Xiao chun Zhou, Wenjun zhang, Yingying Wang were involved in data acquisition; Weiwei Hu contributed to statistical analysis and manuscript drafting; Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that question spertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSaini V, Guada L, Yavagal DR. Global Epidemiology of Stroke and Access to Acute Ischemic Stroke Interventions. Neurology. 2021;97(20 Suppl 2):S6\u0026ndash;16.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNakamura H, et al. Current status of stroke in hemodialysis patients on a remote island. PLoS ONE. 2023;18(9):e0288731.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee M, et al. Low glomerular filtration rate and risk of stroke: meta-analysis. BMJ. 2010;341:c4249.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFu J, et al. Prevalence and Impact on Stroke in Patients Receiving Maintenance Hemodialysis versus Peritoneal Dialysis: A Prospective Observational Study. PLoS ONE. 2015;10(10):e0140887.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCollaborators GBDMD. Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990\u0026ndash;2019: a systematic analysis for the Global Burden of Disease Study 2019. 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PLoS ONE. 2023;18(1):e0280025.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHung PH, et al. Erythropoietin Use and the Risk of Stroke in Patients on Hemodialysis: A Retrospective Cohort Study in Taiwan. J Am Heart Assoc. 2021;10(14):e019529.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen B, Wang C, Li W. Serum albumin levels and risk of atrial fibrillation: a Mendelian randomization study. Front Cardiovasc Med. 2024;11:1385223.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBielewicz J, et al. Worse Neurological State During Acute Ischemic Stroke is Associated with a Decrease in Serum Albumin Levels. J Mol Neurosci. 2016;58(4):493\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen F, et al. Stroke mortality attributable to high red meat intake in China and South Korea: An age-period-cohort and joinpoint analysis. Front Nutr. 2022;9:921592.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBabu MS, et al. Serum albumin levels in ischemic stroke and its subtypes: correlation with clinical outcome. Nutrition. 2013;29(6):872\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBelayev L, et al. Albumin treatment reduces neurological deficit and protects blood-brain barrier integrity after acute intracortical hematoma in the rat. Stroke. 2005;36(2):326\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSoeters PB, Wolfe RR, Shenkin A. Hypoalbuminemia: Pathogenesis and Clinical Significance. JPEN J Parenter Enter Nutr. 2019;43(2):181\u0026ndash;93.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHe H, Guo J. Serum albumin: a risk of stroke? Am J Emerg Med. 2017;35(1):186\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKitamura M, et al. Association between serum calcium levels and prognosis, hematoma volume, and onset of cerebral hemorrhage in patients undergoing hemodialysis. BMC Nephrol. 2019;20(1):210.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee SJ, Lee IK, Jeon JH. Vascular Calcification-New Insights Into Its Mechanism. Int J Mol Sci, 2020. 21(8).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eInoue Y, et al. Low serum calcium levels contribute to larger hematoma volume in acute intracerebral hemorrhage. Stroke. 2013;44(7):2004\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYou S, et al. Serum Calcium and Phosphate Levels and Short- and Long-Term Outcomes in Acute Intracerebral Hemorrhage Patients. J Stroke Cerebrovasc Dis. 2016;25(4):914\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMorotti A, et al. Association Between Serum Calcium Level and Extent of Bleeding in Patients With Intracerebral Hemorrhage. JAMA Neurol. 2016;73(11):1285\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi PK, Ng JK, McIntyre CW. Inflammation and Peritoneal Dialysis. Semin Nephrol. 2017;37(1):54\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePan L, et al. Platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio associated with disease activity in patients with Takayasu's arteritis: a case-control study. BMJ Open. 2017;7(4):e014451.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBalta S, Ozturk C. The platelet-lymphocyte ratio: A simple, inexpensive and rapid prognostic marker for cardiovascular events. Platelets. 2015;26(7):680\u0026ndash;1.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang G et al. Prognostic Value of Platelet to Lymphocyte Ratio in Sepsis: A Systematic Review and Meta-analysis. Biomed Res Int, 2022. 2022: p. 9056363.\u003c/span\u003e\u003c/li\u003e \u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"maintenance hemodialysis(MHD), stroke, hypertension, anemia, albumin, calcium, platelet lymphocyte ratio (PLR), risk factors","lastPublishedDoi":"10.21203/rs.3.rs-6337092/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6337092/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eOBJECTIVE\u003c/h2\u003e \u003cp\u003eBoth stroke and CKD have high morbidity and mortality rates, these two disease pose a serious threat to patient\u0026rsquo;s lives. To investigate the risk factors for stroke in patients undergoing maintenance hemodialysis (MHD), aiming to propose targeted preventive and therapeutic strategies. Additionally, our study seeks to explore the mechanisms underlying stroke in MHD patients.\u003c/p\u003e\u003ch2\u003eRESULTS\u003c/h2\u003e \u003cp\u003eThe study included 70 patients in the MHD group who had experienced a stroke, with 48 males and 22 females, and an average age of 59.34\u0026thinsp;\u0026plusmn;\u0026thinsp;11.56 years. In the non-stroke MHD group, 69 patients were included, with 45 males and 24 females, and an average age of 59.01\u0026thinsp;\u0026plusmn;\u0026thinsp;8.42 years. Univariate logistic analysis showed that a history of hypertension, hemoglobin, albumin, and blood calcium levels were significantly associated with the occurrence of stroke in MHD patients. However, there were no statistically significant differences between the stroke and non-stroke groups in terms of history of diabetes mellitus, the presence of atrial fibrillation, serum levels of parathyroid hormone, blood phosphorus, triglycerides, and total cholesterol. Further multifactorial logistic regression analysis revealed that higher blood calcium levels [0.187, (0.040, 0.864), p\u0026thinsp;=\u0026thinsp;0.032] was a protective factor against stroke.\u003c/p\u003e\u003ch2\u003eCONCLUSION\u003c/h2\u003e \u003cp\u003eHistory of hypertension, anemia, albumin and serum calcium levels were identified as risk factors for stroke in MHD patients compared to non-stroke MHD patients, and further multivariate logistic regression analysis showed that higher calcium levels [0.187, (0.040, 0.864), p\u0026thinsp;=\u0026thinsp;0.032] were protective factor for stroke.\u003c/p\u003e","manuscriptTitle":"Elements contributing to the risk of stroke in individuals on maintenance hemodialysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-17 10:59:00","doi":"10.21203/rs.3.rs-6337092/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":"4e8a83bd-4886-44bc-b2cc-c74bb92e7d3f","owner":[],"postedDate":"April 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-07-14T05:08:34+00:00","versionOfRecord":[],"versionCreatedAt":"2025-04-17 10:59:00","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6337092","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6337092","identity":"rs-6337092","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}