Skip to main content

Impact of stroke history on the presence of cerebral microbleeds in hemodialysis patients

Abstract

Introduction

Cerebral microbleeds (CMBs) are detected on gradient-echo T2*-weighted magnetic resonance imaging (MRI). Clinically, CMBs are often detected after stroke, including in cases of intracerebral hemorrhage and ischemic cerebrovascular disease. Hemodialysis (HD) patients are widely known to have a high incidence of stroke, and HD patients without stroke history have been reported to have a high prevalence of CMBs. In this study, we investigated whether history of stroke affects the prevalence of CMBs in HD patients.

Methods

A cross-sectional study was performed in 241 HD patients who underwent brain T2*-weighted MRI. We compared the prevalence of CMBs between the patients with and without a history of stroke. Moreover, the relationship between history of stroke and presence of CMBs was examined by multivariate logistic regression analysis.

Results

Among these patients, 22 (9.1%) had a history of stroke. CMBs were detected in 70 patients (29.0%). The prevalence of CMBs was significantly higher in patients with a history of stroke compared to those without this history (54.5 vs. 26.5%, p = 0.012). In the multivariable analysis adjusted for background characteristics, history of stroke was a significant and independent factor related to CMBs (OR: 3.24, 95%CI: 1.18–8.89, p = 0.02).

Discussion/conclusions

As has been reported for non-dialysis patients, our results showed a high prevalence of CMBs in HD patients with a history of stroke, and indicated that a history of stroke is significantly and independently associated with CMBs in HD patients.

Peer Review reports

Introduction

T2*-weighted magnetic resonance imaging (MRI) is an extremely sensitive technique for detecting hemorrhagic lesions. Cerebral microbleeds (CMBs) are detected as small, round hypointense lesions on gradient-echo T2*-weighted MRI. The prevalence of CMBs is 3.1 to 23.5% in healthy populations with no cerebrovascular disease [1, 2], 18 to 68% in patients with ischemic stroke (IS) [2], and 47 to 83% in patients with intracerebral hemorrhage (ICH) [2]. Pathologically, the lesions are due to focal hemosiderin deposition associated with previous microhemorrhages resulting from bleeding-prone small-vessel diseases, such as hypertensive arteriopathy (including lipohyalinosis and arteriolosclerosis) and cerebral amyloid angiopathy (CAA) [3]. The location of CMBs differs according to the cause, with deep CMBs and strictly lobar CMBs mainly caused by hypertensive arteriopathy and CAA, respectively [4, 5].

Older age [1, 2, 6, 7], hypertension [1, 2, 7], diabetes mellitus [6], low total cholesterol [7, 8], chronic kidney disease (CKD) [9,10,11,12,13,14], presence of APOE4 [15], and use of antithrombotics [16] have been shown to be risk factors for CMBs in cohorts with stroke and in community-dwelling elderly individuals. Moreover, CMBs are a risk factor for future ICH and IS in patients after ICH, IS, and transient ischemic attack (TIA) [5, 17,18,19], as well as in stroke-free individuals [17, 19, 20].

In hemodialysis (HD) patients, we and others have found high prevalences of CMBs of 19.3 to 54% [21,22,23,24], and the presence of CMBs is an independent and strong predictor of ICH [25]. HD patients with a history of stroke are presumed to have a high incidence of CMBs as with non-HD patients. However, no studies have been made on the relationship of stroke history and the presence of CMBs in HD patients. We conducted a cross-sectional study to investigate whether history of stroke affects the prevalence of CMBs in HD patients.

Materials and methods

Study design and participants

We performed a cross-sectional study on 241 HD patients who had received an MRI as a screening examination at Osaka City University Hospital and Ohno Memorial Hospital from November 2005 to November 2011. For patients who had received multiple MRIs, we used the results of the first MRI. This study protocol was approved by the ethics committee of Osaka City University (No. 1415). Informed consent was obtained from all subjects prior to their participation in the study.

Magnetic resonance imaging

The protocol for MRI was derived from our previous study [22]. All patients underwent brain MRI using a superconducting magnet at a field strength of 1.5 T for proton density, T1-, T2- weighted FLAIR MRI and two-dimensional (2D) gradient echo T2*-weighted MRI were performed in axial planes with 5-mm thick slices and an interslice gap of 1.5 mm. CMBs were defined as focal areas of signal loss consisting of homogeneous, rounded lesions with diameters of 2 to 5 mm on T2*-weighted MRI. Hypointensities of the globus pallidus, which are probably due to calcification or flow void artifacts of the pial vessel, were excluded. MR images were assessed independently by two neuroradiologists who were blinded to all clinical information.

Definition of risk factors

The background factors that needed to be adjusted when performing multivariable analysis on how much stroke history affects the presence of CMBs were selected from the available data on the risk factors of arteriosclerosis and CMBs. To evaluate factors associated with CMBs, we investigated history of stroke, age, sex, dialysis duration, hemoglobin, hypertension (HT), diabetes mellitus (DM), dyslipidemia (DL), current smoking, body mass index (BMI), albumin, cardiovascular disease (excluding stroke), use of antithrombotics, and use of statin. Stroke histories and patient histories were confirmed by checking all medical records.

Those with a clear episode of ICH or cerebral infarction were included, but patients with TIA were not included. Also, cardiovascular disease (excluding stroke) was defined as the following conditions: angina, myocardial infarction, the need for coronary angioplasty and coronary bypass surgery, congestive heart failure, valvular heart disease, atrial fibrillation, and peripheral arterial disease. HT was defined as (a) administration of antihypertensive agents and/or a history of this disorder; (b) systolic blood pressure > 140 mmHg; or (c) diastolic blood pressure > 90 mmHg, with blood pressure measured before HD. DM was defined as 1) administration of insulin or oral antidiabetic agents or 2) prior diagnosis according to the Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus of the American Diabetes Association [26]. DL was defined as low-density lipoprotein cholesterol > 140 mg/dl, triglyceride > 150 mg/dl, and high-density lipoprotein cholesterol < 40 mg/dl or medical treatment for hyperlipidemia. Blood samples were taken from the arterial line prior to HD sessions. BMI was calculated as weight (kg)/height2 (m2).

Statistical analysis

Baseline demographic and clinical characteristics were summarized using percentages and counts for categorical variables and medians and interquartile ranges [25th-75th percentile] for continuous variables. Differences of these variables between subjects with and without a history of stroke were examined by χ2 and Mann–Whitney U test for categorical and continuous variables, respectively. Multivariable logistic regression analysis was performed to examine the association of history of stroke with presence of CMBs with adjustment for age, sex, dialysis duration, HT, DM, DL, current smoking, use of antithrombotics, BMI, Hb, albumin, cardiovascular disease (excluding stroke), and use of statin. In the regression analysis, categorical variables were used as dummy variables (male = 0, female = 1; absence = 0, presence = 1; smoker = 1, non- smoker = 0; yes = 1, no = 0). All statistical tests were performed with a two-sided significance level of 5% using R ver. 4.0.2 (https://www.r-project.org/foundation/) with the “rms” package.

Results

Characteristics of the subjects at MRI (Table 1)

Table 1 Baseline characteristics of study subjects at MRIa

Clinical characteristics of the 241 HD patients at MRI are shown in Table 1. Among these patients, 22 (9.1%) had a history of stroke, including 12 with cerebral infarction, 9 with ICH, and 1 with subarachnoid hemorrhage. Pre- and post-dialysis diastolic blood pressures were significantly low in patients with a history of stroke, but other parameters were not significantly different between patients with and without a history of stroke (Table 1).

Prevalence of CMBs in patients with / without a history of stroke (Fig. 1)

Fig. 1
figure1

Prevalence of CMBs in patients with and without a history of stroke (54.5% vs. 26.5%, p = 0.012)

CMBs were detected in 70 patients (29.0%). The prevalence of CMBs was significantly higher in patients with a history of stroke compared to those without this history (54.5 vs. 26.5%, p = 0.012).

Results of multivariate logistic regression analysis on the presence of CMBs in hemodialysis patients (Table 2)

Table 2 Result of multivariate logistic regression analysis as for the presence of CMBs in Hemodialysis patients

In the multivariable analysis, history of stroke was a significant and independent factor related to CMBs (OR: 3.24, 95%CI: 1.18–8.89, p = 0.02). In addition, age and hypertension were also significant and independent factors related to CMBs.

Discussion/conclusion

In order to investigate the relationship of stroke history and the presence of CMBs in HD patients, we conducted a cross-sectional study in 241 HD patients in which brain T2*-weighted MRI was taken. The prevalence of CMBs was significantly higher in patients with a history of stroke compared to those without this history (Fig. 1). In the multivariable analysis, history of stroke was a significant and independent factor related to CMBs (Table 2). This is the first study to investigate the relationship between history of stroke and presence of CMBs in HD patients.

Studies on CMBs in HD patients have been limited, but higher prevalences compared to healthy populations have been reported despite use of different MRI field strengths, imaging methods, and cohort constitutions (such as age or inclusion of patients with or without a history of stroke). The reasons for the high incidence of CMBs in HD patients include their high incidence of older age and hypertension which cause cerebral small-vessel diseases including CMBs in HD patients [22] as well as the effects of CKD itself on cerebral small-vessel diseases [9,10,11,12,13,14]. Yokoyama et al. [24] found a prevalence of CMBs of 19.3% in HD patients without a history of stroke (n = 57, mean age 58.5 y) using a 0.5 T MRI scanner; whereas Watanabe et al. [23] found a prevalence of 35% in a cohort of HD patients that included 8.8% with a stroke history (n = 80, mean age 62.9 y) using 1.5 T MRI. We [22] previously reported a prevalence of CMBs of 25.1% in HD patients without a history of stroke (n = 57, mean age 58.5 y) using 1.5 T MRI, and Chai et al. [21] recently reported a prevalence of 54% in HD patients without a history of stroke (n = 61, mean age 47 y) using 3D MRI with a 3 T scanner.

In the present study, the prevalence of CMBs was 29.0% in HD patients, including 9.1% with a stroke history (n = 241, median age 60.0 y) using 1.5 T MRI. There was a higher prevalence of CMBs in HD patients with a history of stroke compared to those without this history (54.5 vs. 26.5%, p = 0.012) (Fig. 1). As mentioned above [2], it is well known that among non-HD patients, patients with a stroke history have advanced small-vessel disease and high frequency of CMBs, and the present study showed that this was also true for HD patients with a history of stroke. Our multivariable analysis also indicated a significantly high prevalence after adjustment for background factors (Table 2). Moreover, the presence of CMBs has been reported to become a future risk for ICH in dialysis patients without a stroke history [25]; therefore, this risk is presumed to be higher in patients with a stroke history, but to what extent it is higher needs to be studied in future. In addition, our analysis showed that age and hypertension were also significant and independent factors related to CMBs, which were consistent with previous studies on non-HD patients [1, 2, 6, 7] as well as our previous study on HD patients without history of stroke [22].

There are several limitations in this study. First, the number of cases was relatively small, and studies with more cases are necessary. Second, the cross-sectional design prevents our results indicating causality, and this point requires further examination in longitudinal studies. Third, we reported the prevalence of CMBs based on conventional 2D T2*-weighted MRI, and newer techniques such as 3D T2*-weighted MRI or SWI might have given different results [1, 7]. Thus, further examinations are needed using these newer MRI techniques. Fourth, the statistical problem of overfitting could not be avoided due to the limited number of cases, and an analysis could not be performed according to the type of stroke. A future study of the dependence on the type of stroke is required with a sufficient number of cases.

In conclusion, as has been reported for non-HD patients, our results showed a high prevalence of CMBs in HD patients with a history of stroke, and indicated that a history of stroke is significantly and independently associated with CMBs in HD patients.

Availability of data and materials

The data that support the findings of this study are available, upon reasonable request.

References

  1. 1.

    Greenberg SM, Vernooij MW, Cordonnier C, Viswanathan A, Al-Shahi Salman R, Warach S, et al. Cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol. 2009;8(2):165–74. https://doi.org/10.1016/S1474-4422(09)70013-4.

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Viswanathan A, Chabriat H. Cerebral microhemorrhage. Stroke. 2006;37(2):550–5. https://doi.org/10.1161/01.STR.0000199847.96188.12.

    Article  PubMed  Google Scholar 

  3. 3.

    Offenbacher H, Fazekas F, Schmidt R, Koch M, Fazekas G, Kapeller P. MR of cerebral abnormalities concomitant with primary intracerebral hematomas. AJNR Am J Neuroradiol. 1996;17(3):573–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Charidimou A, Kakar P, Fox Z, Werring DJ. Cerebral microbleeds and recurrent stroke risk: systematic review and meta-analysis of prospective ischemic stroke and transient ischemic attack cohorts. Stroke. 2013;44(4):995–1001. https://doi.org/10.1161/STROKEAHA.111.000038.

    Article  PubMed  Google Scholar 

  5. 5.

    Vernooij MW. Cerebral microbleeds: do they really predict macrobleeding? Int J Stroke. 2012;7(7):565–6. https://doi.org/10.1111/j.1747-4949.2012.00886.x.

    Article  PubMed  Google Scholar 

  6. 6.

    Nighoghossian N, Hermier M, Adeleine P, Blanc-Lasserre K, Derex L, Honnorat J, et al. Old microbleeds are a potential risk factor for cerebral bleeding after ischemic stroke: a gradient-echo T2*-weighted brain MRI study. Stroke. 2002;33(3):735–42.

    CAS  Article  Google Scholar 

  7. 7.

    Vernooij MW, van der Lugt A, Ikram MA, Wielopolski PA, Niessen WJ, Hofman A, et al. Prevalence and risk factors of cerebral microbleeds: the Rotterdam Scan Study. Neurology. 2008;70(14):1208–14. https://doi.org/10.1212/01.wnl.0000307750.41970.d9.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Lee SH, Bae HJ, Yoon BW, Kim H, Kim DE, Roh JK. Low concentration of serum total cholesterol is associated with multifocal signal loss lesions on gradient-echo magnetic resonance imaging: analysis of risk factors for multifocal signal loss lesions. Stroke. 2002;33(12):2845–9.

    CAS  Article  Google Scholar 

  9. 9.

    Kim SH, Shin DW, Yun JM, Lee JE, Lim JS, Cho BL, et al. Kidney dysfunction and cerebral microbleeds in neurologically healthy adults. PLoS One. 2017;12(2):e0172210. https://doi.org/10.1371/journal.pone.0172210.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Laible M, Horstmann S, Mohlenbruch M, Wegele C, Rizos T, Schuler S, et al. Renal dysfunction is associated with deep cerebral microbleeds but not white matter hyperintensities in patients with acute intracerebral hemorrhage. J Neurol. 2015;262(10):2312–22. https://doi.org/10.1007/s00415-015-7840-2.

    Article  PubMed  Google Scholar 

  11. 11.

    Peng Q, Sun W, Liu W, Liu R, Huang Y, Group CS. Longitudinal relationship between chronic kidney disease and distribution of cerebral microbleeds in patients with ischemic stroke. J Neurol Sci. 2016;362:1–6. https://doi.org/10.1016/j.jns.2016.01.015.

    Article  PubMed  Google Scholar 

  12. 12.

    Shima H, Ishimura E, Naganuma T, Yamazaki T, Kobayashi I, Shidara K, et al. Cerebral microbleeds in predialysis patients with chronic kidney disease. Nephrol Dial Transplant. 2010;25(5):1554–9. https://doi.org/10.1093/ndt/gfp694.

    Article  PubMed  Google Scholar 

  13. 13.

    Umemura T, Kawamura T, Sakakibara T, Mashita S, Hotta N, Sobue G. Microalbuminuria is independently associated with deep or infratentorial brain microbleeds in hypertensive adults. Am J Hypertens. 2012;25(4):430–6. https://doi.org/10.1038/ajh.2011.254.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Xu M, Zhang S, Liu J, Luo H, Wu S, Cheng Y, et al. Kidney dysfunction is associated with a high burden of cerebral small vessel disease in primary intracerebral hemorrhage. Curr Neurovasc Res. 2018;15(1):39–46. https://doi.org/10.2174/1567202615666180326094728.

    Article  PubMed  Google Scholar 

  15. 15.

    Greenberg SM, Briggs ME, Hyman BT, Kokoris GJ, Takis C, Kanter DS, et al. Apolipoprotein E epsilon 4 is associated with the presence and earlier onset of hemorrhage in cerebral amyloid angiopathy. Stroke. 1996;27(8):1333–7.

    CAS  Article  Google Scholar 

  16. 16.

    Qiu J, Ye H, Wang J, Yan J, Wang J, Wang Y. Antiplatelet therapy, cerebral microbleeds, and intracerebral hemorrhage: a meta-analysis. Stroke. 2018;49(7):1751–4. https://doi.org/10.1161/STROKEAHA.118.021789.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Charidimou A, Shams S, Romero JR, Ding J, Veltkamp R, Horstmann S, et al. Clinical significance of cerebral microbleeds on MRI: a comprehensive meta-analysis of risk of intracerebral hemorrhage, ischemic stroke, mortality, and dementia in cohort studies (v1). Int J Stroke. 2018;13(5):454–68. https://doi.org/10.1177/1747493017751931.

    Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Charidimou A, Werring DJ. Cerebral microbleeds as a predictor of macrobleeds: what is the evidence? Int J Stroke. 2014;9(4):457–9. https://doi.org/10.1111/ijs.12280.

    Article  PubMed  Google Scholar 

  19. 19.

    Wilson D, Werring DJ. Antithrombotic therapy in patients with cerebral microbleeds. Curr Opin Neurol. 2017;30(1):38–47. https://doi.org/10.1097/WCO.0000000000000411.

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Akoudad S, Portegies ML, Koudstaal PJ, Hofman A, van der Lugt A, Ikram MA, et al. Cerebral microbleeds are associated with an increased risk of stroke: the Rotterdam study. Circulation. 2015;132(6):509–16. https://doi.org/10.1161/CIRCULATIONAHA.115.016261.

    Article  PubMed  Google Scholar 

  21. 21.

    Chai C, Wang Z, Fan L, Zhang M, Chu Z, Zuo C, et al. Increased number and distribution of cerebral microbleeds is a risk factor for cognitive dysfunction in hemodialysis patients: a longitudinal study. Medicine (Baltimore). 2016;95(12):e2974. https://doi.org/10.1097/MD.0000000000002974.

    CAS  Article  Google Scholar 

  22. 22.

    Naganuma T, Takemoto Y, Yamasaki T, Shima H, Shoji T, Ishimura E, et al. Factors associated with silent cerebral microbleeds in hemodialysis patients. Clin Nephrol. 2011;75(4):346–55.

    CAS  Article  Google Scholar 

  23. 23.

    Watanabe A. Cerebral microbleeds and intracerebral hemorrhages in patients on maintenance hemodialysis. J Stroke Cerebrovasc Dis. 2007;16(1):30–3. https://doi.org/10.1016/j.jstrokecerebrovasdis.2006.08.004.

    Article  PubMed  Google Scholar 

  24. 24.

    Yokoyama S, Hirano H, Uomizu K, Kajiya Y, Tajitsu K, Kusumoto K. High incidence of microbleeds in hemodialysis patients detected by T2*-weighted gradient-echo magnetic resonance imaging. Neurol Med Chir (Tokyo). 2005;45(11):556–60; discussion 60.

    Article  Google Scholar 

  25. 25.

    Naganuma T, Takemoto Y, Shoji T, Ishimura E, Okamura M, Nakatani T. Cerebral microbleeds predict intracerebral hemorrhage in hemodialysis patients. Stroke. 2015;46(8):2107–12. https://doi.org/10.1161/STROKEAHA.115.009324.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Gavin JR III, Alberti KG, Davidson MB, DeFronzo RA. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 1997;20(7):1183–97.

    Article  Google Scholar 

Download references

Acknowledgements

We thank the participants for agreeing to share their clinical information for this study.

Funding

This work was supported by grants from the Osaka City University Medical Research Foundation.

Author information

Affiliations

Authors

Contributions

T.N. (corresponding author) contributed to the concept and design of the study, data acquisition and interpretation, and writing of the manuscript. D.K. and A.S. contributed to data analysis and interpretation. Y.T. and U.J. reviewed and revised the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Toshihide Naganuma.

Ethics declarations

Ethics approval and consent to participate

This study protocol was conducted in accordance with the Principles of the Declaration of Helsinki, and was approved by the ethics committee of Osaka City University (No. 1415). Informed consent was obtained from all subjects prior to their participation in the study.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Naganuma, T., Kabata, D., Takemoto, Y. et al. Impact of stroke history on the presence of cerebral microbleeds in hemodialysis patients. BMC Neurol 21, 311 (2021). https://doi.org/10.1186/s12883-021-02320-7

Download citation

Keywords

  • Cerebral microbleeds
  • Dialysis
  • Stroke
  • Medical history