Associations Between Biomarkers of Renal Function With Cerebral Microbleeds in Hypertensive Patients

American Journal of Hypertension, Jun 2015

Cerebral microbleeds (CMBs) have been observed in the elderly and have been regarded as a manifestation of small vessel disease (SVD). Cerebral and glomerular SVD may have a common source of pathogenesis because these organs are closely connected through anatomic and hemodynamic similarities. The purpose of this study was to clarify the associations between kidney biomarker levels and CMBs in hypertensive patients.

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Associations Between Biomarkers of Renal Function With Cerebral Microbleeds in Hypertensive Patients

American Journal of Hypertension Associations Between Biomarkers of Renal Function With Cerebral Microbleeds in Hypertensive Patients Jin-biao Zhang 1 Li-feng Liu 0 Zhen-guang Li 1 Hai-rong Sun 1 Xiao-hua Jü 1 0 Department of Neurology, Liaocheng People's Hospital and Liaocheng Clinical School of Taishan Medical University , Liaocheng , PR China 1 Department of Neurology, Weihai Municipal Hospital, The Affiliated Hospital of Binzhou Medical College , Weihai , PR China BACKGROUND Cerebral microbleeds (CMBs) have been observed in the elderly and have been regarded as a manifestation of small vessel disease (SVD). Cerebral and glomerular SVD may have a common source of pathogenesis because these organs are closely connected through anatomic and hemodynamic similarities. The purpose of this study was to clarify the associations between kidney biomarker levels and CMBs in hypertensive patients. blood pressure; cerebral microbleeds; chronic kidney disease; cystatin C; hypertension; small vessel disease RESULTS UACR and CysC levels were higher in the patients with CMBs than those without, and the eGFR was lower in the patients with CMBs than those Cerebral microbleeds (CMBs) are focal accumulations of hemosiderin-containing macrophages in the perivascular space of small blood vessels in the brain that indicate prev-i ous extravasation of blood1. CMBs may be located in various regions of the brain and persist indefinitely after initial detection, and they are commonly observed not only in patients with ischemic and hemorrhagic stroke but also in normal elderly individuals. More importantly, CMBs may predict future risk of stroke, especially hemorrhagic stroke under antithrombotic therapy.2 Cerebral and glomerular small vessel disease (SVD) may have a common pathogenesis source because these organs are closely connected by anatomic and hemodynamic similarities.3 Chronic kidney disease is emerging as an independent risk factor for not only cardiovascular events but also for stroke and cerebral SVDs, such as silent lacunar infarcts (SLIs) and white matter lesions.4–6 Chronic kidney disease is commonly defined by a reduction in the glomerular filtration rate (GFR) or the presence of proteinuria. Recent studies have indicated that low GFR levels and the presence of proteinuria are associated with the presence of CMBs in TIA or stroke7.,8 Cystatin C (CysC) has been studied as an endogenous marker CONCLUSIONS Kidney biomarker levels are associated with the presence of CMB in hypertensive patients without a history of transient ischemic attack (TIA) or stroke, independent of conventional risk factors, and CysC was a better marker for CMBs than eGFR and UACR. METHODS Study population Subjects were prospectively enrolled from consecutive hypertensive outpatients aged ≥50  years who visited the Department of Neurology at Weihai Municipal Hospital, an affiliate of Binzhou Medical College, with neurological complaints (i.e., headache or dizziness, vertigo, numbness, syncope, or subjective memory impairment) between June 2011 and June 2013. Hypertension was defined as≥140/90  mm Hg at three different times or the use of antihypertensive medications. Carotid intima-media thickness was measured to reflect the severity of atherosclerosis, and magnetic resonance (MR) imaging was performed to evaluate susp-i cious neurological symptoms. When neither neurological symptoms nor a history of stroke or TIA were identified, the patient was considered eligible for the study. During the study period, 964 patients were identified as candidates (Figure 1). We then excluded 51 patients whose MR imaging examinations were not completed. Patients with a history of stroke or TIA (n  =  298), severe dementia (n = 11), or brain surgery (n = 5) and those receiving hemodialysis (n = 6) were excluded to eliminate any effects of clinically evident diseases on CMBs. Patients with infective and inflammatory disorders (n = 7), serious heart diseases (such as recent acute coronary syndrome, life-threatening arrhythmias, and heart failure) n( = 5), liver diseases (e.g., cirrhosis) (n = 3), or cancer (n = 7) and disorders of the hematological system ( n = 3) exhibit increased CysC levels and were thus excluded. The final study population consisted of 568 hypertensive patients. We recorded demographics and medical history in detail. The ethical committee of Weihai Municipal Hospital approved this study, and all participants provided informed consent. In addition, this study was conducted in accordance with the principles of the Declaration of Helsinki. MR imaging assessment All 568 hypertensive participants underwent MR examination with susceptibility-weighted imaging (SWI). In addition, all patients received conventional T1- and T2-weighted, fluid-attenuated inversion recovery sequence, and diffusionweighted imaging scans. MR imaging examinations were performed with a Magnetom Trio whole-body 3.0-T MR scanner (Siemens, Erlangen, Germany) with a 40 mT/m gradient. A  receiver-only eight-channel phased array head coil was used in all acquisitions with an integrated parallel acquisition technique. SWI was obtained as a fully velocitycompensated, three-dimensional gradient echo sequence using the following parameters: repetition time, 27 ms; time of echo, 20 ms; flip angle, 15°; matrix, 350× 445; field of view, 192 × 220 mm; and slice thickness, 1.2 mm. Minimal Enrollment N=964 intensity projection images were reconstructed on a console by overlaying the six adjacent slices from the original SWI, with a slice thickness of 7.2mm. 13–15 The presence and number of CMBs on SWI were independently interpreted by two experienced neuroradiologists and determined by consensus. CMBs were defined as focal areas with very low signal intensity, smaller than 10mm. 16 Hypointense lesions were excluded if they appeared to be vascular flow voids (based on sulcal location or linear shape), basal ganglia mineralization, or artifacts from an adjacent bone or sinus. SLIs were defined as focal lesions >3mm and <15 mm, with a hyperintense rim on fluid-attenuated inversion recovery images, corresponding hyperintensity on T2-weighted images and corresponding hypointensity on T1-weighted images. Furthermore, a white matter lesion was defined as at least one focal lesion in the cerebral white matter with a corresponding hyperintensity on fluid-attenuated inversion recovery images. The Fazekas scale was used to score the white matter lesions. Scores of 0–6 were given for a deep WMH (DWMH) in the temporal, frontal, parietal, and occipital lobe (DWMH; range: 0–24), and scores of 0–2 were given for three periventricular hyperintensities (PVH; range: 0–6)1.7 The interrater reliability for the whole group for the presence of CMBs was k = 0.876, and the intraclass correlation coefficient for the number of CMBs was k  =  0.869, which indicates good agreement. Evaluation of baseline risk factors The diagnosis of diabetes mellitus was based on the use of antidiabetic treatment or repeated pathologic blood tests indicating fasting values ≥7  mmol/l (126 mg/dl) or values load≥11.1 mmol/l (200 mg/dl) 2 h after an oral glucose. A history of smoking was coded if the subject smoked during the 3 months prior to the most recent stroke event. Alcohol was accepted as a risk factor if current consumption reached 300g/week. Blood samples were obtained from patients between 6:00 and 8:00 am after overnight fasting. Total protein, serum albumin, total cholesterol, triglyceride, low-density lipoprotein cholesterol, blood urea nitrogen, and hemoglobin levels were measured by standard laboratory methods. Hyperlipidemia was determined when total cholesterol was ≥200 mg/dl or when low-density lipoprotein cholesterol was ≥130 mg/dl. High-sensitivity C-reactive protein (hs-CRP) levels were determined using a latex-enhanced immunonephelometric method on a Hitachi 7600 autoanalyzer (Hitachi, Tokyo, Japan). The carotid intima-media thickness was measured by Color Doppler ultrasound. The intima-media thickness was calculated by averaging the thickness at 12 sites: the near and far walls of both left and right distal common carotid artery, internal carotid artery, and carotid bifurcation. Measurement of kidney biomarkers Serum CysC was measured with the automated particleenhanced turbidimetric immunoassay using a Hitachi 7600 autoanalyzer. The intra-assay and interassay coefficients of variation for CysC were 0.52–0.84% and 0.46–1.25%, respectively. Serum creatinine was measured by the Jaffe kinetic method on a Hitachi 7600 autoanalyzer. The estimated GFR (eGFR) of each participant was calculated from the serum creatinine (Cr) value and the patient’s age using the abbre-vi ated Modification of Diet in Renal Disease equatio1n8 modi fied by the Chinese coefficient.19 Spot urine samples were collected early in the morning. The urinary albumin concentration was measured using an immunoturbidimetric assay, and urine creatinine was analyzed using the Jaffe reaction. The urine albumin-creatinine ratio (in mg/g) was calculated by dividing the urinary albumin value by the urinary creat-i nine concentration. Statistical analysis Continuous variables are expressed as the mean ± SE; categorical variables are expressed as constituent ratios. All of the statistical analyses were performed using SPSS 13.0 for Windows (SPSS, Chicago, IL). Continuous data were compared between groups using a Student’s t-test, and categorical data were compared using a chi-squared test. We used the multivariate cumulative logistic model to quantify the effects of risk factors on the CMBs. We also performed a multilinear regression analysis of kidney biomarker levels and the number of CMBs. Receiver operating characteristic analysis was performed to evaluate the diagnostic potential of kidney biomarkers. The threshold for statistical signif-i cance wasP < 0.05. RESULTS Patient characteristics CMBs were observed in 106 of 568 hypertensive patients (18.7%). Of the 545 identified CMBs, 145 (26.6%) were located in the basal ganglia, 83 (15.2%) in the thalamus, 59 (10.8%) in the cerebellum, 90 (16.5%) in the brainstem (mostly in the pons), 109 (20.0%) in the subcortical white matter, and 59 (10.8%) in the cortex. In the univariate anal-y sis, age, prevalence of SLI, degrees of PVH and DWMH, hsCRP, urinary albumin/creatinine ratio (UACR), and CysC levels were higher in patients with CMBs than those without CMBs, and the eGFR was lower in patients with CMBs than those without (Table 1). We assessed the use of medications by all enrolled patients. The results indicate no significant differences in medication use between the groups. Adjusted relationship between the presence of CMBs and kidney biomarker levels Multivariate logistic regression analyses were used to determine the association between age, sex, baseline risk factors, serum hs-CRP levels, and kidney biomarker levels in patients with CMBs. Table 2 shows that each 1 SD decrease in eGFR and 1 SD increase in UACR and CysC levels were significantly associated with the presence of CMBs after adjustment for age and sex (Model 1), and after additional adjustments for diabetes, hyperlipidemia, current smoker designation, current drinker designation, the levels of blood pressure, the presence of SLI, WMH (PVH, DWMH) grade, and hs-CRP level (Model 2). The odds ratio (OR) of each kidney biomarker (eGFR, UACR, CysC) for the presence of CMBs was 1.38 (0.85–2.77), 2.03 (1.41–4.31), and 2.46 (1.44–5.93), respectively (Model 2). Furthermore, eGFR and UACR were only associated with the presence of deep or infratentorial CMBs (OR: 1.95, 95% confidence interval (CI): 1.37–3.27, P < 0.05; OR: 2.25, 95% CI: 1.66–4.46, P < 0.01 (Model 2)). No significant differences were found between eGFR and UACR levels and the presence of pure lobar CMBs in the multivariate logistic analysis (Table  2). The associations between CysC levels and deep or infratentorial CMBs or lobar CMBs remained significant after adjustment for age and sex (Model 1)  and after ad-di tional adjustments for diabetes, hyperlipidemia, current drinker designation, the levels of blood pressure, the presence of SLI, WMH (PVH, DWMH) grade, and hs-CRP level (OR: 2.59, 95% CI: 1.57–6.22, P  <  0.05; OR: 1.57, 95% CI: 1.15–4.85, P < 0.05 (Model 2)). Diagnostic value of kidney biomarkers for CMBs in hypertensive patients Receiver operating characteristic curve analysis was pe-r formed to verify the diagnostic accuracy of kidney biomarkers for CMBs in hypertensive patients. CysC levels exhibited fair diagnostic value for CMBs, with an area under the curve of 0.80 (95% CI: 0.76–0.86), whereas the area under the curve for UACR and eGFR were only 0.69 (95% CI: 0.65–0.74) and 0.63 (95% CI: 0.58–0.67), respectively (Figure 2). Logistic regression analysis indicated that the comb-i nation of CysC and UACR levels (B  =  2.583, SE  =  0.457, P  <  0.001) significantly discriminated the patients with CMBs from those without, even after adjustment for age and sex, diabetes, hyperlipidemia, current drinker designation, the levels of blood pressure, the presence of SLI, WMH (PVH, DWMH) grade, and hs-CRP level. Correlation between the number of CMBs and kidney biomarker levels To strengthen the association of kidney biomarker levels with CMBs, multivariate regression analysis confirmed the association of serum kidney biomarker levels and number of CMBs after adjustments for age, sex, hypertension, diabetes, hyperlipidemia, current smoker designation, current drinker designation, the levels of blood pressure, the presence of SLI, WMH (PVH, DWMH) grade, and hs-CRP. In the patients with deep or infratentorial CMBs, the number of CMB increased as eGFR decreased and UACR and CysC levels increased (P = 0.041, adjusted R2 total = 0.190; P  =  0.037, adjusted R2 total  =  0.222; P  =  0.021, adjusted R2 total  =  0.263). In the patients with pure lobar CMBs, the number of CMBs increased as CysC levels increased (P  =  0.032; adjusted R2 total  =  0.233). No correlation was observed between eGFR or UACR levels and the number of CMBs. American Journal of Hypertension 28( 6 ) June 2015 741 n (%), number of subjects (percentage); P values were obtained by chi-squared test for categorical variables, by independent t-test (two sided) for continuous variables. Abbreviations: ARB, angiotensin receptor blocker; ACEI, angiotensin-converting enzyme inhibition; BMI, body mass index; BUN, blood urea nitrogen; CMB, cerebral microbleed; DBP, diastolic blood pressure; DM, diabetes mellitus; DWMH, deep white matter hyperintensities; eGFR, estimated glomerular filtration rate; FBG, fasting blood glucose; hs-CRP, high-sensitivity C-reactive protein; IMT, intima-media thickness; IQR, interquartile range; LDL, low-density lipoprotein cholesterol; NIHSS, The National Institutes of Health Stroke Scale; PVH, periventricular hyperintensities; SBP, systolic blood pressure; SLI, silent lacunar infarction; TC, total cholesterol; UACR, urine albumin/creatinine ratio. DISCUSSION This cross-sectional hospital-based study demonstrated that in hypertensive patients without a history of stroke or TIA, eGFR, and UACR are independently associated with the prevalence of deep or infratentorial CMBs but not pure lobar CMBs. Our findings are in agreement with the populationbased Rotterdam Scan Study, which showed that risk factors for CMBs differed with their location.20,21 CysC is independently associated with CMBs in both deep or infratentorial and lobar locations. Furthermore, CysC exhibited fair dia-g nostic value of CMBs, with an area under the curve of 0.80. 742 These results were also supported by a recent study that demonstrated an association between elevated CysC levels and markers of SVD, such as white matter lesions and subclinical lacunar infarction, in community-based elderly patients2.2 The kidney and brain are end organs that are vulnerable to hypertensive damage because their vascular beds have very low resistance and are passively perfused at high flow throughout systole and diastole. Therefore, it is important to consider the hemodynamic similarities of vascular beds as a factor for the association between CMBs and chronic kidney disease. Some studies have indicated that low GFR s l e v e l r e k r a m o i b y e n d i k n i e s a e r c n i D S 1 r e p s u t a t s s B M C r o f ) I C % 5 9 ( s o it a r s d d O . 2   e l b a T ) 2 2   =   n ( s B M C r a b o l e r u P ) 6 0 1 = n ( s B M C y n A 2 l e d o M ) 4 8   =   n ( s B M C l a i r o t n e t a r f n i r o 1 p l eeD edoM 2 l e d o M 1 l e d o M 2 l e d o M 1 l e d o M .eM .PARC itvcepoeae tsneehgBCM tsneehgBCM tsenheBCM x ,seag -sdh r-C ith ith ith fro ,an ityn daep rdaepw rpeadw w tde eda iitvs r jsudA r)gH -seh com com c1om l:od1M ,(VPHDMW i,-sghhPCR P  .*5< †P 10 ‡P.0 0 . 0 e 0  0<   0< levels and the presence of proteinuria are associated with the presence of CMBs in TIA or stroke.7,8 One recent study from Umemura et  al.23 showed that microalbuminuria but not low eGFR levels was independently associated with deep or infratentorial CMBs in hypertensive adults without a history of stroke or TIA. Our study found that both eGFR and microalbuminuria were independently associated with the prevalence of deep or infratentorial CMBs in hypertensive patients without a history of stroke or TIA. Compared with Umemura et al., we detected CMBs by SWI sequences that employ a high-resolution three-dimensional gradientrecalled echo sequence with a long echo time, utilizing both magnitude and phase information2,4 making these modalities more sensitive at detecting CMBs than conventional gradient-echo T2* sequences.13 The sample size of this study was also relatively larger. CysC is a cysteine proteinase inhibitor that is released at a constant rate from all nucleated cells. The protein is filtrated freely by the glomerulus and is almost completely reabsorbed and catabolized in the renal tubule9s,.10 CysC has been considered one of the more specific and sensitive endogenous markers of kidney function.9,25 CysC is a marker for impaired endothelial function, not just in the glomerulus but also throughout the vascular tree. Hence, as a novel marker of renal function, elevated CysC levels may be associated with the presence of CMBs. Our previous study also found that elevated levels of CysC are associated with the presence of CMBs in acute stroke patients, independent of conventional risk factors2.6 Elevated levels of CysC and the presence of CMBs may be the end organ damage that results from a hypertensive insult. No location-specific association of CMBs with CysC was observed, indicating that CMBs are a marker for the general severity of SVD and can be seen as the common downstream product of two separate pathways: hypertensive vasculopathy and cerebral amyloid angiopathy. Our data raise the possibility that CysC is important to the pathogenesis of any CMB. Some largescale studies have shown that deep or infratentorial CMBs are generally associated with atherosclerotic microangiop-a thy and that pure lobar CMBs can commonly be attributed to vascular β-amyloid (Aβ) deposition (cerebral amyloid angiopathy)2.0,27 CysC plays a role in the different processes and stages of atherosclerotic disease2.8,29 The pathogenesis of atherosclerotic disease may be an imbalance between the expression of cysteine cathepsins and their endogenous inhibitor, CysC, in atherosclerotic lesions in humans.30 CysC also plays an important role in the pathogenesis of cerebral amyloid angiopathy3.1 CysC is also involved in many pathological processes, including oxidative stress and inflammation.31,32 In our study, the association between the number of CMBs and serum CysC was also significant in patients with pure lobar CMBs. However, the causality between serum CysC levels and cerebral amyloid angiopathy or CMB path-o genesis has not yet been established. Our results have some limitations. First, the cross-sectional design limits causal inferences, and further follow-up is needed. Second, our results are limited to the cohort of elderly individuals with hypertension, and therefore, they cannot be generalized to the general population. Third, the small sample size of the pure lobar CMBs creates limitations in the multivariate analysis of associations between kidney markers (especially CysC) and pure lobar CMBs. In conclusion, in hypertensive patients without a history of stroke or TIA, low eGFR and microalbuminuria are only associated with an increased prevalence of deep or infrate-n torial CMBs. Higher CysC levels were observed in subjects with CMBs, regardless of their location. Furthermore, CysC was a better marker for CMBs than eGFR and UACR, and exhibited fair diagnostic value. 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Zhang, Jin-biao, Liu, Li-feng, Li, Zhen-guang, Sun, Hai-rong, Jü, Xiao-hua. Associations Between Biomarkers of Renal Function With Cerebral Microbleeds in Hypertensive Patients, American Journal of Hypertension, 2015, 739-745, DOI: 10.1093/ajh/hpu229