Urinary Immunoglobulin G Is a Novel Biomarker for Atherosclerotic Burden in Mild Acute Ischemic Stroke Patients

Abstract

Aims: Urinary immunoglobulin G (IgG) may be a stronger marker of atherosclerosis than microalbuminuria are because urinary IgG reflects proteinuria level and size-selectivity loss. Microalbuminuria—not urinary IgG—is associated with mild acute ischemic stroke (MAIS).

Methods: Using the Jikei University School of Medicine Stroke Registry, we selected and screened patients with symptomatic acute ischemic stroke (onset-to-door time ≤ 24 h). The exclusion criteria were (1) on-admission NIHSS scores ＞10, (2) a modified Rankin Scale (mRS) score ≥ 2 prior to stroke onset, (3) incomplete data (no urinalysis ≤ 3 days after admission or no mRS score at 90 days from stroke onset), and (4) an active malignancy. Patients at 90 days post-discharge were divided into those with favorable mRS scores of 0–1 and those with unfavorable mRS scores of 2–6. Clinical backgrounds were compared for (1) patients with positive and negative urinary IgG results, and (2) patients with favorable and unfavorable outcomes.

Results: Of our study’s 210 patients (164=male, median age=68, median eGFR=53.2 ml/min/1.73 m²), 30 (14%) presented with positive urinary IgG, which was associated with cardiovascular risk factors. Higher BNP, higher D-dimer, lower eGFR, and higher CAVI were associated with higher positive urinary IgG. The favorable group, comprising 155 (74%) patients, had higher negative urinary IgG than the unfavorable group (89% vs 76%, P=0.026). No statistical difference emerged regarding microalbuminuria (29% vs 29%, P=1.000).

Conclusion: In MAIS, urinary IgG was associated with both the presence of atherosclerosis and an unfavorable outcome at 90 days after stroke onset.

Highlights

・Urinary IgG reflects proteinuria level and size-selectivity loss.

・Urinary IgG may be a stronger marker of atherosclerosis than microalbuminuria.

・In mild acute ischemic stroke patients, urinary IgG is a marker of atherosclerosis.

・In mild acute ischemic stroke patients, urinary IgG is a marker of outcome 90 days after the onset.

・Urinary IgG may be an important marker for noninvasive and rapid testing of atherosclerotic burden.

1.Introduction

High levels of protein in urine (proteinuria) are associated with a loss of the charge barrier of the glomerular basement membrane, and disrupt the size barrier^{1, 2)}. When a loss of the charge barrier occurs, an abnormal loss of protein (mainly albumin) can also occur. With disruption of the size barrier, increasing numbers of proteins of larger molecular weight cross the glomerular capillary wall, and the amount of immunoglobulin G (IgG) increases progressively^{3, 4)}. In other words, microalbuminuria are associated with the glomerular charge barrier, whereas urinary IgG is associated with the glomerular size barrier^{5, 6)}. In physiologic conditions, proteins whose size is similar to that of IgG (molecular radius=55 Å) are completely restricted from filtration because their radius is greater than that of the pores of the glomerular basement membrane. It is important to bear in mind that the extent and the nature of glomerular injury are manifested in both the level of proteinuria and the size distribution of urinary proteins, because the levels of proteinuria and of size selectivity are not necessarily correlated⁶⁾.

Microalbuminuria, a marker of both renal injury and endothelial dysfunction, are associated with systematic arteriopathy^{7, 8)}. Indeed, it is thought that a relatively simple assessment of renal structure could shed light on systemic vasculature; in other words, leaky renal vessels reflect the permeability of vasculature in general and have been linked to an individual’s susceptibility to target organ damage⁹⁾. Urinary IgG excretion has been used as a marker for determining the severity of glomerular damage^{4, 6)} and is potentially a more sensitive biomarker for early or mild glomerular injury than other glomerular and tubular biomarkers¹⁰⁾. Although albuminuria including microalbuminuria have been associated with stroke risk^{7, 11)}, the relationship between urinary IgG and stroke risk is unknown. Urinary IgG may be a stronger marker of stroke risk than microalbuminuria, because urinary IgG combines information regarding both the level of proteinuria and the loss of size selectivity⁶⁾. Therefore, the primary aim of our present study is to assess the characteristics of mild acute ischemic stroke (MAIS) patients with respect to urinary IgG excretion. Our secondary aim is to investigate the relationship between urinary IgG and outcome of MAIS.

2.Methods

2-1. Patient Selection

Patients were selected from the Jikei University School of Medicine Stroke Registry (Jikei Stroke Registry), a prospective database of patients who are admitted with stroke to Jikei University Hospital, a tertiary medical center located in the center of Tokyo. We prospectively screened consecutive patients with stroke who had been admitted to hospital between October 2018 and June 2022. The inclusion criterion was admission to hospital not more than 24 hours after symptomatic MAIS presented in patients (i.e., an onset-to-door time ≤ 24 h). The selection process rested on four exclusion criteria: (1) the patient’s National Institutes of Health Stroke Scale (NIHSS) score¹²⁾ on admission was ＞10 ¹³⁾, (2) the patient had a modified Rankin Scale (mRS) score ≥ 2 prior to the onset of the present stroke, (3) incomplete data (no urinalysis had been performed ≤ 3 days after admission or the patient’s mRS score at 90 days from stroke onset was unavailable), and (4) the patient had an active malignancy, which is strongly associated with poor outcome.

2-2. Collection of Clinical Data

We collected the following clinical data regarding patients admitted to our study: age, sex, laboratory data on admission, comorbidities and cardiovascular risk factors, subtype of ischemic stroke based on the Trial of ORG 10172 in Acute Stroke Treatment classification (large artery atherosclerosis, small vessel occlusion, cardioembolism, stroke of other determined etiology, stroke of undetermined etiology with negative evaluation)¹⁴⁾, NIHSS score¹²⁾ on admission, use of intravenous thrombolysis, performance of mechanical thrombectomy, and an mRS score 90 days after stroke onset. Comorbidities and cardiovascular risk factors were defined as (1) hypertension, use of antihypertensive agents, or any past history of hypertension without any treatment, (2) diabetes mellitus, use of oral hypoglycemic agents or insulin, diet therapy, glycosylated hemoglobin levels (National Glycohemoglobin Standardization Program) ≥ 6.5%, or any past history of diabetes mellitus without any treatment, (3) dyslipidemia, use of cholesterol-lowering drugs, serum low-density lipoprotein-cholesterol ＞140 mg/dL, or any past history of dyslipidemia without treatment, and (4) atrial fibrillation of any type (paroxysmal, persistent, or permanent) detected before or during hospitalization. Medical practitioners have widely used the cardio-ankle vascular index (CAVI) and the ankle-brachial pressure index (ABI) to evaluate arterial stiffening and arterial stenosis or obstruction, and both indices are considered useful for the prevention of microangiopathies^{15, 16)}. We measured CAVI and ABI by using a VaSera VS-1500 or a VaSera VS-3000N (Fukuda Denshi, Tokyo, Japan). CAVI and ABI examinations were performed on the right and left sides, and the mean score was used in analyses³⁾.

2-3. Evaluation of Glomerular Filtration Rate (GFR), Albuminuria, and Urinary IgG

We examined the results from spot urinalysis performed ≤ 3 days after admission. Estimated GFR (eGFR) was calculated from the serum creatinine level on admission (eGFR=194×(serum creatinine (mg/dL))^−1.094×age^−0.287×0.739 (if female) [34]). Urinary albumin excretion was expressed as the urinary albumin/creatinine ratio (UACR) and calculated from urinary albumin estimates based on the latex agglutination method and on levels of urinary creatinine concentration. Normoalbuminuria were defined as a UACR of ≤ 30 mg/g creatinine, microalbuminuria were defined as a UACR of 30–300 mg/g creatinine, and macroalbuminuria were defined as a UACR of ＞300 mg/g creatinine. We relied on an enzyme-linked immunosorbent assay to measure urinary IgG, which was expressed as positive or negative: a positive expression was defined as ≥ 0.2 mg/dL and a negative expression was defined as ＜0.2 mg/dL (i.e., as being below detection sensitivity).

2-4. Statistical Analysis

Patients were categorized according to their mRS scores 90 days after stroke onset; an mRS score of 0–1 represents a favorable outcome and an mRS score of 2–6 represents an unfavorable outcome. We compared (1) the clinical backgrounds of patients who had positive urinary IgG results with the clinical backgrounds of patients who had negative urinary IgG results, and (2) the clinical backgrounds of patients who had favorable outcomes with the clinical backgrounds of patients who had unfavorable outcomes. Continuous and categorical variables are presented as medians with interquartile ranges (IQRs) and as percentages (%). To compare clinical characteristics, we used the chi-squared test and the Fisher exact test for categorical variables, and the Mann–Whitney U test for continuous variables. Second, for continuous variables where there was significant variation in urinary IgG positivity, we divided them into three quintiles and compared the prevalence of urinary IgG by using Pearson’s chi-square test. Finally, we performed a multivariate logistic regression analysis to determine the factors that were independently associated with favorable outcome. Explanatory variables in the multivariate analysis were statistically significant in the univariate analysis or were those that were well-known factors of outcome: age, NIHSS score on admission, and UACR^{17, 18)}. Values of P＜0.05 were considered significant. All statistical analyses were performed with version 27 of the IBM SPSS Statistics software package (IBM-Armonk, New York, NY).

2-5. Standard Protocol Approvals and Registrations

The Regional Ethics and Hospital Management Committee of the Jikei University School of Medicine approved our proposed study and specifically our use of the Jikei Stroke Registry, with the following approval numbers: 29-195 (8811), 29-196 (8812), and 29-197 (8813). The board waived the need for patient consent, instead making an arrangement to give patients from whom data had been collected the opportunity to opt out of this research.

3.Results

3-1. Patients

Of the 627 consecutive patients admitted for symptomatic ischemic stroke during the study period, we enrolled 210 MAIS patients: 164 were male (78%), their median age was 68 years old, their median NIHSS score on admission was 2, and their median eGFR was 53.2 ml/min/1.73 m² (Fig.1, Table 1). Urinary IgG was positive in 30 patients (14%). Favorable outcome was observed in 155 of 210 patients (74%). There were no differences in main clinical variables between enrolled patients and those who were excluded due to incomplete data (Supplemental Table 1).

Fig.1. Flow diagram of patient selection

Note: mRS = modified Rankin Scale.

Table 1.Patient characteristics according to urinary immunoglobulin G findings

	Total (n = 210)	Positive urinary immunoglobulin G (n = 30)	Negative urinary immunoglobulin G (n = 180)	P value
Age, y, median (IQR)	68 (57-76)	72 (55-76)	66 (58-77)	0.501
Sex, Male, n (%)	164 (78)	25 (83)	139 (77)	0.634
Hypertension, n (%)	139 (66)	27 (90)	112 (62)	0.003
Diabetes mellitus, n (%)	45 (21)	12 (40)	33 (18)	0.014
Dyslipidemia, n (%)	101 (48)	20 (67)	81 (45)	0.031
Atrial fibrillation, n (%)	31 (15)	5 (17)	26 (14)	0.781
NIHSS score on admission, median (IQR)	2 (1-3)	2 (1-4)	2 (1-3)	0.766
Glucose (mg/dl), median (IQR)	111 (97-142)	126 (103-168)	109 (97-136)	0.022
Glycosylated hemoglobin (%), median (IQR)	5.8 (5.5-6.3)	6.3 (5.7-6.8)	5.7 (5.5-6.1)	0.007
LDL-cholesterol (mg/dl), median (IQR)	120 (91-146)	116 (96-164)	121 (91-145)	0.964
HDL-cholesterol (mg/dl), median (IQR)	55 (45-71)	55 (39-77)	55 (46-70)	0.994
Triglyceride (mg/dl), median (IQR)	123 (83-168)	123 (75-177)	123 (83-166)	0.713
Brain natriuretic peptide (pg/ml), median (IQR)	32.9 (12.2-77.5)	60.6 (22.8-236.7)	29.5 (11.3-67.3)	0.002
D-dimer (μg/ml), median (IQR)	0.7 (0.6-1.2)	0.8 (0.7-1.7)	0.7 (0.6-1.1)	0.016
eGFR (ml/min/1.73m2), median (IQR)	53.2 (43.0-64.7)	37.5 (17.9-54.4)	55.1 (44.8-67.2)	＜0.001
UACR (mg/g creatinine), median (IQR)	22.5 (9.0-83.0)	766.0 (163.0-2006.0)	18.5 (8.0-54.0)	＜0.001
Normoalbuminuria, n (%)	119 (57)	3 (10)	116 (64)	＜0.001
Microalbuminuria, n (%)	61 (29)	6 (20)	55 (31)	0.283
Macroalbuminuria, n (%)	28 (13)	21 (70)	7 (4)	＜0.001
Mean cardio-ankle vascular index, median (IQR)	9.6 (8.4-10.9)	10.1 (9.3-11.3)	9.4 (8.2-10.8)	0.026
Mean ankle-brachial index, median (IQR)	1.1 (1.1-1.2)	1.1 (1.0-1.2)	1.1 (1.1-1.2)	0.097
TOAST classification, n (%)
Large-artery atherosclerosis	30 (14)	3 (10)	27 (15)	0.583
Small-vessel occlusion	38 (18)	7 (23)	31 (17)	0.444
Cardioembolism	34 (16)	4 (13)	30 (17)	0.793
Other determined etiology	40 (19)	5 (17)	35 (19)	1.000
Undetermined	68 (32)	11 (37)	57 (32)	0.674
Major vessel occlusions, n (%)	29 (14)	3 (10)	26 (14)	0.775
Intravenous thrombolysis, n (%)	41 (20)	2 (7)	39 (22)	0.079
Mechanical thrombectomy, n (%)	14 (7)	1 (3)	13 (7)	0.698
Favorable outcome, n (%)	155 (74)	17 (57)	138 (77)	0.026

eGFR: estimated glomerular filtration rate, HDL: high density lipoprotein, IQR: interquartile range, LDL: low density lipoprotein, NIHSS: National Institutes of Health Stroke Scale, TOAST: Trial of ORG 10172 in Acute Stroke Treatment, UACR: urinary albumin creatinine ratio

Supplemental Table 1.Patient characteristics according to enrolled or excluded due to incomplete data

	Enrolled patients (n = 210)	Excluded patients due to incomplete data (n = 67)	P value
Age, y, median (IQR)	68 (57-76)	65 (55-73)	0.145
Sex, Male, n (%)	164 (78)	52 (78)	1.000
Hypertension, n (%)	139 (66)	39 (58)	0.245
Diabetes mellitus, n (%)	45 (21)	19 (28)	0.248
Dyslipidemia, n (%)	101 (48)	31 (46)	0.888
Atrial fibrillation, n (%)	31 (15)	12 (18)	0.563
NIHSS score on admission, median (IQR)	2 (1-3)	2 (1-3)	1.000
Glucose (mg/dl), median (IQR)	111 (97-142)	122 (106-128)	0.734
Glycosylated hemoglobin (%), median (IQR)	5.8 (5.5-6.3)	5.7 (5.5-6.2)	0.828
LDL-cholesterol (mg/dl), median (IQR)	120 (91-146)	107 (92-136)	0.326
HDL-cholesterol (mg/dl), median (IQR)	55 (45-71)	50 (45-58)	0.151
Triglyceride (mg/dl), median (IQR)	123 (83-168)	112 (70-150)	0.298
Brain natriuretic peptide (pg/ml), median (IQR)	32.9 (12.2-77.5)	34.2 (13.1-79.1)	0.698
D-dimer (μg/ml), median (IQR)	0.7 (0.6-1.2)	0.7 (0.6-1.0)	0.828
eGFR (ml/min/1.73m2), median (IQR)	53.2 (43.0-64.7)	55.3 (44.2-68.6)	0.693
Mean cardio-ankle vascular index, median (IQR)	9.6 (8.4-10.9)	9.5 (8.2-10.8)	0.734
Mean ankle-brachial index, median (IQR)	1.1 (1.1-1.2)	1.1 (1.1-1.2)	0.828
TOAST classification, n (%)
Large-artery atherosclerosis	30 (14)	8 (12)	0.689
Small-vessel occlusion	38 (18)	10 (15)	0.711
Cardioembolism	34 (16)	15 (22)	0.271
Other determined etiology	40 (19)	9 (13)	0.360
Undetermined	68 (32)	25 (37)	0.461
Major vessel occlusions, n (%)	29 (14)	7 (10)	0.539
Intravenous thrombolysis, n (%)	41 (20)	16 (24)	0.488
Mechanical thrombectomy, n (%)	14 (7)	5 (8)	0.786

eGFR: estimated glomerular filtration rate

HDL: high density lipoprotein

IQR: interquartile range

LDL: low density lipoprotein

NIHSS: National Institutes of Health Stroke Scale

TOAST: Trial of ORG 10172 in Acute Stroke Treatment

3-2. Comparison between Positive and Negative Urinary IgG Patients

Table 1 lists the characteristics of the study patients relative to the patients’ positive or negative urinary IgG status. Positive urinary IgG was associated not only with the three cardiovascular risk factors of hypertension, diabetes mellitus, and dyslipidemia, but also with high BNP levels, high D-dimer levels, low eGFR levels, and high CAVI levels. Furthermore, positive urinary IgG was associated with high UACR levels and a high prevalence of macroalbuminuria. There was no difference in the prevalence of microalbuminuria.

We compared the prevalence of urinary IgG in the three quartiles of BNP, D-dimer, eGFR, and CAVI. Higher BNP, higher D-dimer, lower eGFR, and higher CAVI increased the prevalence of positive urinary IgG, as shown in Fig.2.

Fig.2. We compared the prevalence of urinary IgG in the three quartiles of BNP, D-dimer, eGFR, and CAVI using Pearson’s chi-square test

Higher BNP, higher D-dimer, lower eGFR, and higher CAVI were associated with an increased prevalence of positive urinary IgG.

Notes: BNP = brain natriuretic peptide, CAVI = cardio-ankle vascular index, eGFR = estimated glomerular filtration rate.

3-3. Comparison between Favorable-Outcome and Unfavorable-Outcome Patients

Table 2 lists the characteristics of the study patients according to the patients’ 90-day outcome status: favorable or unfavorable. Favorable outcome was associated with young age and low NIHSS score on admission, but not with cardiovascular risk factors. The favorable group had higher negative urinary IgG than the unfavorable group (89% vs 76%, P=0.026). No statistical difference emerged regarding microalbuminuria (29% vs 29%, P=1.000). In conducting the multivariate analysis for favorable outcome, we selected explanatory variables: age, sex, the prevalence of negative urinary IgG, UACR, well-known factors of outcome, and factors that were statistically significant in the univariate analysis (see Fig.3). Negative urinary IgG was associated with favorable outcome, while there was no statistical difference in UACR.

Table 2.Patient characteristics according to outcome at 90 days after stroke onset

	Favorable outcome (n = 155)	Unfavorable outcome (n = 55)	P value
Age, y, median (IQR)	65 (56-73)	72 (63-79)	0.004
Sex, Male, n (%)	120 (77)	44 (80)	0.850
Hypertension, n (%)	98 (63)	41 (75)	0.139
Diabetes mellitus, n (%)	33 (21)	12 (22)	0.614
Dyslipidemia, n (%)	77 (50)	24 (44)	0.530
Atrial fibrillation, n (%)	23 (15)	8 (15)	1.000
NIHSS score on admission, median (IQR)	1 (0-3)	3 (2-4)	＜0.001
Glucose (mg/dl), median (IQR)	110 (97-137)	125 (103-174)	0.068
Glycosylated hemoglobin (%), median (IQR)	5.8 (5.5-6.2)	5.9 (5.5-6.7)	0.081
LDL-cholesterol (mg/dl), median (IQR)	121 (91-146)	118 (95-145)	0.897
HDL-cholesterol (mg/dl), median (IQR)	54 (45-69)	56 (46-73)	0.237
Triglyceride (mg/dl), median (IQR)	129 (87-171)	112 (72-148)	0.051
Brain natriuretic peptide (pg/ml), median (IQR)	29.8 (12.1-68.6)	49.1 (13.0-130.2)	0.176
D-dimer (μg/ml), median (IQR)	0.7 (0.6-1.1)	0.8 (0.6-1.2)	0.128
eGFR (ml/min/1.73m2), median (IQR)	52.9 (43.7-67.4)	54.4 (41.4-61.1)	0.634
UACR (mg/g creatinine), median (IQR)	19.0 (8.0-77.0)	32.0 (13.0-156.5)	0.046
Normoalbuminuria, n (%)	93 (60)	26 (47)	0.115
Microalbuminuria, n (%)	45 (29)	16 (29)	1.000
Macroalbuminuria, n (%)	17 (11)	11 (20)	0.107
Urinary immunoglobulin G/urinary creatinine (mg/g creatinine), median (IQR)	0.00 (0.00-0.00)	0.00 (0.00-0.00)	0.021
Positive urinary immunoglobulin G, n (%)	17 (11)	13 (24)	0.026
Mean cardio-ankle vascular index, median (IQR)	9.3 (8.2-10.8)	10.4 (9.2-11.3)	0.011
Mean ankle-brachial index, median (IQR)	1.1 (1.1-1.2)	1.1 (1.1-1.2)	0.114
TOAST classification, n (%)
Large-artery atherosclerosis	17 (11)	13 (24)	0.026
Small-vessel occlusion	31 (20)	7 (13)	0.308
Cardioembolism	26 (17)	8 (15)	0.832
Other determined etiology	30 (19)	10 (18)	1.000
Undetermined	51 (33)	17 (31)	0.867
Major vessel occlusions	20 (13)	9 (16)	0.503
Intravenous thrombolysis	32 (21)	9 (16)	0.557
Mechanical thrombectomy	7 (5)	7 (13)	0.055

eGFR: estimated glomerular filtration rate, HDL: high density lipoprotein, IQR: interquartile range, LDL: low density lipoprotein, NIHSS: National Institutes of Health Stroke Scale, TOAST: Trial of ORG 10172 in Acute Stroke Treatment, UACR: urinary albumin creatinine ratio

Fig.3. Forest plot of the association of various factors with outcome at 90 days after stroke onset

Our multivariate analysis revealed that negative urinary immunoglobulin G was independently associated with favorable outcome. Explanatory variables in the multivariate analysis were age, sex, NIHSS score on admission, UACR, negative urinary immunoglobulin G, mean cardio-ankle vascular index, large-artery atherosclerosis.

Note: NIHSS = National Institutes of Health Stroke Scale. UACR = urinary albumin creatinine ratio

4.Discussion

There are two major findings of the present study. First, urinary IgG was associated with not only cardiovascular-risk factors, such as hypertension, diabetes mellitus, and dyslipidemia, but also high BNP levels, high D-dimer levels, low eGFR, and high CAVI levels. These findings suggest that urinary IgG may become a novel strong biomarker for atherosclerotic burden in MAIS. Second, urinary IgG was associated with outcome at 90 days, independent of cardiovascular-risk factors. Microalbuminuria and eGFR, which reflect disorders similar to urinary IgG, were not associated with outcome. These findings suggest that urinary IgG may have various aspects beyond its simple reflection of glomerular damage such as microalbuminuria.

To the best of our knowledge, this is the first study to reveal an association between urinary IgG and cardiovascular risk factors in MAIS patients. Urinary IgG, as a measure of both the selectivity and magnitude of proteinuria, is a strong indicator of the glomerular and tubulointerstitial injury caused by microangiopathy⁶⁾. Our study shows that urinary IgG was positively associated with three cardiovascular-risk factors: hypertension, diabetes mellitus, and dyslipidemia. Moreover, we found a relationship between urinary IgG and four markers: BNP, D-dimer, eGFR and CAVI. Although it is well established that BNP reflects left ventricular dysfunction, recent findings in the literature have shown that BNP is associated with atherosclerosis and peripheral arterial disease, because a high level of aortic stiffness, as demonstrated by high CAVI levels, results in left ventricular afterload^{19, 20)}. We have found evidence that D-dimer, as a byproduct of fibrinolysis, may play a role in the diagnosis of two serious clinical disorders: venous thromboembolism and disseminated intravascular coagulation. However, this is not the only clinical scenario in which D-dimer may be of significance; previous research has suggested that D-dimer is an important biomarker in coronary and carotid artery atherosclerosis and aortic disease^{21, 22)}. The above findings from the present study and previous studies indicate that urinary IgG reflects atherosclerotic burden in MAIS. A recent study noted a relationship between urinary IgG and deep and infratentorial cerebral microbleeds³⁾. This finding is consistent with our present study’s finding that urinary IgG is positively associated with atherosclerosis. As we move toward preventive medicine in the coming years, it is important for clinicians to make effective use of noninvasive biomarkers. Thanks to rapid and noninvasive tests, urinary IgG has the potential to become a cost-effective tool in the diagnosis of atherosclerotic burden.

Our study found an association between urinary IgG and unfavorable outcome at 90 days after mild stroke onset. In our cohort, the patients with positive urinary IgG results had a slightly higher NIHSS score on admission than did patients with negative urinary IgG results. These results suggest that a high NIHSS score on admission contributes to poor prognoses in stroke patients. It has already been reported that microalbuminuria, a marker similar to urinary IgG, are associated with poor prognoses in ischemic-stroke patients, perhaps because microalbuminuria is indicative of vascular endothelial damage¹⁸⁾. In our study, urinary IgG—not microalbuminuria—was linked to undesirable outcomes in ischemic-stroke patients. This curious pair of results may stem from the fact that microalbuminuria and urinary IgG indicate different aspects of glomerular damage. Specifically, microalbuminuria reflect the status of the glomerular charge barrier, whereas urinary IgG reflect the status of the glomerular size barrier^{5, 6)}. Thus, urinary IgG may be a stronger marker of vascular endothelial dysfunction than microalbuminuria are because urinary IgG combines information regarding both proteinuria levels and size-selectivity losses⁶⁾. Endothelial dysfunction may cause dysregulation of cerebral blood flow and blood-brain barrier dysfunction^23-25), and may be associated with poor stroke prognosis.

As with any study, ours has several limitations. First, we evaluated urinary IgG excretion on the basis of a single measurement performed during the patient-participants’ hospitalization. The urine sample was spot urine, not 24-hour urine collection, and may not reflect accurate urinary IgG excretion. Because urine protein excretion can vary throughout the day^{26, 27)}, a random spot urine may underestimate or overestimate proteinuria. Although not validated for IgG in spot urine samples, the UACR in spot urine samples are supported by Kidney Disease: Improving Global Outcomes as appropriate methods to ascertain kidney damage and aid in the diagnosis of chronic kidney disease. Moreover, the study relied on a small sample size of positive urinary-IgG cases. Both the single measurement and the small sample size limit the generalizability of our findings. Second, the inclusion criterion of this study was an NIHSS score on admission ≤ 10 because the hospital that furnished the research data is in a business district, where mild workplace strokes are relatively common²⁸⁾. The criterion, thus, prevents our research findings from being applied to all acute stroke patients.

5.Conclusion

In MIAS, urinary IgG is thought to be a marker of atherosclerosis and of patient outcome 90 days after the onset of a stroke. The present study’s findings provide new insights into the relationship between urinary IgG and MAIS. Despite having received little attention in the past, urinary IgG may be an important marker for noninvasive and rapid testing of atherosclerotic burden.

Abbreviations

ABI: ankle-brachial pressure index

BNP: brain natriuretic peptide

CAVI: cardio-ankle vascular index

CI: confidence interval

eGFR: estimated glomerular filtration rate

IgG: immunoglobulin G

NIHSS: National Institutes of Health Stroke Scale

MAIS: mild acute ischemic stroke

MRI: magnetic resonance imaging

TOAST: Trial of ORG 10172 in Acute Stroke Treatment

UACR: urinary albumin creatinine ratio

IQR: interquartile range

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