Clinical Nutrition ESPEN 59 (2024) 140e148

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Clinical Nutrition ESPEN

journal homepage: http://www.clinicalnutritionespen.com

Original article

Blood urea nitrogen has a nonlinear association with 3-month

outcomes with acute ischemic stroke: A second analysis based on a
prospective cohort study
Pan Zhou a, 1, Ren-li Liu a, 1, Fang-xi Wang a, 1, Hao-fei Hu b, **, Zhe Deng a, *
a
Department of Emergency Medicine, Shenzhen Second People's Hospital / the First Affiliated Hospital of Shenzhen University Health Science Center,
Shenzhen, 518035, China
b
Department of Nephrology, Shenzhen Second People's Hospital / the First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen,
518035, China

a r t i c l e i n f o s u m m a r y

Article history: Background: Evidence regarding the relationship between blood urea nitrogen (BUN) and 3-month
Received 14 July 2023 outcomes in acute ischemic stroke (AIS) patients is still scarce. Therefore, the present study was pre-
Accepted 1 December 2023 formed to explore the link between the BUN and 3-month poor outcomes in patients with AIS.
Methods: A retrospective study of 1866 participants with AIS enrolled from January 2010 to December
Keywords: 2016 at a hospital in South Korea. Binary logistic regression, smooth curve fitting, and a set of sensitivity
Blood urea nitrogen
analyses were used to analyze the association between BUN and 3-month poor outcomes.
Acute ischemic stroke
Results: After adjusting covariates, the results of the binary logistic regression model suggested that the
3-Month poor outcome
Nonlinear relationship
relationship between the BUN and the risk of 3-month poor outcomes for AIS patients was not statis-
Smooth curve fitting tically significant. However, there was a special nonlinear relationship between them, and the inflection
point of the BUN was 13 mg/dl. On the left side of the inflection point, every unit increase in the BUN
reduces the risk of 3-month poor outcomes by 14.1 % (OR ¼ 0.859, 95%CI: 0.780e0.945, p ¼ 0.0019). On
the right side of the inflection point, the relationship is not statistically significant.
Conclusion: There is a nonlinear relationship with saturation effect between BUN level and 3-month
poor outcomes in AIS patients. Maintaining the BUN at around 13 mg/dl can reduce the risk of 3-
month poor outcome in AIS patients.
© 2023 The Author(s). Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and
Metabolism. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).

1. Introduction economic and health is enormous and constantly increasing [3,8].

Acute ischemic stroke (AIS) remains one of the leading causes
of death and disability worldwide [1,2]. In 2019, there were
approximately 12.2 million, 101 million, and 6.55 million global
incident cases of stroke, prevalent cases of stroke, and deaths from
stroke, respectively [3]. Additionally, it affects nearly 800000 in-
dividuals annually in the United States alone [4]. Moreover, the
growing of young people are affected by stroke [5]. Despite ad-
vances in therapeutic options in recent years, about 40 % of AIS
patients still have poor clinical outcomes [6,7]. Its impact on socio-
* Corresponding author.
** Corresponding author.
E-mail addresses: huhaofei0319@126.com (H.-f. Hu), dengz163@163.com
(Z. Deng).
1
Pan Zhou, Ren-li Liu, and Fang-xi Wang contributed equally to this work and are
acknowledged as the co-first authors.
Therefore, early identification of risk factors for poor prognosis in
AIS patients is crucial. Accurately predicting functional outcomes
in patients with AIS can improve clinical progress, easy consulta-
tion and guidance for patients and family members, accelerate
recovery and discharge [9].
Factors found to influence for poor prognosis in AIS have been
reported in several studies, including age, obesity, diabetes, hy-
pertension, heart disease, and the etiology of the stroke [5,10e13].
However, there is still limited research on the relationship between
laboratory investigations and poor prognosis of stroke.
Blood urea nitrogen (BUN) concentration is an easily accessible
marker of kidney function. Interestingly, quite a few recent studies
have indicated that higher BUN independently associated with
mortality in critically ill patients, including cardiogenic shock pa-
tients [14,15]. In addition, a prospective cohort study showed that
the BUN level, rather than glomerular filtration rate (eGFR) and
serum creatinine (Scr), was closely associated with mortality in

https://doi.org/10.1016/j.clnesp.2023.12.001
2405-4577/© 2023 The Author(s). Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
P. Zhou, R.-l. Liu, F.-x. Wang et al.
9420 patients with acute coronary syndromes [16]; furthermore,
another prospective study included 3355 AIS patients suggested
that BUN rather than eGFR and Scr was significantly associated with
in-hospital mortality [17]. These all indicate that BUN may play an
important role as a biomarker. However, studies on the impact of
BUN on 3-month outcomes in patients with AIS are rarely reported.
Therefore, we conducted a work using the published data from a
cohort study in South Korea to explore the relationship between
BUN and 3-month outcomes in AIS patients.
2. Methods
2.1. Study design
This present cohort study was performed using records from the
Korean single center prospective registration system in January
2010 and December 2016 [18]. BUN was the target-independent
variable in this study, while the 3-month outcome in AIS patients
was the dependent variable (dichotomous variable: poor outcome,
favorable outcome).
2.2. Data source
Raw data are available for free download from the DATADRYAD
database (https://datadryad.org/search) provided by Kang MK,
Kim TJ, Kim Y et al. [18], data from: Geriatric nutritional risk
index predicts poor outcomes in patients with acute ischemic
stroke-automated undernutrition screen tool. Dryad Digital Re-
pository: https://doi.org/10.1371/journal.pone.0228738. Accord-
ing to Dryad's terms of service, researchers can use the data for
secondary analysis without violating authors' rights. Here, we
express our gratitude to the authors who provided the data.
Fig. 1. Flowchart of study participants.
141
Clinical Nutrition ESPEN 59 (2024) 140e148
2.3. Study population
The initial researchers used data from a prospective single-
center registry in South Korea, collecting AIS patients admitted
within 7 days of symptom onset [18]. The original research was
conducted with approval from the Institutional Review Board at
Seoul National University Hospital. In addition, the Institutional
Review Board abandoned the need for patient consent (IRB No.
1009-062-332). Therefore, the current secondary analysis does not
require ethics approval. Moreover, the initial study was carried out
in accordance with the Declaration of Helsinki; all methods were
performed out in compliance with the relevant standards and
regulations, which include declarations in the Declarations section.
The same goes for secondary analysis.
The original study initially recruited 2084 patients with AIS.
However, 178 participants were excluded who met the exclusion:
(1) lack of swallowing test or laboratory data within 24 h after
discharge (n ¼ 72); (2) no modified 3-month Rankin Scale (mRS)
score after hospitalization (n ¼ 106). Finally, 1906 individual par-
ticipants were involved in original data analysis. Participants with
abnormal and excessive BUN (three standard deviations above or
below the mean) were not included in the current study (n ¼ 40).
Ultimately, 1866 participants remaining for the secondary analysis.
The process of selecting participants is shown in Fig. 1.
2.4. Variables
2.4.1. BUN
BUN was recorded as a continuous variable. The authors used
the area under the receiver operating characteristic (ROC) curve to
measure BUN as a predictor of 3-month poor outcomes. The sta-
tistical results showed that the cut-off value of BUN was 19.5 mg/dl.
P. Zhou, R.-l. Liu, F.-x. Wang et al.
Then, the BUN was converted to categorical variables according
to the cut-off value of 19.5 mg/dl (<19.5 mg/dl and 19.5 mg/dl)
or quartiles (Q1:< 12 mg/dl, Q2:12e15 mg/dl, Q3:15e19 mg/dl,
Q4:19 mg/dl).
2.4.2. 3-month outcomes in individuals with AIS
The mRS score was used to evaluate 3-month outcomes after the
onset of AIS [18,19]. Related data was obtained by telephone or
outpatient structured interviews [18]. Participants were divided
into two groups: favorable outcomes (mRS scores<3) and poor
outcomes (mRS scores3) [18].
2.5. Covariates
Covariates were chosen based on previous reports and our
clinical expertise [17,20e24]. The following variables were used as
covariates: (1) categorical variables: sex, age, hypertension, dia-
betes mellitus (DM), smoking, previous stroke or transient ischemic
attack (TIA), atrial fibrillation (AF), coronary heart disease (CHD),
stroke etiology; (2) continuous variables: white blood cell (WBC),
red blood cell (RBC), hematocrit (HCT), hemoglobin concentration
(HGB), platelet (PLT), total serum cholesterol (TC), serum triglyc-
eride (TG), serum low-density lipoproteins cholesterol (LDL-c),
serum high-density lipoprotein cholesterol (HDL-c), aspartate
aminotransferase (AST), alanine aminotransferase (ALT), Scr, he-
moglobin A1c (HBA1c), body mass index (BMI), national institute of
health stroke scale (NIHSS) score [3]. Collect laboratory data from
electronic medical records (tested within 24 h of admission) [18].
BMI was calculated as weight (kg) divided by height (m) squared
(kg/m2). Classification of stroke subtypes based on the trial of Org
10172 in the treatment of acute stroke (TOAST) [18].
2.6. Missing data processing
In present study, the number of participants with missing data
of TG, TC, LDL-c, HDL-c, ALT and HBA1C were 102(5.47 %), 1(0.05 %),
94 (5.04 %), 70 (3.75 %), 1(0.05 %) and 375 (20.10 %), respectively.
Missing covariant data were handled by multiple imputations [25].
The imputation model included age, sex, WBC, RBC, HCT, HGB, PLT,
Scr, AST, ALT, LDL-c, HDL-c, TG, TC, HBA1c, BMI, NIHSS score, pre-
vious stroke or TIA, hypertension, DM, smoking, AF, CHD, stroke
etiology. Missing data analysis assumption was based on the
missing-at-random assumption (MAR) [26].
2.7. Statistical analysis
Individuals were stratified by the cut-off value of BUN (<19.5
mg/dl and 19.5 mg/dl) or BUN quartile into Q1 (<12 mg/dl), Q2
(12md/dl-15 mg/dl), Q3 (15mg/dl-19 mg/dl), and Q4 (19 mg/dl)
groups. For continuous variables, use mean (standard deviation) or
median (range) (non-normal distribution) display, and for classified
variables, use number (%) display. The differences between BUN
groups were tested using one-way analysis of variance (normal
distribution), c2 method (classified variables) or KruskaleWallis H
test (skewed distribution).
2.7.1. To analyze the independent linear relationship of the BUN and
3-month poor outcomes in patients with AIS
After collinearity screening (Table S1: HGB, HCT and TC were
excluded), the authors constructed three different models using
univariate and multivariate binary logistic regression models to
detect the relationship between BUN and 3-month poor outcomes
in patients with AIS according to the STROBE statement [27]. The
models were as follows: (1) non-adjusted model (no covariates
were adjusted); (2) minimally-adjusted model (model I: adjusted
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Clinical Nutrition ESPEN 59 (2024) 140e148
for sex, age, hypertension, DM, Smoking, BMI, AF, and CHD); (3)
fully-adjusted model (model II:adjusted age, sex, RBC,PLT, Scr, AST,
ALT, TG, LDL-c, HDL-c,HBA1c, BMI, hypertension, DM, smoking, AF,
CHD, previous stroke or TIA, NIHSS score, and stroke etiology). Ef-
fect sizes were recorded with 95 % confidence intervals (95 % CI).
The authors adjusted for covariances when they were added to the
model and the odds ratio (OR) changed by 10 % or greater [27].
2.7.2. To analyze the nonlinear relationship of the BUN and 3-
month poor outcomes in patients with AIS
Since binary logistic regression models were often suspected of
being incapable of handling nonlinear models, generalized additive
models (GAM) and smooth curve fitting (penalized spline method)
were used to further examine the nonlinear relationship between
the BUN and 3-month poor outcomes. If nonlinearity was detected,
we first calculated the inflection point by a recursive algorithm, and
then establish a two-piece binary logistic regression model on both
sides of the inflection point [28]. Log-likelihood ratio test was used
to determine the most appropriate model describing the associa-
tion between the BUN and 3-month poor outcomes.
2.8. Sensitivity analysis
A series of sensitivity analyses were carried out to check the
robustness of our results. Significantly increased risk of poor
prognosis in patients with hypertension, DM, AF, and CHD [29e32],
therefore, when exploring the association between the BUN and 3-
month poor outcomes in other sensitivity analyses, we excluded
participants with hypertension,DM, AF, and CHD.
All results were prepared according to the STROBE statement
[27]. All analyses were performed using statistical software pack-
ages R (R Foundation)2 and EmpowerStats3 (X&Y Solutions, Inc.,
Boston, MA). P-values less than 0.05 (two-sided) were considered
statistically significant.
3. Results
3.1. Characteristics of individuals
The characteristics of the individuals are shown in Table 1. 1866
individuals were enrolled in the present study, 1139 (61.04 %) of
whom were men. The number of individuals aged <60, 60 to <70,
70 to <80, and 80 years were 433 (23.20 %), 493(26.42 %),
650(34.83 %), and 290 (15.54 %), respectively. The NIHSS scores was
showed a skewed from 0 to 33 with a median (interquartile) of 3 (1,
7). There were 595(31.89 %), 354 (18.97 %), 480 (25.72 %), 169
(9.06 %), and 268 (14.36) individuals who were LAA, SVO, CE, other
determined, and undetermined for stroke etiology, respectively.
BUN was skewed, ranging from 4 to 43 mg/dl, with a median of
15.00 mg/dl (Fig. 2). Compared to patients (BUN<19.5 mg/dl), male,
older, WBC, Scr, HBA1c, NISSS score, previous stroke, hypertension,
DM, AF, CHD, increased significantly in patients (BUN19.5 mg/dl),
while the RBC, HGB, HCT, PLT, LDL-c, and TC were opposite. Addi-
tionally, the etiologies of patients in Q4 group were more likely to
be CE. Similar results can be observed when patients are grouped
by BUN quartiles (Table S2).
3.2. The incidence rate of poor outcomes 3-month after AIS
Table 2 displayed that 531 participants had a poor outcome. The
overall incidence of poor outcomes was 28.46 % (26.41%e30.51 %).
In particular, the incidence of poor outcomes in each group was
26.30 % (BUN<19.5 mg/dl), 34.98 % (BUN19.5 mg/dl); and the
incidence of poor outcomes for the BUN quartiles was Q1: 31.85 %,
Q2: 23.69 %, Q3: 25.09 % and Q4: 33.45 %, respectively. The
P. Zhou, R.-l. Liu, F.-x. Wang et al. Clinical Nutrition ESPEN 59 (2024) 140e148

Table 1 Table 2
Baseline Characteristics of participants (N ¼ 1866). Incidence rate of unfavorable outcome 3-month after AIS.

BUN(mg/dl) Q1 (<19.5) Q2 (19.5) P-value BUN(mg/dl) Participants(n) unfavorable Incidence of unfavorable

outcome events outcome (95 % CI) (%)
Participants 1403 463
(mRS score3)
SEX 0.043
Male 838 (59.73 %) 301 (65.01 %) Total 1866 531 28.46 (26.41,30,51)
Female 565 (40.27 %) 162 (34.99 %) By 19.5 (mg/dl)
AGE (years) <0.001 <19.5 1403 369 26.30 (23.99,28.60)
<60 375 (26.73 %) 58 (12.53 %) 19.5 463 162 34.98 (30.63,39.35)
60-70 391 (27.87 %) 102 (22.03 %) By BUN quartile
70-80 453 (32.29 %) 197 (42.55 %) Q1 336 107 31.85 (26.84,36.85)
80 184 (13.11 %) 106 (22.89 %) Q2 439 104 23.69 (19.70,27.68)
WBC(  109/L) 7.98 ± 2.77 8.52 ± 3.15 0.004 Q3 538 135 25.09 (21.42,28.77)
RBC(  1012/L) 4.41 ± 0.59 4.15 ± 0.67 <0.001 Q4 553 185 33.45 (29.50,37.40)
HGB (g/dl) 13.73 ± 1.89 12.98 ± 2.03 <0.001
CI: confidence.
HCT (%) 40.76 ± 5.24 38.70 ± 5.77 <0.001
PLT (  109/L) 227.17 ± 67.07 214.34 ± 77.90 <0.001
BUN(mg/dl) 13.89 ± 3.16 25.27 ± 5.65 <0.001
Scr(mg/dl) 0.84 (0.71e0.98) 1.10 (0.89e1.41) <0.001 incidence of 3-month poor outcomes in Q1 and Q4 groups was
AST (U/L) 23.00 (19.00e30.00) 22.00 (18.00e29.00) 0.094 higher than that in Q2 and Q3 groups (P < 0.001) (Fig. 3). Consid-
ALT (U/L) 18.00 (14.00e26.00) 18.00 (12.00e26.00) 0.086 ering that renal dysfunction may affect the 3-month poor out-
LDL-c (mmol/L) 2.86 ± 0.98 2.55 ± 0.97 <0.001
comes, the authors also compared the incidence of 3-month poor
HDL-c (mmol/L) 1.20 ± 0.36 1.17 ± 0.36 0.110
TG (mmol/L) 1.28 ± 0.65 1.24 ± 0.63 0.147 outcomes in patients with high and low Scr, which was not sta-
TC (mmol/L) 4.73 ± 1.10 4.41 ± 1.18 <0.001 tistically significant (P ¼ 0.074) (Table S3).
HBA1c (%) 6.25 ± 1.13 6.47 ± 1.14 <0.001
BMI(kg/m2) 23.58 ± 3.29 23.31 ± 3.17 0.116
NIHSS score 3.00 (1.00e7.00) 4.00 (2.00e9.00) <0.001 3.3. The results of univariate analyses using a binary logistic
Previous stroke/TIA 273 (19.46 %) 120 (25.92 %) 0.003 regression model
Hypertension 836 (59.59 %) 341 (73.65 %) <0.001
DM 387 (27.58 %) 199 (42.98 %) <0.001
The univariate analyses showed that 3-month poor outcome
Smoking 562 (40.06 %) 175 (37.80 %) 0.388
AF 270 (19.24 %) 127 (27.43 %) <0.001 had nothing to do with PLT, Scr, HDL-c, and CHD (all P > 0.05), but
CHD 139 (9.91 %) 69 (14.90 %) 0.003 was positively related to AST (odds ratio (OR) ¼ 1.01, 95%CI(confi-
Stroke etiology <0.001 dence interval):1.00e1.02), HBA1c (OR ¼ 1.12, 95%CI:1.03e1.22),
LAA 452 (32.22 %) 143 (30.89 %) and BUN(OR ¼ 1.02, 95%CI:1.01e1.04) (all P < 0.05). Additionally,
SVO 284 (20.24 %) 70 (15.12 %)
female (OR ¼ 1.69, 95%CI:1.38e2.07), patients with age>80 years
CE 329 (23.45 %) 151 (32.61 %)
Other determined 139 (9.91 %) 30 (6.48 %) old (OR ¼ 3.93, 95%CI:2.82e5.48), previous stroke or TIA
undetermined 199 (14.18 %) 69 (14.90 %) (OR ¼ 1.79, 95%CI:1.43e2.27), hypertension (OR ¼ 1.33, 95%
mRS (3) 369 (26.30 %) 162 (34.98 %) <0.001 CI:1.08e1.65), DM (OR ¼ 1.42, 95%CI:1.15e1.75), AF(OR ¼ 2.06, 95%
Values are n (%) or mean ± SD or median (quartile). CI:1.63e2.59), NHISS score 14(OR ¼ 17.58, 95%CI:12.47e24.77),
BUN, blood urea nitrogen; WBC, white blood cell; RBC, red blood cell; HGB, he- and LAA (OR ¼ 1.65,95%CI:1.19e2.29), SVO(OR ¼ 2.48,95%
moglobin concentration; HCT, hematocrit; PLT, platelet; Scr, serum creatinine; AST, CI:1.79e3.45), or other determined (OR ¼ 3.45,95%CI:2.29e5.18) of
aspartate aminotransferase; ALT, alanine aminotransferase; LDL-c, low-density li-
stroke etiology were more likely to experience 3-month poor
poproteins cholesterol; HDL-c, high-density lipoprotein cholesterol; TG, triglycer-
ide; TC, total cholesterol; HBA1c, hemoglobin A1c; BMI, body mass index; NIHSS, outcomes (all P < 0.05). However, RBC(OR ¼ 0.56, 95%CI:0.48e
national institute of health stroke scale; TIA, transient ischemia attack; DM, diabetes 0.66), ALT (OR ¼ 0.00, 95%CI:0.08e1.00), LDL-c (OR ¼ 0.87, 95%
mellitus; AF, atrial fibrillation; CHD, coronary heart disease; LAA, large artery
atherosclerosis; SVO, small vessel occlusion; CE, cardio embolism.

Fig. 2. Distribution of BUN. It presented a skewed distribution in the range from 4 mg/
dl to 43 mg/dl, with a median of 15.00 mg/dl. Fig. 3. Incidence of 3-month poor outcomes according to the quartiles of BUN.

143
P. Zhou, R.-l. Liu, F.-x. Wang et al. Clinical Nutrition ESPEN 59 (2024) 140e148

CI:0.78e0.97), TG (OR ¼ 0.76, 95%CI:0.64e0.90), BMI(OR ¼ 0.91, Table 4

95%CI:0.88e0.94), and smoking (OR ¼ 0.60, 95%CI:0.40e0.74) was Relationship between BUN and unfavorable outcome 3-month after AIS.

negatively associated with the risk of 3-month poor outcomes (all Exposure Crude model Model I Model II
P < 0.05) (Table 3). (OR, 95%CI, P) (OR, 95%CI, P) (OR, 95%CI, P)

BUN 1.02 (1.01, 1.04) 1.01 (0.99, 1.03) 0.99 (0.97, 1.02)
3.4. The results of multivariate analyses using the binary logistic 0.0019 0.2643 0.5231
regression model BUN(quartile)
Q1 Ref. Ref. Ref.
Q2 0.66 (0.48, 0.91) 0.62 (0.44, 0.87) 0.67 (0.46, 1.00)
In order to investigate the relationship between BUN and 3- 0.0117 0.0043 0.0487
month poor outcomes the author used a binary logistic regres- Q3 0.72 (0.53, 0.97) 0.65 (0.47, 0.90) 0.62 (0.42, 0.90)
sion model to construct three models (Table 4). In the unadjusted 0.0303 0.0093 0.0130
Q4 1.08 (0.81, 1.44) 0.82 (0.59, 1.13) 0.69 (0.47, 1.02)
model (the crude model), a 1-unit increase in the BUN was asso-
0.6205 0.2192 0.0620
ciated with a 2 % increase in the risk of 3-month poor outcomes P for trend 0.2199 0.5801 0.0955

OR, odds ratios; CI, confidence, Ref., reference.

Table 3 Model I adjusted for sex, age, hypertension, DM, Smoking, BMI, AF, and CHD.
Influencing factors of unfavorable outcomes in acute ischemic stroke using univar- Model II adjusted for adjusted age, sex, RBC,PLT, Scr, AST, ALT, TG, LDL-c, HDL-
iate regression analysis. c,HBA1c, BMI, hypertension, DM, smoking, AF, CHD, previous stroke or TIA, NIHSS
score, and stroke etiology.
Variable Characteristic OR95%CI P

RBC(  1012/L) 4.34 ± 0.62 0.56 (0.48, 0.66) <0.0001

PLT (  109/L) 223.99 ± 70.11 1.00 (1.00, 1.00) 0.4103 (OR ¼ 1.02, 95%CI: 1.01e1.04, P ¼ 0.0019). However, in the mini-
BUN (mg/dl) 16.71 ± 6.29 1.02 (1.01, 1.04) 0.0019
Scr(mg/dl) 0.88 (0.73e1.07) 1.08 (0.92, 1.25) 0.3565
mally adjusted model and the fully adjusted model, the results of
AST (U/L) 23.00 (19.00e30.00) 1.01 (1.00, 1.02) 0.0131 the multiple regression analysis were not statistically significant
ALT (U/L) 18.00 (13.00e26.00) 0.99 (0.98, 1.00) 0.0188 (all p > 0.05). When converting BUN to a categorical variable, the
HBA1c (%) 6.31 ± 1.13 1.12 (1.03, 1.22) 0.0115 relationship between the highest quartile of BUN and 3-month
LDL-c (mmol/L) 2.79 ± 0.98 0.87 (0.78, 0.97) 0.0095
adverse outcomes was not statistically significant compared with
HDL-c (mmol/L) 1.19 ± 0.36 0.83 (0.63, 1.10) 0.1873
TG (mmol/L) 1.27 ± 0.64 0.76 (0.64, 0.90) 0.0018 the lowest quartile in model II (HR ¼ 0.69, 95%CI: 0.47 to 1.02,
BMI(kg/m2) 23.51 ± 3.26 0.91 (0.88, 0.94) <0.0001 P ¼ 0.0620). Confidence interval distributions showed no statistical
SEX significant relationship between the BUN (classification) derived
Male 1139 (61.04 %) 1.0 from the model and the probability of 3-month poor outcomes
Female 727 (38.96 %) 1.69 (1.38, 2.07) <0.0001
following AIS.
Age (years)
<60 433 (23.20 %) 1.0
60-70 493 (26.42 %) 1.18 (0.86, 1.62) 0.3113 3.5. The nonlinearity addressed by the GAM
70-80 650 (34.83 %) 1.81 (1.35, 2.42) <0.0001
80 290 (15.54 %) 3.93 (2.82, 5.48) <0.0001
GAM was applied to assess whether there was a nonlinear
Previous stroke/TIA
No 1473 (78.94 %) 1.0 relationship between BUN and the risk of 3-month poor outcomes
Yes 393 (21.06 %) 1.79 (1.42, 2.27) <0.0001 in our study (Fig. 4). A nonlinear relationship between BUN and
Hypertension poor outcomes in AIS patients risk was discovered after adjusting
No 689 (36.92 %) 1.0
Yes 1177 (63.08 %) 1.33 (1.08, 1.65) 0.0078
DM
No 1280 (68.60 %) 1.0
Yes 586 (31.40 %) 1.42 (1.15, 1.75) 0.0013
Smoking
No 1129 (60.50 %) 1.0
Yes 737 (39.50 %) 0.60 (0.49, 0.74) <0.0001
AF
No 1469 (78.72 %) 1.0
Yes 397 (21.28 %) 2.06 (1.63, 2.59) <0.0001
CHD
No 1658 (88.85 %) 1.0
Yes 208 (11.15 %) 0.94 (0.68, 1.30) 0.7211
NIHSS score
<6 1273 (68.22 %) 1.0
>¼6, <14 377 (20.20 %) 6.45 (4.99, 8.34) <0.0001
>¼14 216 (11.58 %) 17.58 (12.47, 24.77) <0.0001
Stroke etiology
SVO 354 (18.97 %) 1.0
LAA 595 (31.89 %) 1.65 (1.19, 2.29) 0.0025
CE 480 (25.72 %) 2.48 (1.79, 3.45) <0.0001
Other determined 169 (9.06 %) 3.45 (2.29, 5.18) <0.0001
Undetermined 268 (14.36 %) 1.45 (0.98, 2.14) 0.0607

Values are n (%) or mean ± SD or median (quartile).

OR, odds ratios; CI, confidence; RBC, red blood cell; PLT, platelet; BUN, blood urea
nitrogen; Scr, serum creatinine; AST, aspartate aminotransferase; ALT, alanine
aminotransferase; LDL-c, low-density lipoproteins cholesterol; HDL-c, high-density
lipoprotein cholesterol; TG, triglyceride; TC, total cholesterol; HBA1c, hemoglobin
A1c; BMI, body mass index; TIA, transient ischemia attack; DM, diabetes mellitus; Fig. 4. The nonlinear relationship between BUN and 3-month poor outcomes. A
AF, atrial fibrillation; CHD, coronary heart disease; NIHSS, national institute of nonlinear relationship was detected after adjusting for age, sex, RBC,PLT, Scr, AST, ALT,
health stroke scale; LAA, large artery atherosclerosis; SVO, small vessel occlusion; TG, LDL-c, HDL-c,HBA1c, BMI, hypertension, DM, smoking, AF, CHD, previous stroke or
CE, cardio embolism. TIA, NIHSS score, and stroke etiology.

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P. Zhou, R.-l. Liu, F.-x. Wang et al.
for age, sex, RBC,PLT, Scr, AST, ALT, TG, LDL-c, HDL-c,HBA1c, BMI,
hypertension, DM, smoking, AF, CHD, previous stroke or TIA, NIHSS
score, and stroke etiology (Log-likelihood ratio test P ¼ 0.037).
Using a two-stage linear regression model, the inflection point of
BUN detection was 13 mg/dl. When BUN 13 mg/dl, the authors
observed that low BUN levels were associated with increased risk
for poor outcomes (OR ¼ 0.859, 95%CI: 0.780e0.945, P ¼ 0.0019).
However, when BUN >13 mg/dl, the result showed that elevated
BUN levels might be associated with an increased risk of poor
outcomes, but the results were not statistically significant (OR:
1.014, 95%CI: 0.988 to 1.041, P ¼ 0.2973) (Table 5).
3.6. Sensitivity analysis
To verify the robustness of our findings, we performed a series of
sensitivity analyses. Firstly, the authors excluded participants with
hypertension in the sensitivity (n ¼ 689). The nonlinear relation-
ship between BUN and 3-month poor risk remain existed after
adjusting for age, sex, RBC,PLT, Scr, AST, ALT, TG, LDL-c, HDL-
c,HBA1c, BMI, hypertension, DM, smoking, AF, CHD, previous stroke
or TIA, NIHSS score, and stroke etiology. Using the recursive algo-
rithm, the inflection point of 11 mg/dl was first obtained, and then
the OR and CI around the inflection point were calculated using a
two-stage binary logistic regression model. On the left side of the
inflection point, the OR and 95%CI were 0.762 (0.607, 0.957). On the
right side of the inflection point, the OR and 95%CI were 0.978
(0.926, 1.034). Then, after excluding patients with CHD, AF, or hy-
pertension, similar phenomena can be observed (Fig. 5, Table 6).
The inflection points are all 12 mg/dl for excluding patients with
DM, AF, or CHD. These subgroup analyses indicate that low BUN
levels were associated with increased risk for poor outcomes on the
left side of the inflection point (all P < 0.05), whereas there is no
statistical significance on the right side of the inflection point (all
p > 0.05).
4. Discussion
The purpose of this study was to investigate the relationship
between BUN and the 3-month prognosis of AIS patients. Our re-
sults manifested that there was a nonlinear rather than linear
relationship between BUN at admission and 3-month outcomes.
Moreover, a threshold effect curve was observed, and different
correlations of BUN on 3-month outcomes were detected on both
sides of the inflection point. With 13 mg/dl as an inflection point for
BUN, patients with AIS have a remarkably different risk of 3-month
poor outcomes. When patients with BUN13 mg/dl, a 1 unit
decrease in BUN was related to a 14.1 % increase in the risk of 3-
month poor outcomes (OR ¼ 0.859, 95 % CI: 0.780 to 0.945).
However, when patients with BUN >13 mg/dl at admission, their
relationship is uncertain and requires further research.
Previous studies suggest that BUN can serve as a predictive
factor for critically ill patients, even stronger than Scr and eGFR
[14e16,33]. Especially, Shoujiang et al. reported that the BUN was
closely associated with an increased risk of all-cause in-hospital
Table 5
The result of the two-piecewise linear regression model.
Unfavorable outcome: OR (95%CI)
Fitting model by standard linear regression 0.993 (0.970, 1.015)
Fitting model by two-piecewise Cox regression
Inflection point of BUN 13
13 0.859 (0.780, 0.945)
>13 1.014 (0.988, 1.041)
P for log-likelihood ratio test 0.003
OR, odds ratios; CI, confidence.
Clinical Nutrition ESPEN 59 (2024) 140e148
mortality in AIS patients, superior to Scr and eGFR [17]. In this
study, patients with elevated BUN (18.77 mg/dl) had a signifi-
cantly higher risk of in-hospital mortality. In our study, similarly,
patients with elevated BUN (Q4:19 mg/dl) had a significantly
increased risk of 3-month poor outcome (P < 0.001), and BUN is a
risk factor for 3-month poor outcome in univariate analysis. How-
ever, it was not suggested that BUN is an independent risk factor for
3-month poor outcome in multivariate regression analysis. The
most likely reason for this difference is that the dependent variable
was a 3-month poor outcome in our study. Compared to in-hospital
mortality, 3-month poor outcome is more complex as it is influ-
enced by more confounding factors. Even, the linear relationships
may not accurately reflect the correlation between BUN and 3-
month poor outcome. After classifying the BUN variables accord-
ing to quartiles, the multivariate adjustment model results show
that, taking the first quartile (Q1) as a reference, the second quartile
(Q2), the third quartile (Q3) and the fourth quartile (Q4) had OR
values of 0.67, 0.62 and 0.69, respectively. The OR values demon-
strates a downward trend from Q1 to Q3, and an upward trend from
Q3 to Q4. These all indicate that there may be a nonlinear rela-
tionship between the BUN and 3-month poor outcomes in AIS
patients. Therefore, we attempt to further explore the nonlinear
relationship between BUN and 3-month poor outcome.
In the present study, the authors used logistic regression with
cubic spline functions and smooth curve fitting (the cubic spline
smoothing) to test whether there is a nonlinear relationship be-
tween BUN and 3-month poor outcome. Ultimately, the authors
observed a non-linear association between BUN and the risk of
adverse 3-month outcomes. In addition, an inflection point of
13 mg/dl could be obtained, and then the OR and CI around the
inflection point were calculated by two piecewise logistic regres-
sion models. On the left side of the inflection point (13 mg/dl), the
OR (95%CI) was 0.859 (0.780e0.945) (Table 5). However, on the
right side of the inflection point (>13 mg/dl), this relationship was
not statistically significant. In addition, to verify whether this curve
relationship is robust, we excluded hypertension, DM, AF, and CHD
patients for subgroup analysis. After excluding patients with hy-
pertension, DM, AF, and CHD, these inflection points were 11 mg/dl,
12 mg/dl, 12 mg/dl and 12 mg/dl, respectively (Table 6). Meanwhile,
the relationship has statistical significance on the left side of the
inflection point, but not on the right side of the inflection point. In
other words, the curves of these subgroups are similar to the all
participants, and the inflection points are close to all participants.
Therefore, these results all prompt us to believe that the nonlinear
relationship between BUN and 3-month poor outcome is robust.
However, the reasons for the nonlinear relationship between
the BUN and the risk of 3-month poor outcomes in patients with
AIS are unclear. On the one hand, low BUN may imply insufficient
protein intake or even malnutrition [34], which may affect neuro-
logical repair. Beside, AIS is an acute metabolic stress state, espe-
cially when multiple systems are activated [35], resulting in a surge
in energy demand. Thus, Lower levels of BUN may deprive AIS
patients of the foundation for early neurological repair. On the
contrary, excessive energy and nutrient reserves exceed the needs
of early neural repair. On the other hand, the higher BUN reflects
the deterioration of patient hemodynamics [36], which also means
that the deteriorated hemodynamics become a key factor in poor
stroke prognosis and mortality [37,38].Therefore, on the left side of
P
the inflection point, there is a negative correlation between BUN
0.5231
and the probability of 3-month poor outcomes. On the right side of
the inflection point, the relationship is not statistically significant,
0.0019 possibly due to the worsening of the patient's condition and other
0.2973 confounding factors being more critical.
Several strengths of our study can be found. First, compared to
previous reports limited to linear relationships, our study is a
145
P. Zhou, R.-l. Liu, F.-x. Wang et al. Clinical Nutrition ESPEN 59 (2024) 140e148

Fig. 5. The nonlinear relationship between BUN and 3-month poor outcomes after excluding patients with hypertension(a), DM(b), AF(c), or CHD(d), respectively. In each subgroup,
the model is not adjusted for the stratification variable.

Table 6
The result of the two-piecewise linear regression model.

Unfavorable outcome: Patients without hypertension Patients without DM Patients without AF Patients without CHD
(n ¼ 689) (OR,95%CI,P) (n ¼ 1280) (OR,95%CI,P) (n ¼ 1469) (OR,95%CI,P) (n ¼ 1658) (OR,95%CI,P)

Fitting model by standard linear regression 0.954 (0.908, 1.003)0.0664 0.989 (0.961, 1.018)0.4638 0.983 (0.957, 1.010)0.2204 0.992 (0.968, 1.017)0.5268
Fitting model by two-piecewise Cox regression
Inflection point of BUN 11 12 12 12
Inflection point 0.762 (0.607, 0.957)0.0193 0.810 (0.703, 0.934)0.0036 0.847 (0.741, 0.969)0.0159 0.823 (0.724, 0.935)0.0027
> Inflection point 0.978 (0.926, 1.034)0.4364 1.011 (0.979, 1.045)0.5027 0.999 (0.969, 1.030)0.9628 1.01 1 (0.983, 1.039)0.4530
P for log-likelihood ratio test 0.050 0.005 0.0028 0.004

OR, odds ratios; CI, confidence.

DM, diabetes mellitus; AF, atrial fibrillation; CHD, coronary heart disease.

significant improvement. The authors examined nonlinear re-
lationships using GAM and smoothing curve fitting to determine
the optimal inflection point for the effect of BUN on 3-month poor
outcomes. Second, multiple imputation methods were used to
handle missing data to improve statistical power and reduce po-
tential bias. Third, these results were robustly checked by sub-
group analysis to ensure their reliability. In addition, the
application of BUN may be enhanced when considering the fact
that it is general laboratory data that are of low cost and easy to
accessible.
There are still some limitations in this work. First, this research
only included the Korean population. Therefore, these results of
this study using other geographic and ethnic groups require further
validation. Second, similar to the characteristics of all observational
studies, this work may have unmeasured or uncontrolled con-
founding covariates, although identified potential confounders

146
P. Zhou, R.-l. Liu, F.-x. Wang et al.
were controlled for. Third, some variable information was not
detailed. For example, the original research database provided age
stratified information in 10 intervals rather than the specific age of
the patient, which may have resulted in incomplete information on
variables. In the future, we can consider how to design our research
to obtain more accurate variable data.
In conclusion, this present study demonstrates a specific
nonlinear relationship and saturation effect between BUN and 3-
month poor outcome in the Korean AIS patients. When the BUN
was 13 mg/dl, the BUN was significantly negatively correlated
with the probability of 3-month poor outcomes. When BUN was
>13 mg/dl, their relationship was not statistically different. These
data are expected to provide reference for the clinicians to control
BUN. From a treatment perspective, maintaining the BUN at around
13 mg/dl can reduce the risk of 3-month poor outcome in AIS pa-
tients. Therefore, abnormal BUN can support identify high-risk
populations with 3-month poor outcome for AIS patients in
South Korea, and provides a decision-making basis for optimizing
ischemic stroke rehabilitation.
Author's contribution
Pan Zhou: data analysis and manuscript draft; Ren-li Liu and
Fang-xi Wang: critical revision of the manuscript for important
intellectual content; Hao-fei Hu: study concept and design; Zhe
Deng: administrative, technical, and material support and study
supervision.
Funding source
This study was supported by Shenzhen Science and Technology
Program (JCYJ20180228163014668). Shenzhen Second People's
Hospital Clinical Research Fund of Guangdong Province High-level
Hospital Construction Project (Grant No.20223357005 & No.2023-
xgyj3357002).
Declaration of competing interest
The authors declare that they have no conflict of interest.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.clnesp.2023.12.001.
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