Skip to main content
Download PDF

The prognostic value of combined uric acid and neutrophil-to-lymphocyte ratio in acute ischemic stroke patients treated with intravenous thrombolysis

BMC Neurology volume 24, Article number: 183 (2024) Cite this article

Abstract

Background

Serum uric acid (UA) and the neutrophil-to-lymphocyte ratio (NLR) have been reported to be associated with outcomes in acute ischemic stroke (AIS). However, whether UA is related to the prognosis of AIS patients undergoing intravenous thrombolysis (IVT) remains inconclusive. We sought to explore the combined effect of UA and NLR on the prognosis of AIS treated with IVT.

Methods

A total of 555 AIS patients receiving IVT treatment were enrolled. Patients were categorized into four groups according to the levels of UA and NLR: LNNU (low NLR and normal UA), LNHU (low NLR and high UA), HNNU (high NLR and normal UA), and HNHU (high NLR and high UA). Multivariable logistic regression analysis was used to evaluate the value of serum UA level and NLR in predicting prognosis. The primary outcomes were major disability (modified Rankin scale (mRS) score 3–5) and death within 3 months.

Results

After multivariate adjustment, a high NLR (≥ 3.94) increased the risk of 3-month death or major disability (OR, 2.23; 95% CI, 1.42 to 3.55, p < 0.001). However, there was no statistically significant association between a high UA level (≥ 313.00 µmol/L) and clinical outcome. HNHU was associated with a 5.09-fold increase in the risk of death (OR, 5.09; 95% CI, 1.31–19.83; P value = 0.019) and a 1.98-fold increase in the risk of major disability (OR, 1.98; 95% CI 1.07–3.68; P value = 0.030) in comparison to LNNU.

Conclusions

High serum UA levels combined with high NLR were independently associated with 3-month death and major disability in AIS patients after IVT.

Peer Review reports

Introduction

Acute ischemic stroke (AIS) remains the second leading cause of both disability and death worldwide. Intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator (rt-PA) is considered to be the most effective medical reperfusion treatment within 4.5 h of symptom onset in AIS patients. However, the prognosis of patients with AIS after IVT may be affected by modifiable factors such as C-reactive protein, white blood cell count and neutrophil-lymphocyte ratio (NLR) [1,2,3,4]. Hence, useful biomarker detection is essential for early risk assessment and effective treatment after IVT.

Uric acid (UA), the end product of purine metabolism in humans, is a major endogenous antioxidant with neuroprotective effect in the blood and an easily detectable and reliable biomarker in clinical practice [5]. However, it can also act as a pro-oxidant depending on the chemical microenvironment [6]. The role of UA in the prognosis of stroke is also conflicting [7]. With respect to preclinical studies, when serum UA levels were elevated, reduced brain damage and improved functional outcome were shown in a transgenic mouse (UOX+/-) model of focal ischemic stroke [8]. Moreover, a systematic review and meta-analysis of rodent data showed that UA significantly reduced infarct size and neurofunctional deficits [9]. With regard to AIS patients, the tertiary analysis of the URICO-ICTUS trial suggested that the combination of rt-PA and UA may prevent early ischemic deterioration [10]. In addition, a low serum UA level at Days 3 and 4 of onset was reported to be negatively associated with DWI volume at diagnosis [11]. Nevertheless, a retrospective study suggested that a high level of UA [≥ 340 µmol/L (5.712 mg/dl)] was related to stroke recurrence in older patients [12]. Furthermore, a U-shaped relationship between UA and functional outcomes in patients with AIS was found by Zhang and colleagues [13]. Patients with higher serum UA levels (> 380 µmol/L) or lower serum UA levels (≤ 250 µmol/L) were more likely to have a poor outcome compared to the baseline group (UA level 316–380 µmol/L). Some prospective cohort studies demonstrated that higher serum uric acid levels were associated with 3-month better functional outcome in AIS patients with IVT [14, 15]. Notably, a meta-analysis showed that there was no significant correlation between serum UA levels and the prognosis of AIS [16]. Thus, it is important to clarify the relationship between UA and the prognosis of AIS patients undergoing IVT [7, 17]. The inflammatory response plays an essential role in the pathophysiology of AIS. After AIS, the number of circulating neutrophils increases while the number of lymphocytes decreases, leading to an increased NLR. The NLR has become a relatively popular marker of inflammation. Previous studies have shown that the admission NLR could be a predictor of major disability and mortality [18]. A recent study demonstrated that the Day 1 NLR was better than the admission NLR as a biomarker for predicting AIS outcome after reperfusion treatment [19]. An additive interaction between serum UA and NLR in ischemic stroke recurrence was found in a population study [12]. Consistent with the results, the positive additive interaction between UA and NLR was also observed in cardiac death plus reinfarction for coronary artery disease patients [20]. However, the relationship between the combined effect of UA and NLR and the prognosis of AIS patients after IVT is not clear.

In the present study, we examined whether the serum UA level was associated with prognosis and further investigated the combined effect of UA and NLR on outcomes in AIS patients after IVT.

Materials and methods

Study participants

From May 2010 to May 2017, we consecutively enrolled AIS patients treated with intravenous rt-PA (Boehringer Ingelheim, Germany) within 4.5 h of onset and who were from the Soochow Stroke Registry system at our comprehensive stroke center in Suzhou, China. rt-PA was used according to the specific guidelines. The methods of participant enrollment have been described previously [2]. The exclusion criteria were as follows: an unclear time of symptom onset, diagnosis of a tumor, stroke mimics and incomplete clinical data. Finally, a total of 555 AIS patients receiving rt-PA treatment were retrospectively enrolled. Patients receiving intravenous rt-PA plus mechanical thrombectomy were not enrolled in the study. 28 patients who underwent surgery for acute brain edema were also not included in the study. Routine antithrombotic agents and additional medications were given as needed 24 h after thrombolysis, as described in our previous publication [2]. The study protocol was approved by the Ethics Committee of the Second Affiliated Hospital of Soochow University(JD-HG-2023-81), and informed consent was obtained from all participants or patient care providers.

Data collection

Demographic characteristics, lifestyle risk factors, medical history, clinical laboratory tests and imaging (computed tomography and magnetic resonance imaging) were collected at the time of enrollment. A standard questionnaire was administered by trained staff to obtain all this information. The National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin Scale (mRS) were used to assess stroke severity by trained neurologists. NIHSS scores at admission and 24 h after IVT were obtained, and mRS scores at admission and 3 months were obtained. According to the Trial of Org 10,172 in the Acute Stroke Treatment (TOAST) criteria, stroke etiology was determined based on a review of all medical records during hospitalization. All serum biochemical parameters were measured at admission using an Olympus Au5400 automatic biochemical analyzer (First Chemical Co., Ltd., Japan).

Outcome assessment

The primary outcome was defined as the composite of death or major disability (mRS score 3–6) at the 3-month follow-up. The secondary outcomes included major disability (mRS score 3–5), odds of a 1-unit higher mRS and death. Deaths were reported by family members and/or were obtained from death certificates and medical records. The causes of death(neurological) in the study sample included cerebral hernia (28 patients), symptomatic intracranial hemorrhage (6 patients) and ischemic stroke (10 patients). The cause of death (non-neurological) in the study sample included myocardial infarction (3 patients), heart failure(3 patients), pneumonia(9 patients).

Statistical analysis

To evaluate the combined effect of UA and NLR on the prognosis of AIS treated with IVT, we divided the study subjects into four groups: those with a UA level lower than the median and an NLR level lower than the median; those with a UA level lower than the median and an NLR level higher than the median; those with a UA level higher than the median and an NLR level lower than the median; and those with a UA level higher than the median and an NLR level higher than the median. Continuous variables were expressed as the mean ± standard deviation (SD) or as the median (interquartile range, IQR) and were compared using analysis of variance or the Wilcoxon rank-sum test. Categorical variables were expressed as the frequency (percent) and were compared using the chi-square test. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by using a logistic regression model. Potential covariates such as age, sex, time from onset to thrombolysis, current smoking, alcohol consumption, admission NIHSS score, systolic blood pressure, plasma glucose, history of hyperlipidemia, hypertension, coronary heart disease, stroke, diabetes mellitus, and stroke subtypes were adjusted for in the multivariate model. A sensitivity analysis was performed to test the robustness of our findings. The continuous and categorical net reclassification index (NRI) and integrated discrimination improvement (IDI) were calculated to evaluate the predictive value of adding the combination of NLR and UA to conventional risk factors. A 2-sided p value < 0.05 was established as the level for statistical significance. All analyses were conducted using SAS statistical software (version 9.4, Cary, North Carolina, USA).

Results

Characteristics of the study population and clinical outcomes for binary of UA and NLR

The characteristics of the study patients are presented in Table 1. The patients with both high NLR and UA (HNHU group) accounted for 25% of the total studied participants. In comparison to the LNNU group, the HNHU group was more likely to be older and have higher admission NIHSS and mRS scores. In addition, HNHU patients differed in sex, current smoking, admission systolic blood pressure and metabolic profile. After adjusting for age, sex, time from onset to thrombolysis, current smoking, alcohol consumption and other covariates, a high NLR (≥ 3.94) was found to be an independent predictor of death or major disability (OR, 2.23; 95% CI, 1.42 to 3.55, p < 0.001; Table 2). Similar associations between a high NLR (≥ 3.94) and secondary outcomes are shown in Table 2. However, no statistically significant association between high UA level (≥ 313.00 µmol/L) and clinical outcome was detected.

Table 1 Characteristics of the participants according to NLR and UA among AIS patients after IVT
Full size table
Table 2 ORs and 95% CI of clinical outcomes for binary of UA and NLR among AIS patients after IVT
Full size table

The association of NLR and UA with clinical outcomes

The association of NLR and UA with clinical outcomes among AIS patients after IVT is presented in Table 3. In the multivariate analysis, the HNHU group demonstrated a 5.09-fold increase in the risk of death (95% CI 1.31–19.83; P value = 0.019; Table 3) in comparison to the LNNU group after multivariate adjustment. Similarly, the HNHU group exhibited a 1.98-fold increase in the risk of major disability (95% CI 1.07–3.68; P value = 0.030; Table 3). However, the HNNU group was not linked to death (OR, 3.72; 95% CI 0.93–14.87; P value = 0.064; Table 3) or major disability (OR, 1.60; 95% CI 0.87–2.94; P value = 0.128; Table 3).

Table 3 Combined effects of NLR and UA on clinical outcomes among AIS patients after IVT
Full size table

Reclassification and discrimination statistics for clinical outcomes by combination of NLR and UA

Table 4 shows whether adding the combination of NLR and UA to conventional risk factors improved the risk prediction of prognosis. Adding the combination of NLR and UA to the conventional model significantly improved the discriminatory power for death or major disability (continuous net reclassification index 43.76%; integrated discrimination improvement 2.04%), major disability (continuous net reclassification index 27.17%) and death (continuous net reclassification index 58.16%; integrated discrimination improvement 1.89%).

Table 4 Reclassification and discrimination statistics for clinical outcomes by combination of NLR and UA among AIS patients after IVT
Full size table

Discussion

Our study showed that concurrent high NLR and high serum UA levels are associated with increased risks of 3-month major disability and death. But there is no significant correlation between serum UA level and the prognosis of AIS patients with IVT.

An observational study showed that each milligram per deciliter increase in serum UA was associated with a 12% increase in the odds of good clinical outcome in patients with AIS [21]. Subsequently, in a rat model of thromboembolic stroke, exogenous administration of UA extended the benefits of rt-PA [22]. Likewise, a pilot trial showed that an infusion of 1 g UA following rt-PA reduced circulating biomarkers related to poor clinical outcomes without serious adverse effects [23]. In a subsequent clinical study, an intravenous infusion of 1 g UA was given in combination with rt-PA infusion. The proportion of patients with excellent outcome (an mRS score of 0–1, or an mRS score of 2 if the premorbid mRS was 2, at 90 days) was not significantly different between the UA group and placebo group [24]. The reanalysis of the clinical trial revealed that UA administration significantly elevated the proportion of excellent outcomes in women but not in men and that UA may prevent early ischemic stroke progression [10]. However, serum UA levels were not measured in that clinical trial, resulting in an unknown magnitude and duration of UA elevation following UA administration. A recent study showed that a high baseline UA level was positively associated with a good 3-month outcome in acute ischemic stroke patients with reperfusion therapy [25]. According to baseline UA levels, patients were classified into three tertiles: T1 (123–303 µmol/L), T2 (304–385 µmol/L) and T3 (385–704 µmol/L). The grouping method and selection of the study population may explain the inconsistent findings between our study and the study above. Therefore, more studies are needed to further investigate the relationship between serum UA and the prognosis of AIS patients after IVT.

The NLR is significantly associated with clinical outcomes in AIS. Meta-analyses have shown that an elevated NLR is correlated with an increased risk of ischemic stroke, unfavorable functional outcome at 3 months and increased mortality [26]. Our results showed that a high NLR level was an independent predictor for poor clinical outcome in AIS after IVT, and this is in line with our previous study [2].

The correlation between UA and NLR has gained substantial attention recently. One study showed that the NLR was positively correlated with UA in patients with chronic kidney disease [27]. However, in a study on multiple sclerosis, a negative correlation was observed between the NLR and UA [28]. The findings of the same study indicated that combined evaluation of NLR and UA may be a more effective approach in determining disability in patients with multiple sclerosis than assessing these parameters separately. These studies showed that there is a correlation between UA and the NLR, but this correlation may vary in different diseases. Previous studies have demonstrated that both UA and NLR are closely related to AIS, but few studies have examined UA, NLR, and AIS together. A recent study suggested that patients with high UA and high NLR levels are at greater risk for AIS recurrence [12]. Our study explored the combined effect of NLR and UA on the outcomes of AIS patients after IVT, and we found that high NLR and serum UA levels are associated with increased risks of 3-month major disability and death. The possible mechanisms are oxidation and inflammation.

In general, the reference interval of serum UA is 1.5 to 6.0 mg/dl in women and 2.5 to 7.0 mg/dl in men. Hyperuricemia is defined as a serum UA level greater than 6.0 mg/dL in women and 7.0 mg/dL in men [29]. Only suitable concentrations of serum UA may have a protective effect. In our study, the demarcation point of UA was 313 µmol/L (5.3 mg/dl). One dose‒response study showed a J-shaped trend between ascending UA levels and a higher risk of suffering from ischemic stroke. When the UA reached 5.25 mg/dl, it started to become statistically significant [30]. Therefore, it is reasonable to speculate that the high level of UA (> 5.3 mg/dl) acts as a pro-oxidant. A previous experimental study showed that increased UA (> 6 mg/dl) was associated with endothelial dysfunction and increased oxidative stress [31].

UA can also induce inflammation. A population study reported a positive relationship between serum UA and acute-phase reactants, such as C-reactive protein, fibrinogen and complement C3 [32]. The same study also examined the effect of UA on the expression of inflammatory biomarkers in vitro and found that hyperuricemia might induce inflammation by activating the proinflammatory NF-κB signaling cascade. Another study found that hyperuricemia (up to 50 mg/dL) can exacerbate chronic inflammation by altering the balance of interleukin-1β/interleukin-1Ra [33]. Moreover, elevated UA (9 mg/dl) was reported to induce vascular inflammation by upregulating the (pro) renin receptor in human umbilical vein endothelial cells [34]. Inflammatory biomarkers such as C-reactive protein and fibrinogen are upregulated following AIS [2]. The correlations of these biomarkers with increased mortality and poor functional outcome of stroke have been reported. Thus, we speculate that high UA may exacerbate poor prognosis in AIS patients with a high NLR through oxidation and inflammation.

UA and NLR were easily accessible biomarkers of oxidative stress and inflammation from daily blood examinations and can be easily translated into clinical practice. To date, no studies have investigated the relationship between the combined effect of UA and NLR and the outcomes of AIS patients after IVT. This is the innovative point and a major strength of this research. However, several limitations should also be noted. First, this study was a single-center study, and the population was relatively small, which may limit the generalization of our findings. Second, a subgroup analysis with stratification by sex was not performed to assess the effect of UA on the prognosis of AIS patients after IVT. Third, UA and NLR levels were only measured at admission. Without consecutive measurements, we have no data to examine the correlation between UA and NLR variations and stroke prognosis. Last, A clinical study showed that cerebral infarcts in the territory of the anterior cerebral artery have a better prognosis than infarcts in the territory of the middle cerebral artery [35]. It is reasonable to investigate the effect of the combination of uric acid and neutrophil-to-lymphocyte ratio on the different vascular cerebral topographies. Since cerebral infarcts in the ACA territory were infrequent, there was not a sufficient sample size in our study to conduct tratified analysis of different infarcted areas. Future studies are necessary to explore the effect of the combination of uric acid and neutrophil-to-lymphocyte ratio on the different vascular cerebral topographies.

Conclusion

There might be no significant association between UA and the prognosis of AIS patients with IVT. The combination of high UA and high NLR may be a predictor of 3-month death and major disability in AIS patients with IVT. This study suggests that strict control of UA and inflammatory parameters may help to improve outcomes for patients with ischemic stroke.

Data availability

The datasets used and analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

UA:

Serum uric acid

NLR:

Neutrophil-to-lymphocyte ratio

AIS:

Acute ischemic stroke

rt-PA:

Recombinant tissue plasminogen activator

IVT:

Intravenous thrombolysis

NIHSS:

National Institutes of Health Stroke Scale

Mrs:

Modified Rankin Scale

TOAST:

Trial of Org 10172 in the Acute Stroke Treatment

SD:

Standard deviation

IQR:

Interquartile range

OR:

Odds ratio

CI:

Confidence interval

NRI:

Net reclassification index

IDI:

Integrated discrimination improvement

References

  1. Cheng Y, Luo J, Lin Y, Zeng Y, Yu J, Lin Y. Impact of hyperglycaemia on complications in patients who had a stroke after thrombolysis. Postgrad Med J. 2021;97 1154:792–7. https://doi.org/10.1136/postgradmedj-2020-138736.

    Article  Google Scholar 

  2. Shi J, Peng H, You S, Liu Y, Xu J, Xu Y, et al. Increase in neutrophils after recombinant tissue plasminogen activator thrombolysis predicts poor functional outcome of ischaemic stroke: a longitudinal study. Eur J Neurol. 2018;25(4):687–e45. https://doi.org/10.1111/ene.13575.

    Article  CAS  PubMed  Google Scholar 

  3. Liu Y, Li G, Jia J, Liu X, Guo J, Zhao X. Clinical significance of neutrophil to lymphocyte ratio in ischemic stroke and transient ischemic attack in young adults. BMC Neurol. 2022;22(1:481). https://doi.org/10.1186/s12883-022-03011-7.

  4. Wang C, Zhang Q, Ji M, Mang J, Xu Z. Prognostic value of the neutrophil-to-lymphocyte ratio in acute ischemic stroke patients treated with intravenous thrombolysis: a systematic review and meta-analysis. BMC Neurol. 2021;21(1:191). https://doi.org/10.1186/s12883-021-02222-8.

  5. Campbell BC, Davis SM, Donnan GA. Uric acid for stroke: glimmer of hope or false dawn? Lancet Neurol. 2014;13 5:440–1. https://doi.org/10.1016/S1474-4422(14)70019-5.

    Article  Google Scholar 

  6. Vassalle C, Mazzone A, Sabatino L, Carpeggiani C. Uric Acid for Cardiovascular Risk: Dr. Jekyll or Mr. Hide? Dis. 2016;4(1:12). https://doi.org/10.3390/diseases4010012.

  7. Zhang Y, Churilov L, Meretoja A, Teo S, Davis SM, Yan B. Elevated urea level is associated with poor clinical outcome and increased mortality post intravenous tissue plasminogen activator in stroke patients. J Neurol Sci. 2013;332(1–2):110–5. https://doi.org/10.1016/j.jns.2013.06.030.

    Article  CAS  PubMed  Google Scholar 

  8. Cutler RG, Camandola S, Feldman NH, Yoon JS, Haran JB, Arguelles S, et al. Uric acid enhances longevity and endurance and protects the brain against ischemia. Neurobiol Aging. 2019;75:159–68. https://doi.org/10.1016/j.neurobiolaging.2018.10.031.

    Article  CAS  PubMed  Google Scholar 

  9. Aliena-Valero A, Baixauli-Martín J, Castelló-Ruiz M, Torregrosa G, Hervás D, Salom JB. Effect of uric acid in animal models of ischemic stroke: a systematic review and meta-analysis. J Cereb Blood Flow Metab. 2021;41(4):707–22. https://doi.org/10.1177/0271678x20967459.

    Article  CAS  PubMed  Google Scholar 

  10. Amaro S, Laredo C, Renú A, Llull L, Rudilosso S, Obach V, et al. Uric acid therapy prevents early ischemic stroke progression: a tertiary analysis of the URICO-ICTUS Trial (Efficacy Study of Combined Treatment with Uric Acid and r-tPA in Acute ischemic stroke). Stroke. 2016;47 11:2874–6. https://doi.org/10.1161/strokeaha.116.014672.

    Article  Google Scholar 

  11. Fernández-Gajardo R, Matamala JM, Gutiérrez R, Lozano P, Cortés-Fuentes IA, Sotomayor CG. Relationship between infarct size and serum uric acid levels during the acute phase of stroke. PLoS ONE. 2019;14 7:e0219402. https://doi.org/10.1371/journal.pone.0219402.

    Article  CAS  Google Scholar 

  12. Zhu HY, Zhao SZ, Zhang ML, Wang Y, Pan ZM, Cheng HR, et al. Elevated serum uric acid increases the risk of ischemic stroke recurrence and its inflammatory mechanism in older adults. Front Aging Neurosci. 2022;14:822350. https://doi.org/10.3389/fnagi.2022.822350.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhang X, Huang ZC, Lu TS, You SJ, Cao YJ, Liu CF. Prognostic significance of uric acid levels in ischemic stroke patients. Neurotox Res. 2016;29 1:10–20. https://doi.org/10.1007/s12640-015-9561-9.

    Article  CAS  Google Scholar 

  14. Sun Z, Feng J, He M, Wang M, Zhang Y, Wang N, et al. Higher uric acid is associated with better discharge recovery and short-term outcome in stroke patients treated with thrombolysis. Neurol Sci. 2021;42 8:3225–31. https://doi.org/10.1007/s10072-020-04919-z.

    Article  Google Scholar 

  15. Amaro S, Urra X, Gomez-Choco M, Obach V, Cervera A, Vargas M, et al. Uric acid levels are relevant in patients with stroke treated with thrombolysis. Stroke. 2011;42(1 Suppl):S28–32. https://doi.org/10.1161/STROKEAHA.110.596528.

    Article  CAS  PubMed  Google Scholar 

  16. Zhang M, Wang Y, Wang K, Yin R, Pan X, Ma A. Association between uric acid and the prognosis of acute ischemic stroke: a systematic review and meta-analysis. Nutr Metab Cardiovasc Dis. 2021;31 11:3016–23. https://doi.org/10.1016/j.numecd.2021.07.031.

    Article  CAS  Google Scholar 

  17. Cheng Z, Zhan Z, Fu Y, Zhang WY, Xia L, Xu T, et al. U-Shaped Association between serum Uric Acid and Hemorrhagic Transformation after Intravenous Thrombolysis. Curr Neurovasc Res. 2022;19 2:150–9. https://doi.org/10.2174/1567202619666220707093427.

    Article  CAS  Google Scholar 

  18. Liu YL, Wu ZQ, Qu JF, Qiu DH, Luo GP, Yin HP, et al. High neutrophil-to-lymphocyte ratio is a predictor of poor short-term outcome in patients with mild acute ischemic stroke receiving intravenous thrombolysis. Brain Behav. 2020;10 12:e01857. https://doi.org/10.1002/brb3.1857.

    Article  Google Scholar 

  19. Chen S, Cheng J, Ye Q, Ye Z, Zhang Y, Liu Y, et al. Day 1 neutrophil-to-lymphocyte ratio (NLR) predicts stroke outcome after intravenous thrombolysis and mechanical thrombectomy. Front Neurol. 2022;13:941251. https://doi.org/10.3389/fneur.2022.941251.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Del Turco S, Bastiani L, Minichilli F, Landi P, Basta G, Pingitore A, et al. Interaction of Uric Acid and Neutrophil-to-lymphocyte ratio for cardiometabolic risk stratification and prognosis in coronary artery Disease patients. Antioxid (Basel). 2022;11 11:2163. https://doi.org/10.3390/antiox11112163.

    Article  CAS  Google Scholar 

  21. Chamorro A, Obach V, Cervera A, Revilla M, Deulofeu R, Aponte JH. Prognostic significance of uric acid serum concentration in patients with acute ischemic stroke. Stroke. 2002;33 4:1048–52. https://doi.org/10.1161/hs0402.105927.

    Article  Google Scholar 

  22. Romanos E, Planas AM, Amaro S, Chamorro A. Uric acid reduces brain damage and improves the benefits of rt-PA in a rat model of thromboembolic stroke. J Cereb Blood Flow Metab. 2007;27 1:14–20. https://doi.org/10.1038/sj.jcbfm.9600312.

    Article  CAS  Google Scholar 

  23. Amaro S, Soy D, Obach V, Cervera A, Planas AM, Chamorro A. A pilot study of dual treatment with recombinant tissue plasminogen activator and uric acid in acute ischemic stroke. Stroke. 2007;38 7:2173–5. https://doi.org/10.1161/STROKEAHA.106.480699.

    Article  CAS  Google Scholar 

  24. Chamorro A, Amaro S, Castellanos M, Segura T, Arenillas J, Martí-Fábregas J, et al. Safety and efficacy of uric acid in patients with acute stroke (URICO-ICTUS): a randomised, double-blind phase 2b/3 trial. Lancet Neurol. 2014;13 5:453–60. https://doi.org/10.1016/s1474-4422(14)70054-7.

    Article  Google Scholar 

  25. Wang C, Cui T, Wang L, Zhu Q, Wang A, Yuan Y, et al. Prognostic significance of uric acid change in acute ischemic stroke patients with reperfusion therapy. Eur J Neurol. 2021;28 4:1218–24. https://doi.org/10.1111/ene.14643.

    Article  Google Scholar 

  26. Song SY, Zhao XX, Rajah G, Hua C, Kang RJ, Han YP, et al. Clinical significance of baseline neutrophil-to-lymphocyte ratio in patients with ischemic stroke or hemorrhagic stroke: an updated Meta-analysis. Front Neurol. 2019;10:1032. https://doi.org/10.3389/fneur.2019.01032.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Yilmaz G, Sevinc C, Ustundag S, Yavuz YC, Hacıbekiroglu T, Hatipoglu E, et al. The relationship between mean platelet volume and neutrophil/lymphocyte ratio with inflammation and proteinuria in chronic kidney disease. Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation. Saudi Arabia. 2017;28(1):90–4. https://doi.org/10.4103/1319-2442.198152.

    Article  Google Scholar 

  28. Bolayir A, Cigdem B, Gokce SF, Yilmaz D. The relationship between neutrophil/lymphocyte ratio and uric acid levels in multiple sclerosis patients. Bratisl Lek Listy. 2021;122 5:357–61. https://doi.org/10.4149/bll_2021_060.

    Article  Google Scholar 

  29. Maiuolo J, Oppedisano F, Gratteri S, Muscoli C, Mollace V. Regulation of uric acid metabolism and excretion. Int J Cardiol. 2016;213:8–14. https://doi.org/10.1016/j.ijcard.2015.08.109.

    Article  PubMed  Google Scholar 

  30. Qiao T, Wu H, Peng W. The relationship between elevated serum uric acid and risk of Stroke in Adult: an updated and dose-response Meta-analysis. Front Neurol. 2021;12:674398. https://doi.org/10.3389/fneur.2021.674398.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Li P, Zhang L, Zhang M, Zhou C, Lin N. Uric acid enhances PKC-dependent eNOS phosphorylation and mediates cellular ER stress: a mechanism for uric acid-induced endothelial dysfunction. Int J Mol Med. 2016;37 4:989–97. https://doi.org/10.3892/ijmm.2016.2491.

    Article  CAS  Google Scholar 

  32. Spiga R, Marini MA, Mancuso E, Di Fatta C, Fuoco A, Perticone F, et al. Uric acid is Associated with inflammatory biomarkers and induces inflammation Via activating the NF-κB signaling pathway in HepG2 cells. Arterioscler Thromb Vasc Biol. 2017;37 6:1241–9. https://doi.org/10.1161/atvbaha.117.309128.

    Article  Google Scholar 

  33. Crișan TO, Cleophas MC, Oosting M, Lemmers H, Toenhake-Dijkstra H, Netea MG, et al. Soluble uric acid primes TLR-induced proinflammatory cytokine production by human primary cells via inhibition of IL-1Ra. Ann Rheum Dis. 2016;75 4:755–62. https://doi.org/10.1136/annrheumdis-2014-206564.

    Article  CAS  Google Scholar 

  34. Yang X, Gu J, Lv H, Li H, Cheng Y, Liu Y, et al. Uric acid induced inflammatory responses in endothelial cells via up-regulating(pro)renin receptor. Biomed Pharmacother. 2019;109:1163–70. https://doi.org/10.1016/j.biopha.2018.10.129.

    Article  CAS  PubMed  Google Scholar 

  35. Arboix A, García-Eroles L, Sellarés N, Raga A, Oliveres M, Massons J. Infarction in the territory of the anterior cerebral artery: clinical study of 51 patients. BMC Neurol. 2009;9:30. https://doi.org/10.1186/1471-2377-9-30.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Not applicable. We have no acknowledgments to disclose.

Funding

This work was supported by the National Natural Science Foundation of China (82171296), the Suzhou Science and Technology Development Plan Project (SKY2023180), the Scientific Research Foundation of the Second Affiliated Hospital of Soochow University (SDFEYGJ2009), the Clinical Research Center of Neurological Disease of The Second Affiliated Hospital of Soochow University (ND2023B06), the Scientific research project of Xi’an Health Commission (2024yb48), and the Jiangsu Provincial Medical Key Discipline (ZDXK202217).

Author information

Author notes

  1. Chentao Wang, Meili Zhou and Tingting Kang contributed equally to this work.

  2. Jijun Shi and Weina Kong contributed equally.

Authors and Affiliations

  1. Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, 215004, China

    Chentao Wang, Meili Zhou, Shoujiang You, Yongjun Cao, Weina Kong & Jijun Shi

  2. Department of Neurology, The Nuclear Industry 417 Hospital, Xi’an, Shanxi Province, 710600, China

    Tingting Kang

  3. Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, 215004, China

    Shoujiang You, Yongjun Cao & Jijun Shi

Authors
  1. Chentao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Meili Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tingting Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shoujiang You
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yongjun Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Weina Kong
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jijun Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JJS, WNK and YJC: study concept and design. CTW, MLZ, TTK and SJY: Acquisition of data. CTW and JJS: statistical analysis and interpreted the data. JJS: study supervision. All authors approved the protocol.

Corresponding authors

Correspondence to Weina Kong or Jijun Shi.

Ethics declarations

Ethics approval and consent to participate

The study protocol was approved by the Ethics Committee of the Second Affiliated Hospital of Soochow University (JD-LK-2012-001-01) and performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Informed consent was obtained from all participants or patient care providers.

Consent for publication

Not applicable.

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

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, C., Zhou, M., Kang, T. et al. The prognostic value of combined uric acid and neutrophil-to-lymphocyte ratio in acute ischemic stroke patients treated with intravenous thrombolysis. BMC Neurol 24, 183 (2024). https://doi.org/10.1186/s12883-024-03628-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12883-024-03628-w

Keywords

BMC Neurology

ISSN: 1471-2377

Contact us