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, 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.