White blood cell count and the incidence of hyperuricemia: insights from a community-based study

Abstract

Hyperuricemia (HUA) is a risk factor for chronic kidney disease (CKD). The relationship between HUA and white blood cell (WBC) count remains unknown. A sampling survey for CKD was conducted in Sanlin community in 2012 and 2014. CKD was defined as proteinuria in at least the microalbuminuric stage or an estimated GFR of 60 mL/(min·1.73 m²). HUA was defined as serum uric acid>420 µmol/L in men and>360 µmol/L in women. This study included 1024 participants. The prevalence of HUA was 17.77%. Patients with HUA were more likely to have higher levels of WBC count, which was positively associated with HUA prevalence. This association was also observed in participants without CKD, diabetes mellitus, hyperlipidemia, or obesity. Multivariate logistic regression analysis showed that WBC count was independently associated with the risk for HUA in male and female participants. Compared with participants without HUA, inflammatory factors such as high-sensitivity C-reactive protein, tumor necrosis factor-α, and interleukin 6 increased in participants with HUA. Hence, WBC count is positively associated with HUA, and this association is independent of conventional risk factors for CKD.

Keywords

white blood cell count / hyperuricemia / chronic kidney disease / inflammation

Introduction

The incidence of chronic kidney disease (CKD) continuously increases, and its prevalence rate in China is 10.8%–11.8% [¹,²]. Effective prevention strategies for CKD must be developed to reduce the global burden of end-stage renal disease. Hyperuricemia (HUA) is one of the known risk factors for CKD [³]. Therefore, identifying the risk factors for HUA is a good way to prevent the occurrence of CKD.

Previous studies reported that age, gender, and body mass index (BMI) are the risk factors for HUA [⁴]. Uric acid (UA) has been recognized to be damaging because it activates cytosolic phospholipase A2 (cPLA2), inflammatory transcription factor nuclear factor-κB [⁵], tumor necrosis factor, monocyte chemotactic protein-1 [⁶], and cyclooxygenase-2 [⁷]. Some clinical studies showed that UA, white blood cells (WBCs), high-sensitivity C-reactive protein (hs-CRP), and lipoproteins are positively associated with subclinical thoracic atherosclerosis [⁸], cardiovascular disease (CVD) [⁹], and metabolic syndrome [¹⁰]. Additionally, UA levels are inversely associated with neutrophil ratios in patients suffering from stroke [¹¹]. However, the relationship between HUA and WBC remains unknown. Therefore, a community-based survey for CKD was conducted in Sanlin in 2012 and 2014. In this study, estimated GFR (eGFR) was calculated by the MDRD equation [¹²]. HUA was defined as serum UA>420 µmol/L in males and>360 µmol/L in females or a history of anti-HUA medication use [¹³]. Subjects with a diabetic history or those with fasting blood glucose>7 mmol/L or 2 h postprandial blood glucose>11 mmol/L were categorized as diabetic [¹]. CVD was defined as a history of myocardial infarction, chronic heart failure, left ventricular hypertrophy, and/or stroke/TIA. Hypertension was diagnosed as systolic blood pressure (SBP)≥140 mmHg or diastolic blood pressure (DBP)≥90 mmHg or a history of antihypertensive medication use [¹⁴]. The survey included 1156 participants, of which 1024 provided complete information. The mean age of the sample was 55.86 years. The survey included 116 participants who had CKD. The prevalence of HUA was 17.77% (182/1024).

WBC counts were elevated in participants with HUA

Table 1 shows the participants’ demographic characteristics and biochemical test results. In males, participants with HUA were more likely to have higher BMI (P<0.01), waist hip rate (WHR; P<0.01), BUN (P = 0.01), WBC count (P<0.01), hemoglobin (Hb; P = 0.01), prevalence of CVD (P = 0.02) and hyperlipidemia (P = 0.02), and lower eGFR (P<0.01). In females, participants with HUA were more likely to be older (P<0.01) and had higher SBP (P<0.01); DBP (P<0.01); BMI (P<0.01); WHR (P<0.01); BUN (P<0.01); WBC count (P<0.01); prevalence of diabetes (P = 0.03), hypertension (P<0.01), and hyperlipidemia (P<0.01); and lower eGFR (P<0.01).

WBC levels were positively associated with prevalence of HUA

To clarify the association between WBC levels and HUA, we classified all participants into sextile according to their WBC count: (2.80–4.80)×10⁹/L, (4.81–5.49)×10⁹/L, (5.50–6.07)×10⁹/L, (6.08–6.76)×10⁹/L, (6.77–7.74)×10⁹/L, and (7.75–14.1)×10⁹/L for quartile 1, 2, 3, 4, 5, and 6, respectively. We found a positive correlation between WBC count and HUA prevalence. The prevalence rate was 11.2% among participants with WBC count in the first level and increased to 13.50%, 17.60%, 12.90%, 24.7%, and 26.32% in levels 2, 3, 4, 5, and 6, respectively (P for trend<0.01; Table 2). This finding suggests that participants with higher WBC count are more likely to have HUA.

Association between WBC count and HUA was present in participants without CKD, DM, hyperlipidemia, or obesity

To explore whether the link between WBC count and HUA is independent of CKD, DM, hyperlipidemia, and obesity, we compared the WBC count between participants without CKD, DM, hyperlipidemia, or obesity. In participants without CKD, DM, hyperlipidemia, and/or obesity, WBC counts were significantly higher in HUA participants than in non-HUA participants. The results are shown in Table 3. These results suggest that the link between WBC count and HUA is not influenced by CKD, DM, hyperlipidemia, and obesity.

Elevated WBC counts were independently associated with increased risk of HUA

Fig.1 shows that after adjustment for age, WBC, SBP, DBP, BMI, WHR, BUN, Hb, red blood cell (RBC), eGFR, medical history (CVD, hypertension, DM, and hyperlipidemia), and health-related behaviors (cigarette smoking, alcohol drinking, and gym), participants with high WBC counts remained at increased risk for HUA (P for trend<0.01).

Gender is one of the major factors closely associated with HUA, so we divided the group by gender. To explore whether elevated WBC count was independently associated with increased risk for HUA, we performed a multivariate logistic regression analysis in four models adjusting for different variables. These models yielded similar findings. WBC count was a strong risk factor for HUA in males and females (Table 4). Additionally, we performed logistic regression in non-elderly (age<60 years) and elderly (age≥60 years) participants. We found that WBC count was significantly associated with risk for HUA in non-elderly (OR (95% CI) = 1.25 (1.08–1.43), P<0.01) and elderly (OR(95% CI) = 1.36 (1.09–1.69), P = 0.01) participants.

Inflammatory factors were increased in participants with HUA

WBC is an indicator of inflammation. We selected 81 participants randomly from the cohort. We detected the serum hs-CRP, tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), and IL-10 in participants with HUA (N = 38) and without HUA (N = 43). Compared with participants without HUA, Ln(hs-CRP) (4.04±0.84 ng/mL vs. 3.09±1.31 ng/mL, P<0.01), TNF-α (3.42±0.62 pg/mL vs 2.14±0.16 pg/mL, P = 0.05), and IL-6 (11.69±2.31 pg/mL vs. 5.14±1.74 pg/mL, P = 0.03) in participants with HUA were upregulated. However, no significant difference in IL-10 (P = 0.71) was observed between participants with HUA and without HUA (Fig. 2).

Discussion

This cross-sectional study revealed that compared with non-HUA patients, HUA patients had higher levels of WBC counts. Moreover, further analysis showed that WBC count was positively associated with incidence of HUA. This relationship was independent of age, gender, health-related behaviors (smoking, drinking, and gym), medical history (CVD, hypertension, DM, hyperlipidemia), and laboratory tests (SBP, DBP, BMI, BUN, Hb, WBC, eGFR). This study also found that WBC count was a risk factor for HUA independent of conventional CKD risk factors.

Previous studies showed that age, gender, BMI, WHR, and CVD were risk factors for HUA. Recently, circulating inflammatory cell counts and atherosclerosis were independently related with UA [¹⁵]. Su et al. [¹⁶] analyzed 522 male and 255 female subjects and found a significant relationship between the level of UA and WBC count, RBC count, and Hb. In our study, we found that WBC count was positively associated with the incidence of HUA by logistic analysis, and this association was independent of conventional CKD risk factors. Furthermore, we checked our conclusion by linear regression in our data. When adjusted for age, SBP, DBP, BMI, WHR, and WBC count, Hb and WBC were independent risk factors. However, when adjusted for age, SBP, DBP, BMI, WHR, WBC and RBC count, and eGFR, WBC was an independent risk factor. We confirmed that WBC count was an important independent risk factor for HUA in people with or without CKD.

The role of WBC count in other diseases has been studied. An analysis that involved 18 907 subjects over the age of 65 years showed that WBC was associated with metabolic syndrome regardless of gender [¹⁷]. Consistent with this result, a strong relationship between WBC count and features of metabolic syndrome independent of smoking in Japanese men was found [¹⁸]. Also, previous study found that elevated WBC count was associated with arterial stiffness [¹⁹]. Additionally, a similar relationship was found in diseases such as stroke [¹¹], diabetes [²⁰,²¹], hypertension [²²], and CVD [²³].

WBCs function as “cleaner,” and they clear inflammatory cytokines. They are an indicator of inflammation. We found that compared with participants without HUA, inflammatory factors such as TNF-α and IL-6 were increased in participants with HUA. However, the mechanism by which UA influences the inflammation is unknown. Under physiological concentrations, UA is a powerful antioxidant that can scavenge superoxides, hydroxyl radicals, and singlet oxygen [²⁴]. UA also acts as a proinflammatory factor and activates cytoplasmic phospholipase A2 and inflammatory transcription factors in renal proximal tubule cells [⁵]. Other studies reported that increasing serum UA levels are accompanied with TNF-α [²⁵], monocyte chemotactic protein-1 in the kidney [⁶], and cyclooxygenase-2 in blood vessels [⁷]. Ruggiero et al. found that UA was positively and significantly associated with several inflammatory markers in 957 healthy elderly subjects [²⁶]. These studies indicated that the relationship between WBC count and HUA can be explained by the activation of inflammation.

Summary

This cross-sectional study, involving a large Chinese population, revealed that WBC count was positively associated with HUA, and this association was independent of CKD conventional risk factors.

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