Impact of white blood cell count on the development of contrast-induced acute kidney injury in patients receiving percutaneous coronary intervention

Introduction

Contrast-induced acute kidney injury (CI-AKI) is a common complication arising among patients receiving percutaneous coronary intervention (PCI) and is associated with increased morbidity, mortality, and healthcare resource utilization (Davenport, Perazella & Nallamothu, 2023; Davenport et al., 2020; Gupta et al., 2005; McCullough et al., 2006; Rihal et al., 2002). PCI often requires the administration of an iodinated contrast medium, which is often cited as the cause of CI-AKI. The incidence of CI-AKI is 2% for the general population (Demircelik et al., 2015); however, patients receiving PCI are at higher risk of developing CI-AKI, and patients who also suffer from chronic kidney disease and/or diabetes have a risk of almost 50% (Finn, 2006; Goldfarb et al., 2009).

The prognostic impact of CI-AKI depends on the persistence of renal function deterioration and the degree of kidney injury (James et al., 2011; Maioli et al., 2012). Currently, there is no effective medication used to treat CI-AKI emphasizes the need for clinical efforts to prevent its development prior to diagnosis (Toso et al., 2014). Several conditions and factors, including diabetes, chronic kidney disease, anemia, advanced age, congestive heart failure, and using a large amount of contrast media (CM) in procedures, can increase a patient’s chances of developing CI-AKI (McCullough et al., 1997; Mehran et al., 2004; Wi et al., 2013).

The inflammation response has been found to significantly impact the development of CI-AKI (Demircelik et al., 2015; Kocas et al., 2015; Kurtul et al., 2016; Kwasa, Vinayak & Armstrong, 2014; Liu et al., 2012). White blood cell (WBC) count, leukocyte count, platelet-to-lymphocyte ratio, and WBC differential are widely recognized as indications of inflammation (Kocas et al., 2015; Shah et al., 2017; Sun et al., 2018). Shah et al. (2017) discovered an independent association between increased major adverse cardiovascular events (MACE) and baseline WBC count in patients undergoing PCI for acute coronary syndrome (ACS) and stable coronary artery disease. Yet, to our knowledge, no studies have investigated using WBC count as a predictor of CI-AKI risk in PCI patients. Thus, this study aimed to investigate the relationships between pre-procedure WBC count and CI-AKI incidence in patients with coronary artery disease receiving PCI.

Methods

The study protocol was approved by the ethics committee of the Third Xiangya Hospital of Central South University, and the approval number was R15006. Each of the subjects enrolled in this study provided informed consent to participate. We have received written informed consent from participants in our study. ClinicalTrials.gov identifier: NCT02888652. This study was performed according to the STROBE checklist.

Results

Two centers enrolled 1300 patients for PCI between September 2015 and July 2017. Eleven patients did not complete hydration and were excluded. In total, 1,013 patients met the study criteria (Fig. 1). In this study, all patients were given intravenous hydration. Of the total patients, 213 (21%) underwent emergency PCI and were treated with sodium bicarbonate for hydration.

All patients completed a follow-up evaluation at the one-year mark, either in person or via phone. Table 1 shows the baseline clinical characteristics stratified by CI-AKI, including patient demographics and clinical, biochemical, angiographic, and procedural variables. The incidence of CI-AKI was 4.8% (49/1013). Patients with CI-AKI (referred to as the “CI-AKI group” hereafter) had a significantly higher WBC count than those without CI-AKI (referred to as the “Non-CI-AKI group” hereafter) (10.41 ± 5.37 vs. 8.09 ± 3.10 10³ mL, respectively; P = 0.004) and had a significantly lower chance of having used statins (P = 0.022) compared with patients in the Non-CI-AKI group. Female patients, low blood pressure, peripheral vascular disease (PVD), intra-aortic balloon pump (IABP), heart failure (I-III), lower hemoglobin, and higher fasting glucose were more likely to develop CI-AKI. There were no significant differences in age, hypertension incidence, and type of coronary artery disease between the patients with and without CI-AKI.

Univariate and multivariate logistic regression analyses were used to analyze the effects of multiple variables, as presented in Table 2. Based on the outcomes of the univariate analyses, age ≥75 years, Female, PVD, LBP, ACS, DM, fasting glucose, PVD, eGFR <60 mL/min, heart failure(I-III), WBC count, P/L, Hb, IABP, EF, LDL, HDL, TC, use of Iohexol, and use of statins, were selected for multivariate logistic regression analyses. Apart from low Hb (OR 0.97,95% CI [0.95–0.99]; P =0.002), fasting glucose (OR 1.10,95% CI [1.00–1.20]; P =0.043), Iohexol (OR 4.55,95% CI [1.37–15.14]; P =0.014), WBC count (OR 1.12,95% CI [1.03–1.21]; P =0.006) remained significant and independent in predicting the occurrence of CI-AKI. The use of statins was identified as effective in preventing CI-AKI development (OR 0.24,95% CI [0.05–1.21]; P = 0.044).

ROC curve analysis of pre-procedural WBC count found that pre-procedural WBC count could be used to predict CI-AKI incidence. [area under the curve = 0.684 (95% confidence interval 0.545−0.723), P = 0.002] (Fig. 2). A cut-off value of ≥11.03 × 10 $\stackrel{ˆ}{}$9/L was identified as optimal in predicting CI-AKI incidence, providing a sensitivity of 41.0% and specificity of 86.5%.

The follow-up period ended in September 2018, with complete 12-month follow-up data for all patients. One-year mortality occurred in 27 patients (2.7%). The CI-AKI group had a significantly higher incidence of mortality (8.2% vs. 2.4% P = 0.037). In the multivariate analysis, one-year mortality was associated with CI-AKI (OR 3.47,95% CI [1.12–10.74]; P =0.031). The Kaplan–Meier cumulative survival curves of CI-AKI are shown in Fig. 3. Patients who developed CI-AKI had a significantly lower 1-year survival rate than those who did not (91.8% vs. 97.6%, P =0.012).

Discussion

The result of our study suggests that an increase in pre-procedure WBC count at the time of treatment may be related to the development of CI-AKI. In addition, the predictive power of pre-procedural WBC count was independent of other known clinical and laboratory-based predictors of CI-AKI. A count value of ≥11.03*10⁹/L was identified as the optimal cut-off value in the prediction of CI-AKI incidence, with a sensitivity of 41.0% and a specificity of 86.5%.

Some associated conditions and qualities, such as advanced age, anemia, congestive heart failure, diabetes, chronic kidney disease, and large amounts of CM in treatments, have been identified as essential factors predisposing patients to develop CI-AKI (McCullough et al., 1997; Mehran et al., 2004; Wi et al., 2013). Moreover, a number of popularized risk score models, such as the Bartholomew and Mehran scoring systems, have been developed to evaluate a patient’s risk of developing CI-AKI (Bartholomew et al., 2004; Mehran et al., 2004). However, these systems do not consider inflammatory factors and require a patient’s entire medical history to assess the risk, making them inconvenient for clinical practice. Clinicians need a sensitive, inexpensive, easily obtainable clinical indicator to assess a patient’s risk of CI-AKI prior to PCI.

Thus far, no adjunctive pharmaceutical has been found to effectively treat CI-AKI, which emphasizes the need for accurate clinical assessment methods to prevent CI-AKI development in patients. Evidence from both clinical and experimental studies supports the idea that statins can effectively prevent the development of CI-AKI (Han et al., 2014; Jia et al., 2009; Leoncini et al., 2014). Statins (including rosuvastatin and simvastatin) may be renoprotective via several mechanisms, including anti-inflammation, attenuation of endothelial dysfunction, anti-proliferation of mesangial cells, protection of podocytes, and inhibition of the uptake of contrast media into renal tubular cells (McCullough et al., 2016). The anti-inflammatory properties of statins are well-documented. Our study also demonstrates that standard dose statins administered in addition to standard hydration can reduce the incidence of renal injury. Statins can reduce the concentrations of pro-inflammatory cytokines and circulating C-reactive protein (CRP) and inhibit vascular reactive oxygen species (ROS) generation (Antoniades et al., 2011; Antoniades et al., 2010; Ascer et al., 2004; Bulcao et al., 2007; Van de Ree et al., 2003). The development of CI-AKI is said to be significantly influenced by inflammation. Gao et al. (2011) and Shacham et al. (2015) both found that CRP can increase CI-AKI incidence in patients receiving PCI. Test of WBC count, leukocyte count, and WBC differential are widely used as inexpensive indicators of inflammation. Our study supports the idea that these measures of inflammation are useful predictors of CI-AKI risk.

Inflammation is considered an independent risk factor in the development of CI-AKI. One of the most cost-effective markers used in detecting inflammation is WBC count. This study provides additional evidence of the clinical usefulness of a cost-effective and standard measure for potential risk stratification in patients undergoing PCI-related CI-AKI. Emerging evidence suggests that a more robust inflammatory and oxidative response is crucial in the development and progression of CI-AKI. Numerous studies have been conducted to evaluate the link between inflammation and the incidence of CI-AKI (Akin et al., 2015; Gao et al., 2011; Kurtul et al., 2016; Yuan et al., 2017). Yuan et al. (2017) found an association between various clinical measures (WBC count, N count, and CRP levels) and CI-AKI incidence in ACS patients who undergo PCI. Similarly, Gao et al. (2011) also found an association between CRP level and the incidence of CI-AKI in patients who underwent PCI. In accordance with these studies, we found that a higher pre-procedure WBC count was independently associated with the development of CI-AKI. Our findings align with the results of Yuan et al. (2017) but extend to the patients not diagnosed with ACS.

To date, the exact mechanism of CI-AKI development is poorly understood. Iodinated contrast media may cause AKI due to direct toxicity, endothelial dysfunction, oxidative stress, and hemodynamic changes (Sendeski, 2011). Although our study cannot fully clarify the plausible mechanism behind the association between higher pre-procedure WBC count and CI-AKI risk, we posit a hypothesis. After administering contrast media during PCI, the highly concentrated contrast media can restrict fluid flow through the medullary vessels and tubules, thus prolonging its contact with the vascular endothelium and the tubular epithelial cells (Akcay, Nguyen & Edelstein, 2009; Seeliger et al., 2012). As contrast media are commonly cytotoxic, this process causes damage to the tubular and endothelial cells, which as a result, the injured kidneys triggers the transport of various leukocytes, such as neutrophils, lymphocytes, macrophages, and natural killer cells. Such high concentrations of white blood cells can further enhance the generation of inflammatory mediators such as chemokines and cytokines in endothelial cells and tubular cells, contributing to the recruitment of more leukocytes in the kidneys (Akcay, Nguyen & Edelstein, 2009). There is a possibility that a higher pre-procedure WBC count combined with contrast media exposure during PCI could significantly increase the risk of CI-AKI.

The development of CI-AKI following PCI can affect both short- and long-term mortality, and morbidity and is an expensive complication (Caixeta & Mehran, 2010; Liu et al., 2023; McCullough et al., 2006; Rihal et al., 2002). Considering the prognostic implications of CI-AKI, the early identification of at-risk patients is extremely important. Emerging strategies such as minimalizing contrast media volume, intravascular volume repletion, intra-aortic balloon pump use, and statins use can significantly reduce CI-AKI risk in patients receiving emergency or elective PCI. ROC curve analysis showed that the baseline WBC count was effective in differentiating between patients who developed CI-AKI and those who did not, however, and so this may not be a significant issue. Using WBC counts to identify patients at higher risk would significantly reduce the number of patients developing CI-AKI and is a technique whose utilization should be strongly considered in clinical practice.

Conclusions

Our study confirmed that WBC count is an independent and powerful predictor of risk for CI-AKI in patients undergoing PCI. ROC curve analysis showed that a baseline WBC count of 11.03 was a fair preliminary indicator of creatinine increases, and patients who experienced CI-AKI had a notably lower 1-year survival rate compared to those who did not suffer from CI-AKI. There is mounting evidence supporting the use of WBC count as a prognostic marker for determining CI-AKI risk in patients who receive PCI (Shah et al., 2017). To effectively use this marker in clinical settings, further studies are needed to establish treatment options, identify anti-inflammatory medications, and compare its utility with other known inflammatory markers.

Limitations

This study is not without limitations. First, it is important to note, however, that this study was merely observational and was conducted in two medical centers with a small sample size which may have affected our results. Second, we excluded patients without measured plasma creatine upon admission or 24–72 h after PCI procedure, which may introduce selection bias. Third, C-reactive protein (CRP) is the important of inflammatory factor, However, we just test CRP levels in some high-risk patients. This study would be more convincing with a detailed analysis of cytokines, for example, TNF-α, IL1, and IL6 in the plasma. However, this is just an observation study, so we did not test TNF-α, IL1, and IL6 in patients. Finally, Some variables such as age, kidney disease, and diabetes mellitus in previous studies had no statistical significance in our study, which was perhaps because of the strict definition of CI-AKI we used.Patients who developed CI-AKI showed significant differences in their baseline as compared to those who did not. Despite controlling for potential confounding factors related to known comorbidities and drug use, we cannot completely eliminate the possibility of unmeasured confounders affecting our results. Therefore, our findings should be considered as a hypothesis for further confirmation through additional studies.

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