The Predictive Role of Systemic Inflammatory Markers in the Development of Acute Kidney Failure and Mortality in Patients with Abdominal Trauma

Background: Abdominal trauma is defined as a variety of injuries to the abdominal wall, solid or hollow intra-abdominal organs, and various intra-abdominal vessels. Recently, there has been a significant amount of interest in the establishment of a reliable biomarker that can predict the outcome in patients with an abdominal injury. The purpose of this study is to confirm the predictive role of inflammatory biomarkers and underlying risk factors and the risk of acute kidney insufficiency (AKI) developing and mortality in abdominal trauma patients; Materials and methods: The current study was intended as an observational, analytical, retrospective cohort study and included all patients over 18 years of age with a diagnosis of abdominal trauma confirmed through a CT scan admitted to the County Emergency Clinical Hospital of Targu-Mureș, Romania between January 2017, and December 2021; Results: Non-survivor patients had a greater age (p = 0.02), as well as a higher prevalence of ischemic heart disease (IHD) (p = 0.007), history of myocardial infarction (MI) (p = 0.002), peripheral arterial disease (PAD) (p = 0.01), chronic kidney disease (CKD) (p = 0.01), and all risk factors (p = 0.0004 and p < 0.0001). In terms of injured organs, we have in the second group a higher incidence of kidney injury (p = 0.003) and hemoperitoneum (p = 0.008). Multivariate analysis showed a high baseline value for all inflammatory biomarkers that are independent predictors of adverse outcomes for all recruited patients. Furthermore, for all hospitalized patients, the history of MI (p = 0.03; p = 0.001; and p = 0.003), PAD (p = 0.01; p = 0.01; and p = 0.002), obesity (for all p < 0.0001), CKD (p < 0.001; p = 0.01; and p = 0.001), and kidney injury (p = 0.02; p = 0.004; and p = 0.01) were independent predictors of all outcomes. Moreover, IHD (p = 0.008 and p = 0.02), tobacco (p < 0.0001 and p = 0.02), and hemoperitoneum (p = 0.009 and p = 0.01) were predictors of mortality and composite endpoint, but not for AKI risk, as well as atrial fibrillation [AF] (p = 0.04) as predictors of the composite endpoint Conclusions: Higher monocyte to lymphocyte ratio (MLR), platelets to lymphocyte ratio (PLR), systemic inflammatory index (SII), neutrophil to lymphocyte ratios (NLR), aggregate inflammatory systemic index (AISI), and systemic inflammatory response index (SIRI) levels at admission, according to our data, highly predict AKI risk and death.

Abstract: Background: Abdominal trauma is defined as a variety of injuries to the abdominal wall, solid or hollow intra-abdominal organs, and various intra-abdominal vessels. Recently, there has been a significant amount of interest in the establishment of a reliable biomarker that can predict the outcome in patients with an abdominal injury. The purpose of this study is to confirm the predictive role of inflammatory biomarkers and underlying risk factors and the risk of acute kidney insufficiency (AKI) developing and mortality in abdominal trauma patients; Materials and methods: The current study was intended as an observational, analytical, retrospective cohort study and included all patients over 18 years of age with a diagnosis of abdominal trauma confirmed through a CT scan admitted to the County Emergency Clinical Hospital of Targu-Mures , , Romania between January 2017, and December 2021; Results: Non-survivor patients had a greater age (p = 0.02), as well as a higher prevalence of ischemic heart disease (IHD) (p = 0.007), history of myocardial infarction (MI) (p = 0.002), peripheral arterial disease (PAD) (p = 0.01), chronic kidney disease (CKD) (p = 0.01), and all risk factors (p = 0.0004 and p < 0.0001). In terms of injured organs, we have in the second group a higher incidence of kidney injury (p = 0.003) and hemoperitoneum (p = 0.008). Multivariate analysis showed a high baseline value for all inflammatory biomarkers that are independent predictors of adverse outcomes for all recruited patients. Furthermore, for all hospitalized patients, the history of MI (p = 0.03; p = 0.001; and p = 0.003), PAD (p = 0.01; p = 0.01; and p = 0.002), obesity (for all p < 0.0001), CKD (p < 0.001; p = 0.01; and p = 0.001), and kidney injury (p = 0.02; p = 0.004; and p = 0.01) were independent predictors of all outcomes. Moreover, IHD (p = 0.008 and p = 0.02), tobacco (p < 0.0001 and p = 0.02), and hemoperitoneum (p = 0.009 and p = 0.01) were predictors of mortality and composite endpoint, but not for AKI risk, as well as atrial fibrillation [AF] (p = 0.04) as predictors of the composite endpoint Conclusions: Higher monocyte to lymphocyte ratio (MLR), platelets to lymphocyte ratio (PLR), systemic inflammatory index (SII), neutrophil to lymphocyte ratios (NLR),

Introduction
Abdominal trauma is defined as a variety of injuries to the abdominal wall, solid or hollow intra-abdominal organs, and various intra-abdominal vessels [1]. Depending on the mechanism of injury, abdominal trauma can be classified into blunt and penetrating trauma. Nevertheless, abdominal trauma is associated with high morbidity and mortality rates, the abdomen being the third most affected body region in trauma [2]. According to recent studies, abdominal trauma mortality rates are reported to range from 1 to 20% globally, which is largely due to population diversity [3][4][5][6][7][8]. Recent literature reports the spleen, liver, and kidney as being the most commonly affected organs [9][10][11].
We classify acute kidney insufficiency (AKI) as one of the most dangerous posttraumatic complications, with an incidence of up to 10% [12][13][14][15][16], and it can occur secondary to rhabdomyolysis in the case of crushing [17], or more commonly by impaired kidney perfusion [18].
Recently, there has been a significant amount of interest in the establishment of a reliable biomarker that can predict the outcome in patients with an abdominal injury. One of the most accessible biomarkers is the neutrophil-to-lymphocyte ratio (NLR). The ratio has been proven to be a valid predictor for the outcome of patients with COVID-19 infection [19][20][21][22], breast cancer [23], cardiovascular disease [24][25][26][27][28], and kidney disease [21,29]. Additionally, the platelet-to-lymphocyte ratio (PLR) is another widely researched biomarker, found to have great prediction power in the outcome of patients in the fields of oncology [30], orthopedy [25,31], and trauma care [32]. Moreover, the other hematological ratios, monocyte-to-lymphocyte ratio (MLR), systemic inflammatory index (SII), systemic inflammatory response index (SIRI), and aggregate inflammatory systemic index (AISI) have proved their prediction regarding the poor outcome in numerously chronic and acute pathologies [19][20][21]25,28]. The role of neutrophils, lymphocytes, and platelets in the modulation of inflammatory processes has been extensively described in the literature [33,34].
In works published by Bi et al. [35], Guangging et al. [36], Tang et al. [37], and Ntalouka et al. [38], the predictive role of NLR and PLR in the risk of AKI occurrence as an adverse event following gastrointestinal and hepatobiliary surgery, on-pump coronary artery bypass, and non-cardiac surgery patients, respectively, in the case of the endovascular treatment of aortic aneurysm, was demonstrated abdominally.
This study aims to verify the predictive role of inflammatory biomarkers and underlying risk factors and the risk of acute kidney insufficiency (AKI) developing and mortality in abdominal trauma patients.

Study Design
The current investigation was intended as an observational, analytical, and retrospective cohort study that included all patients over the age of 18 who had been diagnosed with abdominal trauma confirmed through a CT scan admitted to the County Emergency Clinical Hospital of Targu-Mures , , Romania between January 2017 and December 2021. Exclusion criteria were as follows: patients who died in the first 24 h, patients with bone fractures who required hospitalization in orthopedics, and patients with septic shock, hematological diseases, or thromboembolic events in the last two months.
Patients in the research were initially classified as "survivors" or "non-survivors" based on their bad prognosis during their hospitalization. To determine the risk of AKI, mortality, and a composite endpoint of AKI and mortality, the optimal cut-off values for NLR, MLR, PLR, SII, SIRI, and AISI were employed.
In terms of abdominal trauma at computed tomography (CT) scan, we recorded the presence of injury at the level of the following organs: liver, spleen, pancreas, kidney, small bowel, large bowel, and the presence of hemoperitoneum.

Study Outcomes
The primary endpoints were the risk of AKI, in-hospital mortality rate, and a composite endpoint of AKI and mortality. Outcomes were stratified for all optimal inflammatory biomarkers of cut-off values at baseline.
In terms of AKI classification, we used the kidney disease improving global outcomes (KDIGO) guidelines, based on the increased serum creatinine level or urine output range from stage I to III [39].

Statistical Analysis
SPSS for Mac OS version 28.0.1.0 was used for statistical analysis (SPSS, Inc., Chicago, IL, USA). Chi-square tests were used to assess the associations of all systemic inflammatory markers with category factors, while Student t-tests or Mann-Whitney tests were used to assess differences in continuous variables. To assess the predictive power and establish the cut-off of inflammatory markers, the receiver operating characteristic (ROC) curve analysis was utilized. The ROC curve analysis was used to determine the appropriate NLR, MLR, PLR, SII, SIRI, and AISI cut-off values based on the Youden index (Youden Index = Sensitivity + Specificity − 1, ranging from 0 to 1). A multivariate logistic regression analysis with variables with p < 0.1 was performed to find the independent predictors of the AKI risk, mortality, and a composite endpoint of the AKI and mortality.
To evaluate if the baseline of these indicators was predictive of AKI risk, death, and common endpoints in patients with abdominal injuries, receiver operating characteristic curves of all hematological ratios were generated (Figures 1-3). Table 2 shows the ideal cut-off value determined by Youden's index, the areas under the curve (AUC), and the prediction accuracy of the markers. .0001 AH = arterial hypertension; GFR = glomerular filtration rate; IHD = ischemic heart disease; AF = atrial fibrillation; BUN = blood urea nitrogen; CHF = chronic heart failure; MI = myocardial infarction; COPD = chronic obstructive pulmonary disease; PAD = peripheral arterial disease; CKD = chronic kidney disease; MLR = monocyte to lymphocyte ratio; PLR = platelets to lymphocyte ratio; NLR = neutrophil to lymphocyte ratio; AISI = aggregate index of systemic inflammation; SIRI = systemic inflammation response index; SII = systemic inflammatory index; AKI = acute kidney insufficiency; ICU = Intensive Care Unit; SD = standard deviation.
To evaluate if the baseline of these indicators was predictive of AKI risk, death, and common endpoints in patients with abdominal injuries, receiver operating characteristic curves of all hematological ratios were generated ( Figure 1 Table 2 shows the ideal cut-off value determined by Youden's index, the areas under the curve (AUC), and the prediction accuracy of the markers.        The results were subsequently evaluated after separating the patients into paired groups based on the optimal cut-off value of MLR, PLR, NLR, SII, AISI, and SIRI, according to the ROC. As seen in Table 3, there was a greater incidence of all poor outcomes for all inflammatory biomarkers studied.
A high baseline value for all of the studied markers was an independent prognostic factor of unfavorable outcomes for all enrolled patients, according to multivariate analysis (all p < 0.0001). Furthermore, for all hospitalized patients, the history of myocardial infarction (p = 0.03; p = 0.001; and p = 0.003), PAD (p = 0.01; p = 0.01; and p = 0.002), obesity (for all p < 0.0001), CKD (p < 0.001; p = 0.01; and p = 0.001), and kidney injury (p = 0.02; p = 0.004; and p = 0.01) were independent predictors of all outcomes. Moreover, IHD (p = 0.008 and p = 0.02), tobacco (p < 0.0001 and p = 0.02), and hemoperitoneum (p = 0.009 and p = 0.01) were predictors of mortality and composite endpoint, but not for AKI risk, as well as AF (p = 0.04) as predictors of the composite endpoint (Table 4).

Discussion
This research included 364 patients diagnosed with abdominal trauma. We identified the inflammatory biomarkers in all patients' first admission blood test results and monitored the development of AKI, mortality rate, and a composite outcome of AKI and mortality. Our study's most important outcome is that a high baseline value for NLR, MLR, PLR, AISI, SII, SIRI, cardiovascular disease (MI and PAD), and CKD are strong predictors of all outcomes. Additionally, the presence of a CT scan of kidney injury and obesity can predict all the outcomes. To the best of our knowledge, this is the first study to demonstrate that patients with high hematological ratios had a higher risk of AKI and intra-hospital mortality.
AKI is a well-known concern in polytraumatized patients, with an incidence of up to 36% [40][41][42][43][44][45], leading to a significant increase in mortality rate [46][47][48]. In the work published by Younan et al. [49], in which the dynamic evolution of NLR values in critically ill male trauma patients was analyzed, it was demonstrated that an increase in NLR in the first 48 h is associated with organ failure among male trauma patients. Moreover, Rau et al. [32], demonstrated that the low values of the total number of lymphocytes (OR: 1.1; p = 0.04) are a predictor of mortality in the case of 479 adult patients with polytrauma. Additionally, Ke et al. [50], demonstrated in univariate and multivariate analysis, that PLR (p < 0.001 and p = 0.02) is associated with an increased risk of mortality in the case of a group of 2854 adult trauma patients admitted to the intensive care unit.
According to the literature, the predictive values of hematological reports in polytraumatized patients have increasingly been studied, but with inconsistent findings. Additionally, the demand for prognostic tools in the negative evolution and decompensation of polytrauma patients has recently increased. High NLR values, according to Duchesne et al. [51], are related to early mortality in patients with severe post-traumatic hemorrhage who required a massive transfusion protocol. In contrast, Qiu et al. [52] discovered an association between NLR and the length of stay in the ICU and the duration of invasive mechanical ventilation, but not with mortality.
Regarding PLR, Li et al. [53] analyzed the predictive role of this marker in the case of 170 patients with traumatic brain injury, and in the multivariate analysis, they demonstrated that PLR (HR: 1.52; p = 0.009) is an independent predictor of short-term mortality.
Abu Alfeilat et al. [54], demonstrated that a value of NLR > 5.5, in the case of 294 patients who presented themselves to the emergency department, is a predictive factor in the case of the development of AKI (OR: 6.423; p = 0.031) in the multivariate analysis. Additionally, de Hond et al. [55], demonstrated that hematological ratios are associated with an increased risk of AKI and mortality in the case of a group of 1889 patients who presented to the emergency department with suspected infectious disease. Furthermore, Guangging et al. [36] observed high values of NLR in the group of patients who developed AKI after on-pump coronary artery bypass (2.63 vs. 2.06; p = 0.002).
Although our findings are statistically significant, the study has a few limitations. Firstly, it is a retrospective and monocentric study with patient follow-up only throughout hospitalization. Future prospective multicenter studies with extended follow-ups are advised. Secondly, because the study was retrospective, we were unable to acquire information on chronic treatments used prior to admission (corticosteroids or anti-inflammatories meds). As a result, we were unable to determine how different drugs influence inflammatory biomarkers. Furthermore, there is no available information on the surgery, and we monitored the patients while they were in the hospital, but we are unsure of how many of them required chronic dialysis. In addition, more investigations are required to confirm our conclusions.

Conclusions
Higher levels of systemic inflammatory biomarkers upon admission, according to our data, greatly predict AKI risk and fatality. Additionally, myocardial infarction, obesity, renal damage, PAD, and CKD, were independent predictors of all outcomes in all hospitalized patients. Additionally, IHD, tobacco use, and hemoperitoneum have a predictive role in mortality and the composite endpoints, but not in AKI risk, while AF has a predictive role in the composite endpoint. Considering the simplicity of use and the low cost of these ratios, as well as the high risk of AKI development and mortality in trauma patients, they can be used to classify admission risk groups, improve patient treatment, and create predictive patterns.