Hematological Ratios Are Associated With Acute Kidney Injury And Mortality in Patients That Present With Suspected Infection At The Emergency Department
Aug 19, 2024
Keywords: hematological ratios; emergency department; acute kidney injury; mortality; infection;inflammation
NEW HERBAL FORMULATION FOR KIDNEY DISEASE
1. Introduction
Acute kidney injury (AKI) is a group of syndromes characterized by a rapid decline of renal function [1–3]. The incidence of AKI varies depending on the population and the definition used and has steadily increased over the past few decades [3,4]. AKI is common in critically ill septic patients and is associated with several short- and long-term outcomes, including an increased length of hospital stay, morbidity (e.g., the development of end-stage renal disease with the need for renal-replacement therapy (RRT)), and mortality. Altogether, this results in the impairment of the sustainability of the healthcare system [5–8].
AKI has a complex pathophysiology and in most cases the development is multifactorial. Severe infections and sepsis in critically ill patients make up an important part of the causes of AKI, and there is growing evidence that even patients with less severe infections have a higher risk of developing AKI [9,10]. Inflammation may play an important role in the pathogenesis of AKI in patients with severe infections or sepsis, and evidence shows that AKI can even occur in the absence of hypoperfusion [11]. However, the early recognition and treatment of AKI remains difficult. Therefore, it is important to investigate the risk factors for AKI. Currently, the diagnosis of AKI is mainly dependent on the use of serum creatinine (SCr), which can be relatively delayed and is affected by many factors [12].
Indeed, several studies have focused on biomarkers (e.g., KIM-1, NGAL) to detect AKI in the early phase [13]. However, single biomarkers were proven not to be sensitive enough for the detection of AKI and were not routinely available in daily clinical practice. Recent studies described complete blood count to be associated with AKI [13]. Several hematological ratios that can be calculated from complete blood count (CBC) are associated with inflammation [14–16]. As local and systemic inflammation plays an important role in the initiation and progression of AKI and mortality in patients with infections, hematological ratios could be associated with AKI and mortality in patients with infections. Therefore, this study aimed to investigate the association between inflammatory hematological ratios, which were derived from a routine CBC, and the occurrence of AKI and mortality in patients suspected of having an infection at the emergency department.
2. Materials and Methods
2.1. Study Design
This prospective observational cohort study was performed at the University Medical Center Utrecht (UMCU). The UMCU is a large, tertiary academic teaching hospital located in the Netherlands. Patients described in this study were included between 13 September 2016 and 1 January 2019 and followed until the time of death or censored due to loss of a follow-up or until one year after their emergency department presentation. Clinical data were used from the SPACE cohort (SePsis in acutely ill patients in the emergency room) [17]. This study was reviewed and approved by the Medical Ethical Committee of the UMCU under number 16/594 and registered in the Dutch Trial Register (NTR) under number 6916. Since only pseudonymized data were included, the review board decided that written patient consent was not required. This study was performed by the Declaration of Helsinki.
2.2. Study Population and Data Collection
The SPACE cohort consists of all consecutive patients who meet the following criteria: (1) ≥18 years or older; (2) presentation at the emergency department with a suspected infection defined by the treating physician; (3) registration in the emergency department for the internal-medicine department or one of its subspecialties of oncology, rheumatology, immunology, hematology, nephrology, endocrinology, geriatrics, infectious disease or vascular medicine [17]. For the current analyses, patients receiving RRT, patients without baseline or follow-up SCr, and patients who had a repeated emergency department visit within 30 days were excluded. Demographics, clinical data recorded at the time of presentation in the emergency department and, if applicable, during hospitalization, as well as data on laboratory markers, treatments, and outcomes were collected for all eligible patients in this cohort. Data on immune status, comorbidities, diagnosis at admission, and diagnosis at discharge were manually extracted from the Electronic Health Records (EHR) by independent researchers and reviewed using a set of predefined and standardized definitions. All available data on SCr within 30 days after presentation were extracted from the EHR. The qSOFA score was calculated by assigning one point each for respiratory rate ≥22 breaths/min, systolic blood pressure ≤100 mm Hg, and altered mental status) and was considered positive in the case of a score ≥2 [18]. Comorbidities were quantified using the Charlson Comorbidity Index (CCI) [19].
Additional data were retrieved using the Utrecht Patient-Oriented Database (UPOD). The structure and content of UPOD have been described in more detail elsewhere [20]. Hematological markers were retrieved from the UPOD that were determined by automated blood-cell analyses performed with the Abbot Cell-Dynn Sapphire hematology analyzer (Abbott Hematology, Santa Clara, CA, USA). The UPOD setup saves a wide range of hematological parameters, even if they are not specifically requested by the physician [20].
2.3. Hematological Ratios
From all patients, blood samples that were obtained during a presentation in the emergency department were analyzed to determine the complete blood count as part of the routine clinical care. The hematological ratios were then calculated from the results. The modified delta-neutrophil index (modified DNI) can be determined by subtracting the fraction of segmented neutrophils from the sum of the fractions of total neutrophils and eosinophils. The neutrophil-to-lymphocyte ratio (NLR) (neutrophil count/lymphocyte count) [14], monocyte-to-lymphocyte ratio (MLR) (monocyte count/lymphocyte count) [15], segmented-neutrophil-to-monocyte ratio (SMR) (segmented neutrophil count/monocyte count), platelet-to-lymphocyte ratio (PLR) (platelet count/lymphocyte count) [16], neutrophil-to-lymphocytes-and-platelets ratio (NLPR) ((neutrophil count × 100)/(lymphcytes count × platelet count)) [21] and systemic immune-inflammation (SII) index (platelet count × (neutrophil count/lymphocyte count)) [22] were all calculated from the complete blood count. The modified DNI and SMR were inspired by the previously described delta-neutrophil index (DNI) and segmented-neutrophil-to-mature-monocyte ratio (SeMo), respectively [23,24]. However, since an incomparable method was used to determine leukocyte maturity, other names were chosen to describe these ratios.
2.4. Outcomes and Definitions
The primary outcome of this study was the development of AKI within 30 days after presentation at the emergency department. The diagnosis and staging of AKI were based on the Kidney Disease: Improving Global Outcomes (KDIGO) criteria, and were defined as an increase in SCr of 1.5 times the baseline value or an increase in SCr of 26.5 umol/L relative to the value measured at the emergency department within the first 48 h after presentation (stage 1) [2]. Baseline creatinine was defined as the most recent SCr measurement available from 7 days to 12 months before presentation at the emergency department. The median period between baseline SCr and presentation at the emergency department was 24 days (interquartile range [IQR] 13–56). The highest SCr within 30 days was used to stratify the KDIGO stages of AKI, with an increase of 2.0 to 2.9 times baseline SCr being classified as stage 2, and an increase of >3.0 times baseline SCr or 352.6 umol/L being classified as stage 3.
The secondary outcome was defined as all-cause mortality within 30 days after the emergency department presentation. Sensitivity analyses for AKI and all-cause mortality within 14 days after the emergency department presentation were included to evaluate the robustness of the results.
2.5. Statistical Analyses
(ARBs), diuretics, proton-pump inhibitors (PPIs), and non-steroidal anti-inflammatory drugs (NSAIDs)), disease severity (qSOFA), and the provisional diagnosis in the emergency department. Sensitivity analyses were performed using the same Cox proportional hazard models with different time endpoints for the outcomes. Statistical significance was defined at a p-value <0.05. Statistical analyses were performed with the statistical software package SPSS 25.0 for Windows (IBM Corp, Armonk, NY, USA).
3. Results
3.1. Study Population and Baseline Characteristics
From 3,669 patients, a total of 1,889 patients remained eligible for the final analysis (Figure 1). The baseline characteristics of the included patients are shown in Table 1. The median age was 62 years (IQR 50–70) and 54.5% of the patients were male. Lowerrespiratory tract infection (22.0%) was the most common diagnosis in the emergency department, followed by urinary tract infection (17.7%) and viral respiratory tract infection (15.5%). Of all the patients, 821 (43.3%) were immunocompromised and 98 (5.2%) were considered critically ill based on a qSOFA score of ≥2
Figure 1. Flowchart of study attrition. Abbreviations: AKI, acute kidney injury; ED, emergency department; RRT, renal replacement therapy; SCr, serum creatinine.
3.2. Incidence of AKI
Within the AKI group, there were 123 (76.9%) patients with AKI stage 1, 20 (12.5%) patients with AKI stage 2, and 17 (10.6%) patients with AKI stage 3.
3.3. Hematological Ratios in AKI and Non-AKI Patients
The hematological ratios calculated from the CBC and the distribution between the AKI and non-AKI patients are shown in Table 2. The NLR (median AKI group 8.52, IQR 4.38–17.92 vs. median non-AKI group 6.80, IQR 3.17–12.73), SMR (median AKI group 10.97, IQR 7.03–17.10 vs. median non-AKI group 8.83, IQR 5.62–13.88) and NLPR (median AKI group 4.84, IQR 2.01–10.24 vs. median non-AKI group 3.03, IQR 1.45–6.55) were significantly higher in the AKI group compared to the non-AKI group. Additionally, the distributions of these three ratios differed significantly between the several stages of AKI (Supplemental Figure S1).
Abbreviations: ACE, angiotensin-converting enzyme; AKI, acute kidney injury; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; ED, emergency department; eGFR, estimated glomerular filtration rate; IQR, interquartile range; NSAID, non-steroidal anti-inflammatory drugs; qSOFA, quick Sepsis-Related OrganFailure Assessment.
Table 3 shows the hazard ratios for several hematological ratios and the occurrence of AKI <30 days after the emergency department visit. In the univariate Cox regression, there was a significant association between AKI and the highest tertiles of the NLR, SMR, NLPR, and SII index. After adjustment for age, sex, comorbidities, baseline renal function, immune status, medication use, disease severity, and diagnosis in the emergency department, the highest tertile of the NLR (adjusted HR 1.8, 95% confidence interval [95% CI] 1.2–2.8), middle tertile of the SMR (adjusted HR 1.7; 95% CI 1.1–2.6), highest tertile of the SMR (adjusted HR 2.0; 95% CI 1.3–3.0) and highest tertile of the NLPR (adjusted HR 2.1; 95% CI 1.4–3.2) remained independently associated with the occurrence of AKI <30 days after emergency-department presentation. In a continuous analysis, NLR and SMR were significant as well (adjusted HR 1.002; 95% CI 1.001–1.002 and adjusted HR 1.005; 95% CI 1.003–1.008, respectively).
Abbreviations: HR, hazard ratio; AKI, acute kidney injury; DNI, delta-neutrophil index; NLR, neutrophil to-lymphocyte ratio; MLR, monocyte-to-lymphocyte ratio; SMR, segmented-neutrophil-to-monocyte ratio; PLR, platelet-to-lymphocyte ratio; NLPR, neutrophil-to-lymphocyte-platelet ratio; SII index, systemic immune inflammation index. Bold numbers indicate statistical significance. a Correction made for age, and gender. b Correction made for age, gender, comorbidity score, baseline renal function, immune status. c Correction made for age, gender, comorbidity score, baseline renal function, immune status, medication use. d Correction made for age, gender, comorbidity score, baseline renal function, immune status, medication use, disease severity, and provisional diagnosis in the emergency department.
3.5. Association between Hematological Ratios and Mortality
Of the 1889 patients, 102 died within 30 days (5.4%). The analysis of the Cox proportionalhazard models demonstrated the association between several hematological ratios and 30-day mortality (Table 4). After adjustment for confounders, the highest tertile of the NLR (Adjusted HR 1.7; 95% CI 1.0–2.9), highest tertile of the SMR (adjusted HR 1.8; 95% CI 1.1–3.1), highest tertile of the PLR (adjusted HR 1.7; 95% CI 1.1–2.8), middle and highest tertiles of the NLPR (adjusted HR 2.5; 95% CI 1.4–4.4 and adjusted HR 2.1; 95% CI 1.2–3.7), and highest tertile of the SII index (adjusted HR 1.8; 95% CI 1.1–2.8) were shown to be independently associated with 30-day mortality as compared with the lowest tertiles. In a continuous analysis, NLPR was significantly associated with 30-day mortality (adjusted HR 1.008; 95% CI 1.003–1.013).
Abbreviations: HR, hazard ratio; AKI, acute kidney injury; DNI, delta-neutrophil index; NLR, neutrophilto-lymphocyte ratio; MLR, monocyte-to-lymphocyte ratio; SMR, segmented-neutrophil-to-monocyte ratio; PLR, platelet-to-lymphocyte ratio; NLPR, neutrophil-to-lymphocyte-platelet ratio; SII index, systemic immune\inflammation index. Bold numbers indicate statistical significance. a Correction made for age, gender. b Correction made for age, gender, comorbidity score, baseline renal function, immune status. c Correction made for age, gender, comorbidity score, baseline renal function, immune status, medication use. d Correction made for age, gender, comorbidity score, baseline renal function, immune status, medication use, disease severity, and provisional diagnosis in the emergency department.
