4. Discussion

<30 days after admission to the emergency department. In addition, , NLPR, and the SII index were independently associated with a higher risk of 30-day mortality. Several prior studies that investigated the association between inflammatory Hemato logical ratios and AKI showed similar results. A study of a single emergency room measurement of the NLR reported a cut-off value of 5.5 to be associated with AKI (odds ratio 6.4; 95% CI 2.7–16) [25]. In septic patients, two retrospective studies also demonstrated that NLR was an important risk factor for the occurrence of AKI [26,27]. Furthermore, several studies showed an association between the occurrence of AKI with elevated postoperative or post-coronary angiography NLR levels, implicating the important role of inflammation in the development of AKI [28–30]. Due to a lack of previous studies on the association between the SMR, NLPR, and AKI, it is not possible to compare our results with previous data. In the present study, there was no association between the modified DNI, MLR, PLR, and SII index and the occurrence of AKI. Although some previous studies suggested that these ratios are associated with AKI, they were performed in other settings (e.g., postoperative or ICU) or with other types of ratio measurements (e.g., DNI requires measuring myeloperoxidase-reactive cells and a nuclear lobularity assay) [28,31–35]. 

are associated with mortality [36,37]. A retrospective study of critically ill AKI patients also reported higher NLR levels to be associated with all-cause mortality (HR 1.83; 95% CI 1.66–2.02) [38]. There are a few studies that investigated the association between some sort of neutrophil-monocyte ratio and mortality, which found contradictive results. One study investigated the neutrophil-to-monocyte ratio and found a high value ( Greater than or equal to 17.75) to be associated with mortality in COVID-19 patients [39]. Another study investigated the ratio between segmented neutrophils and mature monocytes (SeMo). This study reported the opposite: a SeMo ratio of <16 in critically ill septic patients was associated with a higher risk of 28-day mortality [23]. A likely explanation for the difference in findings between the study of Fang et al. and our study is the use of a different analyzer with incomparable measuring methods. Additionally, the current study had a different study population. In the study of Fang et al., only patients with severe sepsis or septic shock who were already admitted to the ICU were included, compared to only 98 (5.2%) patients in our population who were considered critically ill based on the qSOFA score. For NLPR, several studies showed the association between higher perioperative levels and postoperative AKI and mortality [21,40,41]. Furthermore, another study indicated that an NLPR of ≥15.48 was associated with 28-day mortality in septic patients, which is concordant with the association of higher NLPR values with AKI and mortality in the present study [42]. In line with the current findings, several studies found an association between high PLR levels, high SII-index values, and mortality [33,34,43,44].

There are several potential pathophysiological reasons why these inflammatory hema-tological ratios are associated with AKI. The pathophysiology of AKI in severe infections and sepsis is complex and multifactorial [9]. Septic AKI is often attributed to an ischemia-reperfusion injury resulting from hypoperfusion and shock. However, studies have found that AKI in patients with infections and sepsis can even occur in the absence of hypoperfusion [10,45]. Moreover, it was shown that an inflammatory response was even present in patients with non-severe infections and AKI [10,46]. The role of inflammation in AKI is still not completely understood, but, likely, pro-inflammatory changes in the endothelial and epithelial cells of the kidney play an important role [47,48]. This is caused by a complex inflammatory process that is triggered by both the innate and adaptive immune system. In the initial phase, renal epithelial cells increase the expression of damage-associated pattern (DAMP) molecules and Toll-like receptors (TLRs). This induces the recruitment of innate immune cells, including neutrophils and macrophages [49,50]. At the same time, macrophages and neutrophils are activated by natural killer T cells that transfer from the vascular system to the renal tissue [51]. Neutrophils are mainly involved during the first 24 hours by endothelium adherence and the release of cytokines, reactive oxygen species, and proteases [52,53]. This is followed by a reaction of the adaptive immune system in which lymphocytes cause cellular damage in combination with the release of pro-inflammatory cytokines [52,53]. 

The present study has several strengths. Our study included a large and well-defined cohort of patients. The SPACE cohort represents a similar population to the population that is generally seen in the emergency department, which makes the results of this study clinically relevant. Additionally, to our knowledge, this is the first study that investigated which hematological ratios are associated with AKI in patients suspected of having an infection at the emergency department. Two studies investigated the association between hematological ratios and the occurrence of AKI in the emergency department [25,31]. However, these studies did not specifically investigate patients that were suspected of having an infection and both studies only investigated a single ratio. Furthermore, sensitivity analyses with different time endpoints for the same outcomes showed similar results, which contributes to the robustness of the main results. Nonetheless, this study also has several limitations. Firstly, although some of the data in the SPACE cohort were collected prospectively, data on SCr levels were collected retrospectively and therefore the occurrence of the primary endpoint of AKI might be underestimated, as only patients with available follow-up SCr data could be included in the analyses. We had no data available on urinary output, limiting our definition of AKI. Additionally, it is known in mice that sepsis reduces muscle perfusion. Consequently, the production of creatinine falls, which limits the usability of SCr for early detection of AKI in septic patients [54]. On top of that, AKI could be underdiagnosed due to dilutional effects of fluid-resuscitation therapy. Secondly, it is important to point out that this study was conducted in a tertiary-care institution and that a considerable amount of the patients were immunocompromised. This might make results less generalizable to other settings since these patients might have a less-reactive immune response. Nonetheless, we corrected for immune status in our analyses and therefore expect this to have a minor influence on our final results. Lastly, we did not have data on the cause of death within the SPACE cohort. Therefore, although this would have been interesting, we were unable to investigate to what extent AKI contributed to mortality

The use of inflammatory hematological ratios as additions to the current practice could be useful for the initiation of early treatment such as the discontinuation of nephrotoxic agents, optimization of volume status and perfusion pressure, and monitoring serum creatinine and urine output [55]. This could prevent or limit the extent of short- and long-term outcomes such as the development of chronic kidney disease or end-stage renal disease with the need for costly and life-impacting interventions such as RRT [6,7]. Nonetheless, the diagnosis of AKI mostly depends on the use of traditional indicators such as serum creatinine, which is fairly delayed and often increases when AKI is already present [56]. Blood count parameters such as NLR, SMR, and NLPR are easily calculated since blood counts are measured in most patients at the emergency department when there is a suspicion of infection. Therefore, these ratios are easily applicable in the emergency-department setting with low costs, even in patients with less severe infections who might still be at risk of developing AKI.

The following are available online at https://www.mdpi.com/article/ 10.3390/jcm11041017/s1, Figure S1: Distribution of hematological ratios after stratification for AKI stage, Table S1: HRs (95% CI) for AKI <14 days after ED presentation, Table S2: HR's (95% CIs) for 14-day all-cause mortality. 

Conceptualization, T.A.P.d.H., G.O., M.K., and K.A.H.K.; methodology, T.A.P.d.H., G.O., L.G., and M.K.; formal analysis, T.A.P.d.H., G.O., L.G., and M.K.; investigation, T.A.P.d.H., G.O., L.G., and M.K.; data curation, T.A.P.d.H. and L.G.; writing-original draft, T.A.P.d.H. and L.G.; writing-reviewing and editing, T.A.P.d.H., G.O., S.H., J.J.O., M.K. and K.A.H.K.;supervisionn, G.O., J.J.O., M.K., and K.A.H.K. All authors have read and agreed to the published version of the manuscript. 

Institutional Review Board Statement: The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board (or Ethics Committee) of the UMC Utrecht (protocol code 16/594/C, date of approval 21 September 2016). 

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