Acute kidney injury (AKI) is characterized by a rapid decrease in renal function.1 AKI is frequent in hospitalized patients and its incidence is higher in critically ill patients, in whom the leading cause of AKI is sepsis, substantiated by multiple cohorts.2–4 Sepsis is the systemic inflammatory response to an infectious insult, which often results in multiple organ dysfunction.5,6

Septic-AKI patients have distinct characteristics than non-septic AKI, that is higher severity scores at admission, more non-renal organ failure and requirement of vasopressors and mechanical ventilation.3,7

AKI has been associated with longer hospital stays, in-hospital mortality, cardiovascular events, progression to chronic kidney disease and long-term mortality.8–10 Septic-AKI also has distinct prognostic implications than non-septic AKI, namely higher short-term mortality rate, prolonged length of hospital stays and higher probability of renal function recovery at hospital discharge.3,7 Therefore, it is vital to detect predictors of AKI and mortality to timely prevent, diagnose and treat this complication.

Recent research has led to improvement in the understanding of the pathophysiology of septic-AKI, which is a complex interaction of hemodynamic, microcirculatory, inflammatory, and immune mechanisms.11–14 Indeed, the role of intrarenal and systemic inflammation appears to be significant in the pathophysiology of septic-AKI and in the associated multi-organ dysfunction.15–17

The neutrophil to lymphocyte ratio (N/L ratio) and neutrophil to lymphocytes and platelets ratio (N/LP ratio) have been associated with AKI in the emergency setting, sepsis, contrast induced-AKI, cardiovascular surgery and abdominal surgery.18–23 These are easily calculated, effective and low-cost markers of systemic inflammation which might be promising in AKI patients.

The prognostic ability of the neutrophils to lymphocytes and platelets ratio (N/LP ratio) has not previously been evaluated in septic-AKI. The aim of this study was to evaluate the prognostic ability of N/LP ratio at admission in septic-AKI patients admitted to an intensive care unit (ICU). For this purpose, we cross-examined data from a retrospective study of critically ill patients admitted with sepsis to the ICU in which the initial goal was to compare the diagnostic sensitivity and prognostic ability of the standard classifications for AKI.24

This is a single center retrospective analysis of septic-AKI patients admitted to the Division of Intensive Medicine of the Centro Hospitalar Universitário Lisboa Norte (CHULN) between January 2008 and December 2014. CHULN is an academic and referral center located in Lisbon, Portugal. This study was approved by the Ethical Committee in agreement with institutional guidelines. Due to the retrospective and non-interventional nature of the study, informed consent was waived by the Ethical Committee.

We identified 722 septic patients. Of these, 323 were excluded as followed: 122 had stage 5 CKD on renal replacement therapy, 144 had been hospitalized for less than 48h and 57 patients did not develop AKI during ICU stay. No patients required renal replacement therapy in the week preceding ICU admission (Fig. 1).

Fig. 1.

Flow-chart of patient selection.

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A final cohort of 399 patients was studied. Demographic variables, clinical and laboratory characteristics are described in Table 2.

In this cohort of septic-AKI patients, mean age was 64.1±15.9 years, the majority were Caucasian (95%), males (57.4%) and the main diagnosis at ICU admission was medical in nature (55.6%). Forty-five percent of patients were hypertensive, 22.1% diabetic and 24.1% had malignancy. Baseline SCr was 1.27±0.6mg/dl. The infection source was abdominal in 42.1%, respiratory in 30.6% and urinary in 10.8% of patients. At ICU admission mean SAPS II value was 50.4±17.3, SCr was 2.44±1.6mg/dl, hemoglobin was 10.5±2.0, serum albumin was 1.89±0.6mg/dl and N/LP ratio was 20.1±78.4. Acidemia was present in 35.8% of patients at admission. The majority of patients were classified as KDIGO stage 3 (51.9%), 25.8% KDIGO stage 2 and 22.3% as KDIGO stage 1. The N/LP ratio was progressively higher with the KDIGO stages but the differences were not statistically significant (KDIGO stage 1 – 13.7±22.1, KDIGO stage 2 – 18.5±31.7, KDIGO stage 3 – 23.6±105.5, p=0.591). During ICU admission, 77.4% patients required mechanical ventilation, 72.7% required vasopressors, 27.1% required renal replacement therapy (RRT), and required mean fluid balance of 4.6±5.4l.

These patients had a length of stay in ICU of 10.0±10.0 days and in hospital of 36.7±38.6 days. The in-hospital mortality in this cohort of septic-AKI patients was 35.8% (KDIGO stage 1 – 13.3%, KDIGO stage 2 – 16.8%, KDIGO stage 3 – 69.9%, p<0.001). Overall, patient survival was 64.2%.

Septic-AKI patients who died within the hospital admission were older (66.6±15.9 vs 62.6±15.7, p=0.016), had a higher incidence of malignancy (32.2% vs 19.5%, p=0.005) and had fewer urinary tract infections (5.6% vs 13.7%, p=0.013). At ICU admission, higher SAPS II (58.1±17.7 vs 46.1±15.6, p<0.001), lower hemoglobin level (9.9±2.0 vs 10.8±1.9, p<0.001) and lower serum albumin (1.78±0.6 vs 1.94±0.56, p=0.010) correlated with mortality. The N/LP ratio at admission was associated with in-hospital mortality in septic-AKI patients (31.59±126.8 vs 13.66±22.64, p=0.028). Need for mechanical ventilation (88.8% vs 71.1%, p<0.001), vasopressors (81.8% vs 67.6%, p=0.002), higher fluid balance (6.87±5.99 vs 3.38±4.6, p<0.001) and RRT (45.5% vs 16.8%, p<0.001) also correlated with mortality (Table 3).

An adjusted multivariate analysis to demographic, clinical, ICU admission variables and during ICU stay factors was conducted, in which a higher N/LP ratio remained as an independent predictor of increased risk of in-hospital mortality in septic-AKI patients (31.59±126.8 vs 13.66±22.64, p=0.028; unadjusted OR 1.01 (95% CI 1.00–1.02), p=0.027; adjusted OR 1.01 (95% CI 1.00–1.02), p=0.015). After a sensitive analysis, a higher NL/P ratio was still associated with in-hospital mortality regardless of KDIGO stage (adjusted OR 1.01 (95% CI 1.00–1.02), p=0.030) (Table 4).

Older age (p=0.004), higher SAPS II (p=0.001), lower hemoglobin (p=0.001), higher fluid balance (p<0.001) and need for RRT (p<0.001) were also associated with mortality in the multivariate analysis (Table 4).

To assess the discriminative ability of N/LP ratio for mortality, a ROC curve was produced. The AUC for mortality prediction in septic-AKI was of 0.565 (95% CI (0.515–0.615), p=0.034) (Fig. 2). The optimal cut-off was assessed to be >14, which has a sensitivity of 33.1% and specificity of 79.7% with a positive predictive value of 1.63 and negative predictive value of 0.84, meaning that almost 80% of patients with a NL/P ratio lower than 14 will survive.

Fig. 2.

AUC of the risk model for the prediction of in-hospital mortality with NL/P ratio in septic-AKI patients.

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In this retrospective cohort, we demonstrated that a higher N/LP ratio at ICU admission was independently associated with in-hospital mortality in septic-AKI patients after adjustment to demographic and clinical variables.

The association of this marker with mortality in this setting highlights the role of inflammation in the pathophysiology of septic-AKI.30 The exact mechanisms involved in septic-AKI are unknown, still, this complex process appears to result from the interaction of hemodynamic changes, microcirculatory dysfunction, tubular cell injury, inflammation, coagulation disturbances and adaptive responses to injury.12,31

AKI develops despite an increased renal blood flow in the initial hyperdynamic state of sepsis.31 It is theorized that the ultrafiltration of toxins and release of inflammatory cytokines prompts tubular cell injury, endothelial dysfunction, reduced microcirculatory flow and interstitial inflammatory cell infiltration.13,15

The role of platelet and leukocyte interactions as a critical step in leukocyte recruitment, activation and migration in inflammation has emerged in recent years.32,33 Both innate and adaptive immune responses are modulated by the interaction of neutrophils, monocytes, lymphocytes and platelets.32,33 There is an intrinsic interaction between inflammation and coagulation pathways in sepsis.34 In the early phases of sepsis platelet/neutrophils complexes are raised, and reduced in severe and complicated sepsis due to peripheral sequestration or sepsis-associated thrombocytopenia.35–37

The systemic inflammation associated with septic-AKI is central in the development of multi-organ failure and long-term outcomes.38 Therefore, the N/LP ratio stands as an indirect and sensitive predictor of inflammation and outcomes in this setting.

The N/L ratio has been described in recent literature as a significant marker for inflammation and a useful predictor of the development of AKI.18–21 In patients with septic shock, Riche et al. reported that the N/L ratio correlated with short and long-term mortality.39 Also, Huang et al. demonstrated that the N/L ratio at admission was associated with mortality in patients with severe sepsis and septic shock.40 In a study by Bu et al., N/L ratio was associated with AKI in patients with sepsis, though there was no association with mortality.41

The N/LP ratio was developed afterwards by Koo et al. who described its association with AKI and short and long-term mortality after cardiovascular surgery.22 In a recent study, we have also reported the significant correlation between the N/LP ratio and AKI in major abdominal surgery, although the ratio did not correlate significantly with in-hospital mortality.23

The NL ratio was not predictive of mortality in this cohort; thus, platelet count was incorporated in the ratio to increase its sensitivity in predicting patient outcomes. This is the first study to report the association between the N/LP ratio and mortality in septic-AKI. In the sepsis setting, thrombocytopenia is a marker of critically ill patients and is a recognized risk factor for mortality, therefore, the incorporation of platelets in the ratio increases its sensitivity in predicting patient outcomes.33

Importantly, the N/LP ratio at admission was an independent predictor of mortality in patients who develop septic-AKI within the first week of admission. More importantly, a NL/P ratio lower than 14 is predictive of patient survival, which further reflects that lower inflammation is associated with lower mortality in critically ill septic patients. Thus, highlighting the role of the N/LP ratio as a significant marker of systemic inflammatory response at ICU admission.

We address some of the important limitations of this study. Firstly, the results may be compromised by the single-center and retrospective nature of the study with a small cohort of patients. Secondly, we could not assess factors which could influence UO, of which we had hourly measurements. Thirdly, the pre-admission SCr level was unknown in nearly 60% of patients, compelling us to calculate an estimated baseline function using the MDRD equation as recommended, which could overestimate AKI incidence. Fourthly, the power of the ROC curve is light and therefore further studies are necessary before generalization. Finally, we did not address cause-specific mortality.

Despite these limitations, our study has several notable strengths. To the best of our knowledge, this is the first study evaluating the association between the N/LP ratio and in-hospital mortality in septic-AKI patients in an ICU. Also, the high specificity of the NL/P ratio reflects that a low ratio is predictive of patient survival. Additionally, AKI was defined and categorized using both creatinine and UO. Finally, despite the retrospective nature of the study, most of the studied variables were registered as part of routine clinical practice on a daily basis and made accessible for analysis.

We highlight the need for further understanding of septic-AKI in order to identify at-risk populations, employ preventive strategies, guaranty an early diagnosis and prompt and adequate treatment, ultimately, improving patient outcomes.

In conclusion, we confirmed that the N/LP ratio at ICU admission was independently associated with in-hospital mortality in septic-AKI patients. The assessment of this ratio is straightforward from a routine blood analysis in ICU patients and can prove useful in identifying patients at risk for mortality.

Ethics approval and consent to participate.

This study was approved by the Ethical Committee in agreement with institutional guidelines. Due to the retrospective and non-interventional nature of the study, informed consent was waived by the Ethical Committee.

There was no funding for this study.

The authors participated as follows: JG and JAF drafted the article, SJ and JG revised the article, JAL revised the article and approved the final version to be submitted for publication.

There is no conflict of interest. The results presented in this paper have not been published previously in whole or part.

The authors give their consent for publication.

All datasets generated and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.