Introduction
Acute kidney injury (AKI) is a common clinical problem in intensive care unit (ICU) patients and independently predicts poor outcome [
1‐
4]. Recently, two large multicentre cohort studies [
5,
6] reported the occurrence of AKI in an estimated 36% of all patients admitted to the ICU. Moreover, additional observational data indicate that the incidence of AKI is rising [
7,
8].
This large and increasing burden of AKI has in part been attributed to shifts in patient demographics (older, more co-morbid illness), severity of illness (multiple organ dysfunction syndrome) and AKI associated with complex interventions (organ transplantation) [
9,
10]. Consequently, the aetiology of AKI in critically ill patients is often multifactorial. However, sepsis has consistently been found to be a leading contributing factor to AKI in critical illness [
11‐
18]. Discriminating between AKI of septic and nonseptic origin may have clinical relevance [
19]. Evolving data suggest that septic AKI may be characterized by a distinct pathophysiology [
9,
20‐
22]. For that reason, septic AKI may be associated with important differences in terms of patient characteristics, response to interventions and clinical outcomes when compared with nonseptic precipitants of AKI.
Regrettably, to date, relatively few studies have focused on describing the epidemiology of septic AKI in critically ill patients [
12‐
18]. Two multicentre studies [
12,
15] have shown that 46% to 48% of all AKI in critically ill patients can be attributed to sepsis [
12,
15]. Alternatively, those studies primary focused on sepsis have described that an estimated 10% to 50% of patients develop AKI [
13,
14,
16‐
18].
Accordingly, in view of the relatively limited data available on septic AKI and its likely importance, we interrogated the Australian and New Zealand Intensive Care Society (ANZICS) Adult Patient Database (APD) to obtain information on all critically ill patients with both sepsis and AKI from 57 Australian ICUs over a 5-year period. Our objectives were as follows: to describe and compare the incidence and clinical characteristics of critically ill patients admitted with sepsis, nonseptic AKI and septic AKI; to describe and compare the severity of AKI stratified by sepsis; and to describe and compare the clinical outcomes of sepsis, nonseptic AKI and septic AKI.
Discussion
We conducted a large multicentre epidemiological ICU study of more than 14,000 cases of sepsis complicated by early AKI. Our principal objectives were to describe the incidence, clinical characteristics and outcomes associated with septic AKI and to compare early septic AKI patients with critically ill patients with nonseptic AKI, sepsis only and neither sepsis nor AKI.
First, we found that early septic AKI is common and present in nearly 12% of all ICU admissions. Importantly, of those admitted with a primary diagnosis of sepsis, 42% had concomitant AKI. Similarly, for those with AKI, an estimated 32% had sepsis as a contributing factor. Second, our findings suggest that septic AKI patients are clinically distinct and have features that differentiate them from patients with nonseptic AKI.
Septic AKI patients are older and have more co-morbid disease. Septic AKI was more likely to be associated with medical admissions; however, if the admission was surgical, then septic AKI was more likely to be associated with an emergency surgical admission.
Septic AKI was also characterized by greater acuity of illness as demonstrated by severity of illness scores and greater aberrancy in vital signs, markers of inflammation and blood chemistry. Third, these distinguishing features of septic AKI appeared to translate into relevant differences in clinical outcomes when compared with nonseptic AKI. For example, septic AKI was associated with greater risks for both ICU and hospital death. This was consistent across all strata of AKI severity when stratified by RIFLE category. Likewise, septic AKI contributed to significantly longer durations of stay in both ICU and hospital.
These findings are largely consistent with and extend data from prior investigations into septic AKI. Observational studies have shown that the incidences of sepsis and AKI are increasing [
7,
8,
10,
29,
30]. Small single centre studies have found that 11% to 37% of all septic patients have concomitant AKI [
13,
14,
18]. The multicentre European Sepsis Occurrence in Acutely Ill Patients (SOAP) study found that 51% of septic patients developed AKI, defined by a Sequential Organ Failure Assessment score above 2 (serum creatinine >177 μmol/l) [
17]. More recently, in a 1-day point prevalence survey for severe sepsis/septic shock from 454 ICUs in Germany, Oppert and coworkers [
16] reported concomitant AKI in 41.4% of septic patients. Likewise, two large multicentre observational studies of critically ill patients with AKI [
12,
15] found sepsis to be a contributing factor in 46% to 48% of episodes of AKI. However, these studies are somewhat limited by their inclusion of only septic patients or only AKI patients, and therefore they provide a potentially biased comparison.
Our data are largely comparable, but we can further illustrate the overall high burden of septic AKI in relation to all ICU admissions (11.7% overall). Moreover, we can show both the high incidence of early AKI accompanying sepsis (42.1%) and sepsis contributing to early AKI (32.4%). In addition, our study is the first to date to compare clinical characteristics and outcomes between septic AKI and nonseptic AKI, sepsis only, and a control cohort with neither sepsis nor AKI. We believe that the generalizability of our study is further strengthened by incorporating data from multiple centres and across a range of hospital types. A reasonable inference from these accumulated data is that sepsis has clearly surfaced as the most significant predictor of AKI in critically ill patients and that the occurrence of septic AKI is likely to increase further.
The findings of our study further support the concept that discriminating septic and nonseptic AKI may have clinical importance. In other words, septic AKI may differ from AKI induced by other factors and from sepsis not complicated by AKI [
19]. The mechanisms that account for these differences remain speculative, but they may relate to the physiological and immune consequences of either sepsis or AKI alone or of their additive and complex interplay. Studies have generally found septic AKI to be associated with older age, greater co-morbid disease, nonsurgical disease, greater severity of illness, more aberrancy in haemodynamic parameters, greater need for mechanical ventilation and vasopressor support, and greater disturbances in inflammation, haematology, and acid-base homeostasis [
12,
14‐
16,
18]. Two studies [
12,
13] have also found septic AKI to be associated with higher central venous filling pressures and lower urine output when compared with nonseptic AKI. Moreover, the concept that septic AKI may have a distinct pathophysiology is supported not only by experimental data and evidence from small clinical studies [
9,
20,
31‐
34] but also by epidemiological data showing 'dose-response' trends in incidence rates and outcomes for septic AKI by either severity of sepsis or AKI.
Rangel-Frausto and coworkers [
11] were the first to show how the incidence of AKI, defined by need for renal replacement therapy, increased significantly according to whether patients had sepsis (24%), severe sepsis (39%), or septic shock (89%). Lopes and colleagues [
14] showed that the rate of AKI increased from 29% to 51% when categorized from severe sepsis to septic shock. This study also found that the relative severity of AKI in septic shock was worse, with a greater proportion classified RIFLE category failure when compared with those with severe sepsis (64% versus 36%). We contend that the differences in pathophysiology between AKI due to sepsis and other aetiologies (ischaemia, toxin, cardiopulmonary bypass) may have important clinical implications for detection of early kidney injury, changes to kidney function and trajectory of AKI, along with the application of potential interventions to attenuate injury and promote kidney recovery.
Furthermore, all prior studies describing septic AKI have consistently concluded that septic AKI contributes to markedly higher mortality than either nonseptic AKI or sepsis alone [
12‐
16,
18]. These studies are in general agreement with our findings. Moreover, we were also able to show a 'dose-response' increase in mortality with greater severity of AKI by RIFLE category in sepsis compared with nonsepsis (Figure
2). We contend this also provides further support for the clinical relevance and robustness of the RIFLE classification system. Similarly, Neveu and coworkers [
15] previously found a near linear increase in mortality for AKI when categorized as nonseptic or associated with either sepsis syndrome or septic shock. This 'dose-response' trend for septic AKI was likewise apparent when evaluating durations of stay in ICU and hospital for survivors by severity of AKI. These data, within the context of prior investigations, logically imply that septic AKI may be distinct, may behave differently and may independently portend a worse prognosis. We contend that these findings have relevance for the management of the septic patient with AKI. Accordingly, a diagnosis of septic AKI may deserve consideration for separate stratification of randomization and
a priori identification for subgroup analysis when applying therapeutic strategies and/or designing future research investigations of the treatment of AKI.
There are limitations to our study. First, we estimated the occurrence of AKI at or within the first 24 hours of ICU admission only. Thus, we are unable to comment on the occurrence and outcomes for patients with ICU-acquired AKI or sepsis, which may be associated with a worse outcome [
35]. We recognize this may result in an underestimate of the true cumulative incidence of septic AKI. However, we believe that our data provide an important approximation of the disease burden associated with septic AKI. Second, we were unable to determine baseline creatinine values or the prevalence of chronic kidney disease with the exception of those with end-stage renal disease. However, this problem is not uncommon. We thus calculated an estimate of baseline function by use of the MDRD equation as recommended by the ADQI group [
24]. Nonetheless, these factors may contribute to a misclassification of some patients and result in an overestimate of the occurrence of septic AKI. Third, we were unable to describe changes over time in kidney function or transition between RIFLE criteria. Finally, we were unable to describe the association of initial RIFLE category to other clinical outcomes such as the proportion of patients receiving renal replacement therapy, long-term survival, or renal recovery beyond hospital discharge. Thus, whether septic AKI contributes to downstream morbidity and mortality conditional on hospital survival remains likely but unknown.
In summary, we conducted a multicentre observational study of the incidence and outcomes of septic AKI in a large heterogeneous cohort of critically ill patients. We showed that septic AKI is common and is associated with a higher burden of illness and greater abnormalities in acute physiology and laboratory parameters compared with either nonseptic AKI or sepsis alone. We have further shown that septic AKI confers an important and independent increase in risk for hospital death that exceeds that of either nonseptic AKI or sepsis alone. In survivors, septic AKI was also associated with prolonged ICU and hospital stays, and a greater likelihood of discharge to rehabilitation or another acute care facility. We contend that these data support the emerging concept that septic AKI may represent a unique pathophysiological condition. Moreover, we believe that future investigations should consider these differences in AKI pathophysiology when applying potential therapeutic interventions.
Competing interests
The authors declare that they have have no competing interests.
Authors' contributions
SMB and RB were responsible for study conception and design. CG was responible for acquisition of data. SMB and RB analyzed and interpreted the data. SMB drafted the manuscript. SMB, CG and RB critically revized the manuscript.