Background
Organ dysfunction remains the third leading cause of death in trauma patients, after hemorrhage and traumatic brain injury [
1]. Among organ failure after trauma, AKI is common, with reported incidence up to 50% and has been independently associated with prolonged hospital length of stay and mortality [
2,
3].
Severe trauma triggers initial AKI risk factors including hemorrhage, rhabdomyolysis, traumatic inflammation and leads to second hits due to emergency surgery or infections that may cause additional renal disorders resulting in renal function impairment. Identifying AKI risk factors after trauma is essential to establish a strategy aiming to prevent AKI and its related complications. Previous studies reporting AKI incidence after trauma focused either on medical history [
4,
5], hemodynamic variables [
6,
7], type of trauma [
8] or rhabdomyolysis [
9] as potential risk factors for AKI, but including all of them would provide a more complete overview of the renal aggression associated with renal dysfunction. Moreover, the prehospital period is hardly taken into account, yet it is a time during which renal aggression is likely to occur (i.e. hypotension, hypoxemia). In addition, most studies included patients who were admitted to the intensive care unit (ICU) after trauma, subsequently selecting those who are the most severely injured, even though attention should also be paid to patients with moderate injuries.
The objectives of this study were (1) to report the prevalence of AKI, (2) to describe risk factors associated with AKI and (3) to explore whether AKI is independently associated with mortality in a multicenter cohort of trauma patients whose characteristics and physiological variables are prospectively collected in a research registry.
Discussion
In this 3-year multicenter observational study, we found that AKI occurred in 13% of trauma patients but this increased up to 42% in patients presenting with hemorrhagic shock. Second, we also found that AKI occurred early, with 96% of AKI diagnosed within the first 5 days after traumatic injury. Third, the model predicting AKI performed well and provided early risk factors for AKI that are markers of hypoperfusion and metabolic aggression (admission lactate value, hemorrhagic shock, minimum prehospital MAP and maximal prehospital heart rate), injury severity (ISS), renal trauma and delayed admission. Fourth, rhabdomyolysis severity (CK peak) was an additional independent risk factor for AKI. Fifth, AKI was independently associated with an increased risk of ICU mortality. To our knowledge, this is the largest multicenter cohort of trauma patients in which AKI risk factors were assessed. For the first time, in association with hospital variables collected early on admission, we report prehospital variables to predict the occurrence of AKI after trauma. This is all the more relevant that AKI has an early onset after trauma, thereby calling for its early prediction to direct treatment aiming to prevent AKI.
The overall incidence of 13% of AKI is consistent with previous studies, though wide ranges of AKI proportions from 1 to 50% have been reported in trauma patients [
2‐
6,
8,
9,
17,
18,
28,
29]. These large differences between studies are likely to be due to AKI criteria, length of follow up and severity of trauma that are different from one study to another [
11]. Our cohort of patients had a median ISS of 14, which is less severe than reported elsewhere [
2,
8]. However, 13% of AKI is significant and calls for attention to patients’ kidney function after trauma. Moreover, when considering subpopulations of patients with an ISS > 16 or requiring blood transfusion, AKI prevalence rose to 21% and 28%, respectively, which was similar to studies including severely injured patients admitted to ICU [
6,
9,
17]. The percentage of AKI (42%) in patients presenting with hemorrhagic shock is among the highest reported in the literature [
2,
4]. In the future, studies investigating AKI prevention should take into account this highly variable rate according to the trauma population to which they refer. Our large proportion of patients with early AKI is consistent with recent findings showing that post-injury multiorgan failure develops early in the course of post-trauma care (median delay of 2 days) [
30,
31], without bimodal distribution [
32].
The severity of trauma injuries (ISS) was associated with AKI in our study, which is inconsistently reported in other studies in the field of trauma [
4,
5,
17]. A high ISS is not in itself an indicator of renal aggression but rather a marker of the amount of wounded tissue that may ultimately promote systemic inflammation and subsequently renal failure [
33,
34]. Severe renal trauma (AIS ≥ 3) was also associated with the occurrence of AKI all stages, suggesting that severe renal parenchyma (or vessel) injuries can decrease functional nephron mass and subsequently lead to a decrease in glomerular filtration rate. We considered several hemodynamic variables in our model. Hemorrhagic shock (> 4 RBC units within 6 h), blood lactate, minimum prehospital diastolic arterial pressure (DAP) and maximum prehospital heart rate were associated with AKI. Blood transfusion is a marker of the amount of bleeding, which in and of itself can lead to hypoperfusion and AKI [
4,
6,
35]. Blood lactate is reported elsewhere to be associated with AKI [
7,
17]. Its value on arrival to the hospital indicates, even in the absence of hypotension, the importance of cumulated metabolic debts due to tissue hypoperfusion [
36]. Interestingly, low prehospital MAP, an early available parameter, added independent information to hemorrhagic shock and blood lactate to predict AKI.
Patients directly transported to a trauma center were less likely to experience AKI than those who were secondarily admitted to the referral trauma center. The most common reasons for such transfers include injuries requiring specialized care that cannot be provided in the first hospital the patient was admitted to, thereby corresponding to under-triage. Early admission to the referral trauma center likely allows earlier hemorrhage control and injury care, preventing renal aggression. Surprisingly, age was not significantly associated with AKI. This has been reported elsewhere [
4,
17] and may be explained by the youthful cohort in our study. We report no significant association between use of vasopressors and AKI. No previous study has ever addressed the link between AKI and the use of vasopressors in trauma patients. However, previous retrospective studies have highlighted an association between the use of vasopressors and mortality in trauma patients [
37‐
39]. By correcting for confounding factors, our group recently reported in a large multicenter study that early use of vasopressors was not associated with mortality in trauma patients presenting with hemorrhagic shock [
15]. Similar to this study, our predictive model takes into account the most relevant factors of illness severity, which may explain the lack of association between vasopressors and AKI. Severity of rhabdomyolysis as assessed by the CK peak was a risk factor for AKI. CK is not nephrotoxic in itself but its level is a measure of the severity of intramuscular content release and as such, the higher the CK peak the more intense the release of intramuscular mediators that have nephrotoxic properties. However, CK peak is reached with a median time of 17 h after trauma and cannot be a relevant early predictor of AKI [
40]. Future studies should focus on early prediction of severe rhabdomyolysis to indicate therapy aiming to prevent rhabdomyolysis-induced AKI. Regarding exposure to nephrotoxic agents, the use of angio-embolization was not a significant risk factor for AKI in the predictive models. This might be due to the negligible nephrotoxic risk promoted by the use of contrast agents for angio-embolization in comparison with inflammation, hypotension and tissue hypoperfusion. However, we cannot rule out contrast nephrotoxicity since every patient underwent contrast-enhanced (total body) CT, which may have increased baseline risk of AKI in the whole population. Moreover, we could not report the amount of contrast agent used during angio-embolization procedures.
Regarding AKI prediction, none of the variables associated with AKI performed satisfactorily to individually discriminate the occurrence of AKI stage I or F. However, by using prehospital and early hospital variables, our logistic regression model performed well to predict AKI stage I or F with an AUC-ROC of 0.85. The model for AKI all stages (R, I or F) performed worse, with an AUC-ROC of 0.80. By comparison, in a well-conducted study, Haines et al. recently used hospital variables to build a model predicting stage 2 or 3 AKI (Kidney Disease Improving Global Outcome (KDIGO) classification) in trauma patients, with an AUC of 0.81, while their model predicting AKI of all stages had an AUC of 0.77 [
35]. Taking into account additional AKI risk factors such as AKI biomarkers or plasma inflammatory markers might help to improve AKI prediction in future studies.
Several investigations have emphasized that AKI is independently linked to adverse clinical outcome in ICU patients [
41] or in trauma patients [
3‐
5,
17,
42]. In the present study, AKI was independently associated with mortality even taking into account standard scores for trauma severity like TRISS. Thus, renal failure represents an additional marker of high risk of mortality in trauma patients.
There are several limitations to our study. This is a retrospective study, though data used in the study were prospectively collected and registered in a research database. Since blood lactate and CK were not systematically measured in trauma patients during the study period, missing values led us to exclude patients from the predictive models. However, the number of AKI patients in our sample far exceeded the number of events that is recommended (at least 10 events (10 patients with AKI) per candidate variable) when building a predictive model and therefore is expected to provide robust estimates [
27]. Data on comorbidities were not collected in our database, including data on chronic kidney disease, which is regularly reported to be a risk factor for AKI in the ICU. However, our trauma patients are young and are likely to have no past medical history, in contrast to the general ICU population. Reporting data on the use of nephrotoxic agents (synthetic colloids, antibiotics and regular angiotensin converting enzyme inhibitors) would have added relevant information to the study but these data are not collected in our database. The TraumaBase group used RIFLE criteria to categorize AKI at the time of the study, which may have underestimated AKI in comparison with more recent classifications (i.e. KDIGO) that are more sensitive for AKI diagnosis in ICU patients [
43]. AKI diagnosis was only based on creatinine criteria. By not taking into account urine output criteria, we may have further underestimated AKI prevalence. We used the lowest serum creatinine value during the first 5 days of the ICU stay as baseline creatinine. This may have resulted in a lower estimate of baseline creatinine than back-calculation through the MDRD formula with a glomerular filtration rate of 75 mL/min per 1.73 m
2. Nevertheless, the definition we used was reported to be more accurate to diagnose AKI in ICU patients than creatinine estimated by MDRD [
44], especially in trauma patients whose baseline serum creatinine is overestimated by MDRD [
20]. Last, this study demonstrated an association between risk factors and AKI but cannot establish causality.
Acknowledgements
Collaborating author names of the TraumaBase® Group: Olivier Langeron, MD, PhD (Sorbonne Universités, UPMC Univ Paris 06 and Department of Anaesthesiology and Critical Care, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, AP-HP, Paris, France); Catherine Paugam-Burtz, MD, PhD (Université Denis Diderot and Beaujon University Hospital, Hôpitaux Universitaires Paris Nord-Val-De-Seine, Clichy, AP-HP, France); Romain Pirracchio, MD, PhD (Université Paris Descartes and Department of Anaesthesiology and Critical Care, Hôpital Européen Georges Pompidou, APHP, Paris, France); Bruno Riou, MD, PhD (Sorbonne Université, UMRS 1166, IHU ICAN and Department of Emergency Medicine, Groupe Hospitalier Pitié-Salpêtrière-Charles Foix, AP-HP, Paris, France); Guillaume de Saint Maurice, MD (Anaesthesiology and Critical Care, Hôpital d’instruction des armées Percy, Clamart, France); Xavier Mazoit, MD, PhD (Department of Anaesthesiology and Critical Care, Hôpital Bicêtre, Groupement Hôpitaux Universitaires Paris Sud, AP-HP, Kremlin Bicêtre, France).