Severely burned patients often develop acute kidney injury (AKI), which contributes to high morbidity and mortality in these patients (1), even if they arrive at the hospital timely with adequate fluid resuscitation (2, 3). The median mortality of AKI was 34.9% in patients with severe burn injury (4), while that was 80% in the patients in need of renal replacement therapy (RRT) (5). To prevent AKI post-burn, it is crucial to identify high-risk factors so that relevant prophylactic measures can be taken in time (6, 7). Advances have been made in the understanding of AKI pathophysiology in these patients. However, this had not been translated to significant advances in treatment or an improvement in mortality outcome until recently. It is still hard to prognosticate and prevent the occurrence or progression of AKI after severe burn injury. Previous research focusing on AKI mostly reports events after general trauma (5), in which the prevalence and risk factors have been properly addressed. However, the inflammatory response, levels of hormone and inflammatory mediators in burn injury are different from those in other kinds of trauma (8). Compared with general trauma, the pathological differences in severe burn injuries make AKI post burn more difficult to predict (6). Severe burn injury initiates AKI-risk factors including trauma stress (5, 9), hypovolemic shock resulted from fluid and protein translocation in early stage, as well as excess tissue fluid returning to blood (10), invasion of pathogenic microorganisms and sepsis in the late stage (11). Therefore, reducing the incidence of AKI and improving the prognosis of burned patients with AKI are still facing significant difficulties and challenges. Prevention and mitigation nephrotoxicity are best strategies to attenuate AKI risk or progression, although AKI is often unavoidable in severely burned patients. Effective prevention and treatment methods are still being explored. Clinical characteristics, inflammatory response, levels of hormone and inflammatory mediators are also different in different periods post severe burn. Therefore, it is reasonable for AKI be classified into early AKI (0–3 days after injury) or late AKI (more than 3 days after injury) depending on its onset time after burn (1). We hypothesized that AKI is frequently encountered and the time of occurrence of AKI is associated with mortality of severely burned patients.

The aims of the present study were (1) to describe the epidemiology of AKI in a large burn center, (2) to evaluate the risk factors for AKI in severely burned patients, and (3) to assess the relationship between AKI (early and late AKI) and mortality.

We conducted a retrospective observational study in the Institute of Burn Research, First Affiliated Hospital (Southwest Hospital) of the Third Military Medical University, China. The institution manages 125 inpatient beds and 18 ICU beds, receives approximately 1,300 burned patients annually (12), and integrates medical treatment, rehabilitation, nursing, and scientific research of burns. The study was approved by the Ethics Committee of the First Affiliated Hospital of Third Military Medical University of PLA (KY201817).

In this retrospective observational study, it was found that firstly, AKI was still a serious issue in severely burned patients with 36.9% occurrence, and AKI was independently associated with a threefold risk of mortality in severely burned patients. Second, it was obvious that AKI occurred early, with 74% of AKI diagnosed within the first 3 days after severe burn injuries, but late AKI had higher mortality. Third, the AKI predicting model was proved to include age, gender, TBSA, full-thickness burns of TBSA, chronic comorbidities (hypertension or/and diabetes), hypovolemic shock of early burns, inhalation injuries, and serum myohemoglobin. Tracheotomy and sepsis were independent risk factors for AKI.

AKI is a common complication in severely burned patients. The incidence of AKI in burned patients varied from 1% to 36% depending on the different population studied and diagnostic criteria, and the mortality among burned patients with AKI was 28% to 100% (20). Other studies have shown that AKI occurred in 53.3% of patients with severe burn injuries, and patients with AKI had a mortality rate of 34.4% (4). In this study, the incidence of AKI was 36.9% in the patients with burn ≥30% TBSA; the total mortality was 34.2% in the patients with AKI, highest in the patients with late AKI with the mortality up to 57.1%, which was higher in burn patients than in general population (5). Therefore, it is crucial to early prevent and diagnose AKI in severely burned patients. However, in our other study, we found the incidence and mortality of AKI have not decreased in the consecutive six years. It is particularly urgent to reduce occurrence of AKI after burn.

In multinomial logistic regression, the study found that age, gender (male), TBSA, full thickness burns of TBSA, hypertension or/and diabetes, tracheotomy and hypovolemic shock of early burns were independently associated with both early and late AKI development, and sepsis was an independent risk factor for late AKI. However, BMI and drink, smoke, ABSI, etiology of burns and inhalation injuries had no influences, which is similar to previous studies (21–23). The risk of the aged and male patients suffering early and late AKI increased by over one to five folds, which is in agreement with some studies (24–26), while others found gender is not a predisposing factor for AKI (10). Considering that more male patients may be engaged in electrical works and suffered electrical injuries which may be a risk factor for AKI, this result was not changed after analyzing the cases of thermal burns (data not shown). The severity of burns is largely determined by burn area and depth. Major burn size is associated with multiple organ dysfunction and poor prognosis, and burn size is an independent predictor of acute renal failure (13). In this study, TBSA and full-thickness burns of TBSA strongly correlated with AKI. Patients with hypertension or/and diabetes underwent chronic pathological changes in organs including the heart, brain, kidneys and blood vessels causing deterioration of renal function, and were more predisposed to AKI (20). Inhalation injury was a severe complication of burn injuries, and was often associated with AKI (23). Though univariate analysis in this study showed significant difference in inhalation injury between the groups, there was no evidence of an independent inhalation injury effect after adjusting for potential confounders. This result is consistent with recent study (27). This could be because most mild to moderate inhalation injuries in this study did not develop to ARDS, which was proved to be a risk factor for AKI. ARDS is an important pathophysiologic link between acute lung injury and AKI and the existence of the “lung-kidney crosstalk” (27–29). Tracheotomy was an independent risk factor for early AKI [OR = 2.34 (1.34–4.01)] and late AKI [OR = 3.71(1.58–8.72)]. This can be explained as that the patients with tracheotomy were more seriously ill with inadequate oxygenation and needed mechanical ventilation support. Meanwhile, there may be complications of secondary pulmonary infection induced by tracheotomy and mechanical ventilation. However, we also included a few patients to perform prophylactic tracheotomy for compression of the neck and laryngeal edema after burns.

There are different pathophysiological features and potential mechanisms for burn-related AKI at different stages after burns. Hypovolemic shock is the main complication of major deep burns in the resuscitative phase, with a hugely harmful influence on the whole course of severe burns (30), when consequent sepsis and MODS increased the mortality accordingly. This study confirmed that hypovolemic shock of early burns is also a risk factor for AKI in severely burned patients. It has always been believed that renal hypoperfusion leads to ischemia and ischemia-reperfusion injury, and timely and aggressive fluid resuscitation can reduce the incidence of AKI and improve prognosis (31). We paid attention to the early fluid resuscitation after burns, and drafted the TMMU protocol for fluid resuscitation in the 1960s, which has been followed to save lives of innumerable burn patients, and until now it is still widely used in China (32). However, aggressive fluid resuscitation did not completely avoid AKI (33, 34). Furthermore, excess resuscitation was associated with some complications, including pneumonia, ARDS and elevated compartment syndromes (33, 35). This study found the earliest onset of AKI was 3 h (or may be earlier) after burns, and AKI was still developed in burn patients who received rapid fluid resuscitation, with normal or slight decrease of urine output. Hemorrhagic shock and septic shock in animal experiments demonstrated that immediate fluid resuscitation was sufficient to restore systemic blood pressure but failed to restore renal tissue oxygenation (36, 37). Therefore, etiology of early AKI is multifactorial, not solely focusing on the amount of fluid received. Renal vasoconstriction by stress-related hormones (catecholamines, angiotensin II, aldosterone, vasopression, etc.), inflammatory mediators, denatured proteins (myoglobin, myoglobinuria, free haemoglobinuria, etc.) are probably also associated with the occurrence of AKI (1). It was also observed that sepsis was the main reason for late AKI 3 days after burns, and was an independent risk factor for late AKI. This was consistent with a former study (36). Interestingly, late AKI occurred before the change of urine volume. On the day of initial diagnosis, urine of patients with late AKI did not decrease (100 mL/h), but sCr increased (156 µmol/L). It is likely that renal blood flow did not decrease, but the creatinine clearance has already been markedly reduced. This confirms that the inflammatory mediators and microcirculation dysfunction mainly caused by sepsis and infection contribute to the development of late AKI (38).

Myohemoglobin (myoglobin) is a harmful product of rhabdomyolysis, which is a clinical syndrome secondary to skeletal muscle injury (39). Rapid release of myohemoglobin is the main cause of renal failure, and the pathophysiology is as follows: renal vasoconstriction with resultant ischemia, tubular obstruction due to myohemoglobin cast formation, and direct nephrotoxicity. In severely burned patients, myohemoglobin was proved to have a very stable predictive value for AKI with pronounced sensitivity and specificity (40), as is also reported in other traumatic injuries (41).

It is interesting to note that decompression escharotomy of circumferential burns probably reduced the risk of AKI development. Circumferential eschar, generally resulted from third-degree burns, can cause compression of the underlying soft tissues as burn edema develops and lead to compartment syndrome (42). With the increase of the compartment pressure, ischemia of the underlying tissues and the distal tissues will result in tissue and muscle necrosis, and lactic acidosis without timely decompression escharotomy. Toxins released from necrotic tissue are an important etiology of AKI. Decompression escharotomy should be considered earlier, especially in patients with very deep thermal and/or electrical injuries, as it may be effective in the prevention of AKI.

Several studies have emphasized that AKI is independently related to adverse clinical outcomes in trauma patients (5) and ICU patients (43). In this cohort, AKI was independently associated with high mortality (28- and 90-day mortality). Thus, renal dysfunction serves as an additional predictor of huge risk of mortality in severely burned patients. Mortality of patients with late AKI was significantly higher than those with early AKI as well as incidence of sepsis, septic shock, and usage of vasopressors. Probably main reason of late AKI was sepsis, which had bad prognosis.

This study is not a multicenter study, though the total number of AKI patients in the sample far exceeded the recommended number for building a model to provide predictions (19). This study evaluated comprehensive characterization of clinical parameters of severely burned patients with AKI, and demonstrated an association between risk factors and AKI occurrence, but has not established causality. Fortunately, the single center study performs a better stability in burn patients’ data managing, diagnosis criteria and treatment, which ensure that the data are more convincible than a multicenter database where subjective factors might be amplified.

A sensitive and specific biomarker for an accurate early diagnosis of AKI is urgently needed even in the absence of subsequent dysfunction. The novel biomarker is probably a produced material of damaged kidney itself, just like the specific cardiac troponin protein produced immediately when myocardial infarction occurs.

AKI which is independently associated with high mortality in severely burned patients, is still highly prevalent. Age, gender, TBSA, full-thickness burns of TBSA, hypertension or/and diabetes, tracheotomy, hypovolemic shock of early burns and sepsis are independent risk factors for AKI. Decompression escharotomy is clearly associated with decreased risk for AKI, especially for late AKI. It is crucial to adopt early effective and individualized prevention strategies for severely burned patients to prevent AKI from taking their lives.