Bimodal distribution of trauma-related acute kidney injury (TrAKI): A clinical review

The severity of trauma injury has been associated with AKI [8,9,11,13,16,23,24,25,26,27,28,29] (Table 1). Injury severity score (ISS), as an established grading score, has been correlated with morbidity and mortality [1,9,10,36,37]. To be mentioned that the basic limitation is that ISS appraises only injuries and not their physiological consequences [1,9,10,36,37]. For example, a patient with severe brain injury and spinal cord trauma has a high ISS but not necessarily hemorrhagic shock or severe systemic inflammatory syndrome, that could both lead to organ dysfunction. On the other hand, a patient with long bone fractures, although has a low ISS, is likely to need massive transfusion and multiple surgical interventions, leading to severe RM and inflammatory response. However, even though ISS may not be an accurate AKI risk factor, it has been related to renal dysfunction [8,11,16,18,23,24,25,26,27,28,29].

Furthermore, direct renal trauma has also been associated with higher AKI prevalence, since kidney parenchyma and vessel injury reflect functional nephron loss, leading to glomerular filtration inability [12,13]. Abdominal injury and increased abbreviated injury scale (AIS), have also reported as risk factors for AKI, since they may indicate the severity of retroperitoneal or intraperitoneal hemorrhage, leading to hypovolemia, renal hypoperfusion and possible ACS [1,11,12,13]. Besides, damage control surgery packing in such cases could further deteriorate the existed intra-abdominal hypertension (IAH), worsening [17,38].

There is increasing evidence for the association between TrAKI and the severity of brain injury [9,12,14,15,18,24], since a low Glasgow Coma Scale (GCS) score has been related to hypoventilation, hypoxemia and secondly to necessity of critical care treatment [17] (Table 1). Moreover, routinely treatment with mannitol in intracranial hypertension has been associated with renal deficiency, while adequate intravascular volume maintenance and low-dose (0.3 g/kg) mannitol infusion, intracranial pressure (ICP)-directed, seems to be beneficial on the occurrence of AKI [15]. The use of antihypertensive agents or an aggressive systolic blood pressure (SBP) reduction in patients with intracerebral hemorrhage have, also, been associated to trigger AKI [9]. Furthermore, severe traumatic brain injury patients, that usually need prolonged ventilatory support, ICU and hospital stay, are exposed to a great number of delayed complications, triggering “late” AKI [24].

Traumatic hemorrhagic shock is a state of inadequate cellular energy production and a major cause of trauma mortality and serious complications among survivors, such as AKI [39]. Acute, severe hemorrhage, by decreasing intravascular blood volume, can cause hypovolemia, hemodynamic instability, cardiac output reduction, inadequate tissue perfusion, cellular hypoxia, organ dysfunction and ultimately death [40].

Consequently, it can affect kidney homeostasis minimizing oxygen delivery through multiple mechanisms. Firstly, hypotension and reduced cardiac output due to hypovolemia directly decreases renal arterial blood supply, when arterial pressure level reaches the inferior limit of autoregulation [37]. Further, the recruitment of mechanisms aiming at stabilizing circulation, such as the activation of the sympathetic system and the renin/angiotensin axis leads to intra-renal vasoconstriction, particular at the efferent limb creating post-glomerular tubular blood hypoperfusion [41]. This is, additionally, aggravated by post-hemorrhagic anemia, which decreases the absolute amount of oxygen delivered to tissues [42]. Indeed, histological studies of hemorrhage-induced AKI demonstrated evidence of acute tubular necrosis, such as loss of tubular brush border, epithelial cell vacuolation up to epithelial desquamation, while hypoxia-inducible factor-1a (HIF-1a) is detected early [42].

On the other side, while hemorrhage itself seems to induce inflammation, resuscitation leads to renal oxidative stress, since the amount of produced superoxide anion can trigger cell apoptosis [37]. Experimental evidence show that 90 minutes of hemorrhagic shock are enough to raise the renal expression of Tumor Necrosis Factor-a (TNFa) and interleukin-6 (IL-6). Adhesion molecules, such as, intercellular adhesion molecule-1 (ICAM-1) and E-selectin are upregulated in endothelial cells, promoting leukocyte deceleration and transmigration into the renal parenchyma [43]. Interestingly, mere ischemia is not capable to induce those alterations, since reperfusion is essential for them to fully develop. Other potent pro-inflammatory mediators, like high-mobility-group-box 1 (HMGB-1) or the receptor for advanced glycation endproducts (RAGE) have also been reported to rise in the renal tissue following hemorrhage, while the role of mediators released from the ischemic gut is also to be taken into account [44].

Severe hemorrhage treatment includes primarily the blood lose minimize, and at the same time monitoring-guided fluid infusion and coagulopathy management, aiming to restore intravascular volume, hemodynamic stability and tissue perfusion [33,39]. Therefore, fluid resuscitation is a cornerstone of pre- and in-hospital trauma care [40]. However, aggressive fluid resuscitation has been associated with exacerbating acute bleeding by increasing hydrostatic pressure and decreasing clot firmness [40].

Permissive hypotension based on maintaining blood pressure at a lower-than-normal level, that ensure an adequate organ perfusion, has been reported to reduce bleeding, minimize blood transfusion and improve mortality [45,46]. Current recommendations suggest for traumatic hemorrhagic shock without severe head injury, to titrate fluids and use early vasopressors to maintain permissive hypotension (target SAP 80–90 mm Hg or MAP 60–65 mm Hg), until hemorrhage control [47]. If traumatic brain injury is associated to severe hemorrhage, guidelines recommend targeting a SBP above 110 mm Hg [47].

Hypotensive resuscitation, in traumatic hemorrhagic shock, aims to minimize the resuscitation volume and blood product transfusion avoiding further bleeding and sustaining organ perfusion, since surgical treatment [45,46,48]. Although hypotensive resuscitation has been correlated with better outcome and non-significant AKI incidence [45,46,48], no study indicates the optimal level of MAP in hemorrhagic shock, in order to prevent renal disfunction [37]. Therefore, a short-term hypotension could be acceptably tolerated, while in case of patient’s deterioration, adequate fluid volume should be infused [49]. To be mentioned that retrospective data indicate an association between prolonged permissive hypotension and organ hypoperfusion and multiorgan dysfunction [50], while seems to increase mortality among elderly trauma patients [51,52,53].

Fluid administration could be harmful itself, due to either the large infused volume or the fluid composition. Fluid resuscitation should be monitoring-guided [15], since while hypovolemia could cause renal ischemia, fluid overload may lead to severe tissue and pulmonary edema, cardiac dysfunction, gastroenteric dysmotility, coagulation disorders, ACS and immunological disturbance [39]. Besides, volume overload has been associated to reperfusion-related inflammation, as it has been shown in experimental models where extended edema, capillary leakage and leukocyte adhesion were observed [39]. In addition, it has been demonstrated that a controlled infusion of crystalloids in elderly patients was associated with a better outcome [54], while when trauma patients received more than 1.5 liter of crystalloid in the ER a higher mortality was marked [55]. Jones et al, also, reported proportional higher mortality and prolonged need of mechanical ventilation, when administrated more than 5 liters crystalloids in patients within 24 hours of trauma [39].

Current guidelines advocate for goal directed fluid administration with repeated 250 ml fluid boluses until regaining of specific blood pressure levels, before bleeding control [40]. These strategies, however, have not been evaluated by large prospective randomized clinical trials, and demographic factors such as age, comorbidities and previous medical history could modify the resuscitation strategy [40]. Recent data, for example, suggests that the elderly could benefit from higher blood pressure goals [45,51,52,53]. Whether larger volumes of infused fluids and blood products or earlier vasopressor initiation would be the appropriate tool to obtain these targets remain unknown [40].

The type of infused fluids seems to play a crucial role in kidney hemostasis and final outcome. Isotonic crystalloid solutions are the first-line therapy for fluid expansion, to correct post-traumatic hypovolemia [37,40]. Normal saline (NaCl 0.9%) was considered as the basic resuscitation fluid until recently, since Ringer’s Lactate, with o slightly lower osmolarity (308 vs. 273 mmol/l respectively) was supposed to increase intracellular space volume and worsening intracranial hypertension [37]. However, NaCl 0.9% has been related to hyperchloremic acidosis, more renal adverse effects [56] and higher mortality compared to Ringer’s Lactate solution [57]. On the other hand, synthetic colloids were proposed as potential fluids with great oncotic ability [37]. However, since June 2013 [58] the US Food and Drug Administration withdrawn hydroxyethyl starch, due to the increase incidence of AKI and mortality, especially among septic patients [33]. On the other hand, although hypertonic saline (7.5% saline) has long been considered to have potential benefits due to rapid restoration of intravascular volume with small intravascular volume administration, reduction of intracranial pressure and modulation of inflammatory response, failed to demonstrate an outcome benefit [59]. After these, although the SPLIT [60], BaSICS [61] and PLUS trial [62] failed to show a benefit regarding mortality or AKI incidence, using balanced crystalloids, like Plasmalyte, as resuscitation fluid, compared with Normal Salin, balanced crystalloids have been promoted as more nephroprotective [63].

Previous studies have presented an increased risk of AKI among trauma patients that required massive blood products transfusion [8,10,11,13,16,23,26,28] (Table 1). However, it is not clarified if the necessity for the transfusion or the transfusion itself is related to AKI. The amount of transfusion could be an index of trauma severity, the blood volume loss, hypovolemia, tissue hypoperfusion and finally tissue ischemia. Besides, transfusion may provoke systemic inflammatory response and cytokine release, leading to renal impairment [11,13]. Additionally, stored red blood cells, following transfusion, gradually release hemoglobin, which not only has direct toxic effects on renal tubules, but also depletes nitric oxide (NO), impeding its vasodilatory effects upon renal vessels [64]. In conclusion, current guidelines recommend minimizing the need of transfusion. After early hemorrhage control, the treatment should focus on correction of metabolic derangements and hypothermia to decrease coagulopathy and substitution according to viscoelastic assays [65] and blood gases analysis with tranexamic acid, fibrinogen concentrate, red blood cells, plasma and platelets [66].

Computed tomography routinely evaluates the severity and anatomical distribution of traumatic area. In most cases, the use of potential nephrotoxic contrast media is required [25,37]. In addition, other possible renal harmful agents, such as aminoglycosides and non-steroidal-anti-inflammatory drugs are widely dispensed to trauma patients. Although latest contrast mediators supposed to be less nephrotoxic, thoughtful awareness is needed regarding to the necessity for contrast assisted imaging, minimizing non-essential radiological exams and unnecessary probable detrimental antibiotics [37].

Rhabdomyolysis severity, as assessed by the creatinine kinase (CK) peak, has been found as an additional independent risk factor for AKI [13,23,25,26,29] (Table 1). RM can be induced by direct insult, such as crush syndrome, extensive muscular injury or major surgery, and indirect muscular injury due to massive hemorrhage or vascular damage [29]. It can be presented either as asymptomatic serum myoglobin and CK elevation, or even as severe AKI with serious disseminated intravascular coagulation. CK, as an index of RM severity, is related to the amount of possible, nephrotoxic, intramuscular content release and reaches the highest level within 17 hours post-traumatic [26]. RM-related AKI is caused by renal vasoconstriction due to myoglobin, tubular obstruction, tissue ischemia, oxidative stress and inflammation [26,37]. Myoglobin promotes superoxide anion production in the vessel wall of afferent arterioles, reducing NO bioavailability. As a result, myoglobin enhances Angiotensin II-induced constriction of renal afferent arterioles, causing renal hypoperfusion and tubular hypoxia [67]. Moreover, myoglobin, may accumulate in renal tubules, which is exacerbated in acidosis, caused by hypovolemia, obstructing renal tubules [37]. Finally, it activates endothelium and neutrophils leading to renal inflammation and ultimate renal fibrosis [37].

The diagnosis of RM is likely to be underestimated among trauma patients. Both CK and myoglobin levels are commonly used biomarkers for diagnosing RM [29]. Implementing measures to diagnose RM and assess its severity can help evaluate patient prognosis from the early days of treatment. Currently, there is no specific therapy, except from preventive measures to mitigate renal impairment [68]. Such measures include primary volume resuscitation, in order to promote renal tubule flow, dilute nephrotoxins such as myoglobin and supply adequate renal perfusion to prevent AKI [68]. To be mentioned that administration of sodium bicarbonate and diuretics, for prevention of AKI, are not recommended [69]. Secondly, electrolytic abnormalities, such as hyperkalemia, hyperphosphatemia, hypocalcemia and hypomagnesemia, should be corrected [70]. Finally, the utilization of RRT in patients with RM should be based on AKI indications since it has no effective preventive role [69,70,71].

Traumatic IAH, defined as an elevation of intraabdominal pressure (IAP) above 12 mm Hg, and ACS as a sustained IAP above 20 mm Hg [37], has been reported to constitute a crucial cause of renal impairment due to kidney vessels and parenchyma compression and cardiac output reduction [72,73]. Major intrabdominal and/or retroperitoneal bleeding, due to pelvic or abdominal trauma could cause IAH in 0–37% of incidence, raising AKI prevalence in 42–50% [72]. AKI in ACS seems to be related to the external renal compression and consequential hypoperfusion. Experimental studies reported direct compression of renal veins and affected GFR, which were returned back to normal as soon as vein flow was restored. This simulates abdominal surgical decompression, which restores diuresis in ACS [73]. Volume overload and invasive mechanical ventilation, in such cases, could further deteriorate renal interstitial edema, increasing intrarenal pressure rapidly, due to capsula’s low compliance [73,74].

Transvesical intra-abdominal pressure measurement remains the strategy of choice to diagnose IAH and ACS [75]. Biomarkers, such as urinary and plasma intestinal fatty acid binding protein (iFABP), have not proved value in predicting IAH-related complications in ICU patients [76,77]. Damage control surgery (DCS) is a surgical strategy that was primarily used in unstable trauma patients and includes an abbreviated surgical procedure aimed at control hemorrhage, open abdomen treatment and delayed repair of anatomical injuries [75]. Of note, deepening of sedation in mechanical ventilated trauma patients with IAH, had not a significant effect in IAH controlling, while required increased vasopressor doses, which finally decrease abdominal perfusion pressure [78].