Physical trauma can affect any individual and is globally accountable for more than one in every ten deaths. Although direct severe kidney trauma is relatively infrequent, extrarenal tissue trauma frequently results in the development of acute kidney injury (AKI). Various causes, including haemorrhagic shock, rhabdomyolysis, use of nephrotoxic drugs and infectious complications, can trigger and exacerbate trauma-related AKI (TRAKI), particularly in the presence of pre-existing or trauma-specific risk factors. Injured, hypoxic and ischaemic tissues expose the organism to damage-associated and pathogen-associated molecular patterns, and oxidative stress, all of which initiate a complex immunopathophysiological response that results in macrocirculatory and microcirculatory disturbances in the kidney, and functional impairment. The simultaneous activation of components of innate immunity, including leukocytes, coagulation factors and complement proteins, drives kidney inflammation, glomerular and tubular damage, and breakdown of the blood–urine barrier. This immune response is also an integral part of the intense post-trauma crosstalk between the kidneys, the nervous system and other organs, which aggravates multi-organ dysfunction. Necessary lifesaving procedures used in trauma management might have ambivalent effects as they stabilize injured tissue and organs while simultaneously exacerbating kidney injury. Consequently, only a small number of pathophysiological and immunomodulatory therapeutic targets for TRAKI prevention have been proposed and evaluated.
Trauma is a major cause of death worldwide. Although direct kidney injury is infrequent, one in four patients with severe injuries subsequently develops trauma-related acute kidney injury (TRAKI).
Trauma management prioritizes stabilizing vital physiological functions; however, several therapeutic interventions, such as mechanical ventilation, mass transfusion or the use of nephrotoxic drugs, which are used to stabilize the patient, often aggravate kidney injury.
TRAKI is a multifaceted syndrome that develops owing to numerous trauma-associated drivers of kidney injury — local and remote tissue damage, hypoxia, microcirculatory disturbances and ischaemia–reperfusion injury, as well as exposure to debris, pathogens and toxins.
Trauma-induced activation of innate immunity also promotes kidney injury — the complement system, the coagulation cascade, leukocytes and platelets function as a first line of defence to limit tissue damage but might also aggravate TRAKI.
The post-trauma immune response can disrupt organ barriers, including the blood–urine barrier, and both the innate immune and the autonomic nervous system are key components of kidney–remote organ crosstalk in TRAKI.
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Cole, E. et al. A decade of damage control resuscitation: new transfusion practice, new survivors, new directions. Ann. Surg. https://doi.org/10.1097/SLA.0000000000003657 (2019).
World Health Organization. Injuries and Violence: the Facts. https://www.who.int/violence_injury_prevention/key_facts/en/ (WHO, 2010).
Harrois, A. et al. Prevalence and risk factors for acute kidney injury among trauma patients: a multicenter cohort study. Crit. Care 22, 344 (2018).
Haines, R. W., Fowler, A. J., Kirwan, C. J. & Prowle, J. R. The incidence and associations of acute kidney injury in trauma patients admitted to critical care: a systematic review and meta-analysis. J. Trauma. Acute Care Surg. 86, 141–147 (2019).
Søvik, S. et al. Acute kidney injury in trauma patients admitted to the ICU: a systematic review and meta-analysis. Intensive Care Med. 45, 407–419 (2019).
The TraumaRegister DGU. et al. Trauma-induced coagulopathy upon emergency room arrival: still a significant problem despite increased awareness and management? Eur. J. Trauma. Emerg. Surg. 45, 115–124 (2019).
Kim, S.-M. et al. Inflammasome-independent role of NLRP3 mediates mitochondrial regulation in renal injury. Front. Immunol. 9, 2563 (2018).
Huber-Lang, M., Lambris, J. D. & Ward, P. A. Innate immune responses to trauma. Nat. Immunol. 19, 327–341 (2018).
O’Connor, M. E., Kirwan, C. J., Pearse, R. M. & Prowle, J. R. Incidence and associations of acute kidney injury after major abdominal surgery. Intensive Care Med. 42, 521–530 (2016).
Grams, M. E. & Rabb, H. The distant organ effects of acute kidney injury. Kidney Int. 81, 942–948 (2012).
Yap, S. C. & Lee, H. T. Acute kidney injury and extrarenal organ dysfunction: new concepts and experimental evidence. Anesthesiology 116, 1139–1148 (2012).
James, M. T., Bhatt, M., Pannu, N. & Tonelli, M. Long-term outcomes of acute kidney injury and strategies for improved care. Nat. Rev. Nephrol. 16, 193–205 (2020).
Simmons, M. N., Schreiber, M. J. & Gill, I. S. Surgical renal ischemia: a contemporary overview. J. Urol. 180, 19–30 (2008).
Gaibi, T. & Ghatak-Roy, A. Approach to acute kidney injuries in the emergency department. Emerg. Med. Clin. North Am. 37, 661–677 (2019).
American College of Surgeons & Committee on Trauma. Advanced Trauma Life Support: Student Course Manual (American College of Surgeons, 2018).
Kuiper, J. W., Groeneveld, A. B. J., Slutsky, A. S. & Plötz, F. B. Mechanical ventilation and acute renal failure. Crit. Care Med. 33, 1408–1415 (2005).
Harrois, A., Libert, N. & Duranteau, J. Acute kidney injury in trauma patients. Curr. Opin. Crit. Care 23, 447–456 (2017).
Ronco, C., Bellomo, R. & Kellum, J. A. Acute kidney injury. Lancet 394, 1949–1964 (2019).
Semler, M. W. et al. Balanced crystalloids versus saline in critically ill adults. N. Engl. J. Med. 378, 829–839 (2018).
Cannon, J. W. et al. Damage control resuscitation in patients with severe traumatic hemorrhage: a practice management guideline from the Eastern Association for the Surgery of Trauma. J. Trauma. Acute Care Surg. 82, 605–617 (2017).
Cotton, B. A., Guy, J. S., Morris, J. A. & Abumrad, N. N. The cellular, metabolic, and systemic consequences of aggressive fluid resuscitation strategies. Shock 26, 115–121 (2006).
Zarychanski, R. et al. Association of hydroxyethyl starch administration with mortality and acute kidney injury in critically ill patients requiring volume resuscitation: a systematic review and meta-analysis. JAMA 309, 678 (2013).
Moeller, C. et al. How safe is gelatin? A systematic review and meta-analysis of gelatin-containing plasma expanders vs crystalloids and albumin. J. Crit. Care 35, 75–83 (2016).
Meißner, A. & Schlenke, P. Massive bleeding and massive transfusion. Transfus. Med. Hemother 39, 73–84 (2012).
Spahn, D. R. et al. The European guideline on management of major bleeding and coagulopathy following trauma: fifth edition. Crit. Care 23, 98 (2019).
Goodnough, L. T., Levy, J. H. & Murphy, M. F. Concepts of blood transfusion in adults. Lancet 381, 1845–1854 (2013).
Van Avondt, K., Nur, E. & Zeerleder, S. Mechanisms of haemolysis-induced kidney injury. Nat. Rev. Nephrol. 15, 671–692 (2019).
Okubo, K. et al. Macrophage extracellular trap formation promoted by platelet activation is a key mediator of rhabdomyolysis-induced acute kidney injury. Nat. Med. 24, 232–238 (2018).
Wang, L. et al. Labile heme aggravates renal inflammation and complement activation after ischemia reperfusion injury. Front. Immunol. 10, 2975 (2019).
Ahuja, S. et al. Associations of intraoperative radial arterial systolic, diastolic, mean, and pulse pressures with myocardial and acute kidney injury after noncardiac surgery: a retrospective cohort analysis. Anesthesiology 132, 291–306 (2020).
Bellomo, R. & Giantomasso, D. D. Noradrenaline and the kidney: friends or foes? Crit. Care 5, 294–298 (2001).
Fähling, M., Seeliger, E., Patzak, A. & Persson, P. B. Understanding and preventing contrast-induced acute kidney injury. Nat. Rev. Nephrol. 13, 169–180 (2017).
Windpessl, M. & Kronbichler, A. Contrast-associated acute kidney injury (CA-AKI) in children: special considerations. Child. Kidney Dis. 23, 77–85 (2019).
Bihorac, A. et al. Incidence, clinical predictors, genomics, and outcome of acute kidney injury among trauma patients. Ann. Surg. 252, 158–165 (2010).
Perkins, Z. B. et al. Trauma induced acute kidney injury. PLoS ONE 14, e0211001 (2019).
Kellum, J. A. Why are patients still getting and dying from acute kidney injury? Curr. Opin. Crit. Care 22, 513–519 (2016).
Kellum, J. A. & Lameire, N., KDIGO AKI Guideline Work Group. Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1). Crit. Care 17, 204 (2013).
Kellum, J. A. & Prowle, J. R. Paradigms of acute kidney injury in the intensive care setting. Nat. Rev. Nephrol. 14, 217–230 (2018).
Xu, K. et al. Unique transcriptional programs identify subtypes of AKI. J. Am. Soc. Nephrol. 28, 1729–1740 (2017).
Stafford-Smith, M. et al. Genome-wide association study of acute kidney injury after coronary bypass graft surgery identifies susceptibility loci. Kidney Int. 88, 823–832 (2015).
Vilander, L. M., Kaunisto, M. A., Vaara, S. T. & Pettilä, V. & FINNAKI study group. Genetic variants in SERPINA4 and SERPINA5, but not BCL2 and SIK3 are associated with acute kidney injury in critically ill patients with septic shock. Crit. Care 21, 47 (2017).
Fatani, S. H. et al. Assessment of tumor necrosis factor alpha polymorphism TNF-α-238 (rs 361525) as a risk factor for development of acute kidney injury in critically ill patients. Mol. Biol. Rep. 45, 839–847 (2018).
Vincent, J.-L. & De Backer, D. Circulatory shock. N. Engl. J. Med. 369, 1726–1734 (2013).
Mizock, B. A. Alterations in fuel metabolism in critical illness: hyperglycaemia. Best. Pract. Res. Clin. Endocrinol. Metab. 15, 533–551 (2001).
Cuthbertson, D. Post-shock metabolic response. Lancet 239, 433–437 (1942).
Ganster, F. et al. Effects of hydrogen sulfide on hemodynamics, inflammatory response and oxidative stress during resuscitated hemorrhagic shock in rats. Crit. Care 14, R165 (2010).
Sun, K. & Xia, H. Serum levels of NLRP3 and HMGB-1 are associated with the prognosis of patients with severe blunt abdominal trauma. Clinics 74, e729 (2019).
Cohen, M. J. et al. Early release of high mobility group box nuclear protein 1 after severe trauma in humans: role of injury severity and tissue hypoperfusion. Crit. Care 13, R174 (2009).
Cheng, Z. et al. Circulating histones are major mediators of multiple organ dysfunction syndrome in acute critical illnesses. Crit. Care Med. 47, e677–e684 (2019).
Kutcher, M. E. et al. Extracellular histone release in response to traumatic injury: Implications for a compensatory role of activated protein C. J. Trauma. Acute Care Surg. 73, 1389–1394 (2012).
Opal, S. M. et al. Relationship between plasma levels of lipopolysaccharide (LPS) and LPS-binding protein in patients with severe sepsis and septic shock. J. Infect. Dis. 180, 1584–1589 (1999).
Charpentier, C. et al. Is endotoxin and cytokine release related to a decrease in gastric intramucosal pH after hemorrhagic shock? Intensive Care Med. 23, 1040–1048 (1997).
Pfeiffer, L. et al. Endotoxinemia and multiple organ failure after polytrauma. Anaesthesiol. Reanim. 21, 91–96 (1996).
Attanà, P. et al. Endotoxin role in cardiogenic shock: a brief report. Int. J. Cardiol. 167, 3031–3032 (2013).
van Poelgeest, E. P. et al. Characterization of immune cell, endothelial, and renal responses upon experimental human endotoxemia. J. Pharmacol. Toxicol. Methods 89, 39–46 (2018).
Gentile, L. F. et al. Is there value in plasma cytokine measurements in patients with severe trauma and sepsis? Methods 61, 3–9 (2013).
Halbgebauer, R. et al. Hemorrhagic shock drives glycocalyx, barrier and organ dysfunction early after polytrauma. J. Crit. Care 44, 229–237 (2018).
van Diepen, S. et al. Temporal changes in biomarkers and their relationships to reperfusion and to clinical outcomes among patients with ST segment elevation myocardial infarction. J. Thromb. Thrombolysis 42, 376–385 (2016).
Williams, L. R. & Leggett, R. W. Reference values for resting blood flow to organs of man. Clin. Phys. Physiol. Meas. 10, 187–217 (1989).
O’Connor, P. M. Renal oxygen delivery: matching delivery to metabolic demand. Clin. Exp. Pharmacol. Physiol. 33, 961–967 (2006).
Cupples, W. A. Interactions contributing to kidney blood flow autoregulation. Curr. Opin. Nephrol. Hypertens. 16, 39–45 (2007).
Ricksten, S.-E., Bragadottir, G. & Redfors, B. Renal oxygenation in clinical acute kidney injury. Crit. Care 17, 221 (2013).
Redfors, B., Bragadottir, G., Sellgren, J., Swärd, K. & Ricksten, S.-E. Effects of norepinephrine on renal perfusion, filtration and oxygenation in vasodilatory shock and acute kidney injury. Intensive Care Med. 37, 60–67 (2011).
Bragadottir, G., Redfors, B., Nygren, A., Sellgren, J. & Ricksten, S.-E. Low-dose vasopressin increases glomerular filtration rate, but impairs renal oxygenation in post-cardiac surgery patients. Acta Anaesthesiol. Scand. 53, 1052–1059 (2009).
Legrand, M. & Payen, D. Understanding urine output in critically ill patients. Ann. Intensive Care 1, 13 (2011).
Hartmann, C. et al. Effects of hyperoxia during resuscitation from hemorrhagic shock in swine with preexisting coronary artery disease. Crit. Care Med. 45, e1270–e1279 (2017).
Riddez, L. et al. Central and regional hemodynamics during acute hypovolemia and volume substitution in volunteers. Crit. Care Med. 25, 635–640 (1997).
Saotome, T., Ishikawa, K., May, C. N., Birchall, I. E. & Bellomo, R. The impact of experimental hypoperfusion on subsequent kidney function. Intensive Care Med. 36, 533–540 (2010).
Nelimarkka, O., Halkola, L. & Niinikoski, J. Renal hypoxia and lactate metabolism in hemorrhagic shock in dogs. Crit. Care Med. 12, 656–660 (1984).
Zarbock, A., Koyner, J. L., Hoste, E. A. J. & Kellum, J. A. Update on perioperative acute kidney injury. Anesth. Analg. 127, 1236–1245 (2018).
Villa, G., Samoni, S., De Rosa, S. & Ronco, C. The pathophysiological hypothesis of kidney damage during intra-abdominal hypertension. Front. Physiol. 7, 55 (2016).
Dalfino, L., Tullo, L., Donadio, I., Malcangi, V. & Brienza, N. Intra-abdominal hypertension and acute renal failure in critically ill patients. Intensive Care Med. 34, 707–713 (2008).
Calzavacca, P., Evans, R. G., Bailey, M., Bellomo, R. & May, C. N. Variable responses of regional renal oxygenation and perfusion to vasoactive agents in awake sheep. Am. J. Physiol. Regul. Integr. Comp. Physiol. 309, R1226–R1233 (2015).
Stumvoll, M., Meyer, C., Mitrakou, A., Nadkarni, V. & Gerich, J. E. Renal glucose production and utilization: new aspects in humans. Diabetologia 40, 749–757 (1997).
Engelmann, B. & Massberg, S. Thrombosis as an intravascular effector of innate immunity. Nat. Rev. Immunol. 13, 34–45 (2013).
Aswani, A. et al. Scavenging circulating mitochondrial DNA as a potential therapeutic option for multiple organ dysfunction in trauma hemorrhage. Front. Immunol. 9, 891 (2018).
Jansen, M. P. B., Florquin, S. & Roelofs, J. J. T. H. The role of platelets in acute kidney injury. Nat. Rev. Nephrol. 14, 457–471 (2018).
Zhang, Q. et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464, 104–107 (2010).
Kanse, S. M. et al. Factor VII-activating protease is activated in multiple trauma patients and generates anaphylatoxin C5a. J. Immunol. 188, 2858–2865 (2012).
Burk, A.-M. et al. Early complementopathy after multiple injuries in humans. Shock 37, 348–354 (2012).
Bihorac, A. et al. Acute kidney injury is associated with early cytokine changes after trauma. J. Trauma Acute Care Surg. 74, 1005–1013 (2013).
Frith, D. et al. Definition and drivers of acute traumatic coagulopathy: clinical and experimental investigations. J. Thromb. Haemost. 8, 1919–1925 (2010).
Vulliamy, P. et al. Histone H4 induces platelet ballooning and microparticle release during trauma hemorrhage. Proc. Natl Acad. Sci. USA 116, 17444–17449 (2019).
Denk, S. et al. Role of hemorrhagic shock in experimental polytrauma. Shock 49, 154–163 (2018).
Singbartl, K., Green, S. A. & Ley, K. Blocking P-selectin protects from ischemia/reperfusion-induced acute renal failure. FASEB J. 14, 48–54 (2000).
Yamasowa, H., Shimizu, S., Inoue, T., Takaoka, M. & Matsumura, Y. Endothelial nitric oxide contributes to the renal protective effects of ischemic preconditioning. J. Pharmacol. Exp. Ther. 312, 153–159 (2005).
Zhou, H.-L. et al. Metabolic reprogramming by the S-nitroso-CoA reductase system protects against kidney injury. Nature 565, 96–100 (2019).
Hamill, R. W., Woolf, P. D., McDonald, J. V., Lee, L. A. & Kelly, M. Catecholamines predict outcome in traumatic brain injury. Ann. Neurol. 21, 438–443 (1987).
Cernak, I., Savic, J., Ignjatovic, D. & Jevtic, M. Blast injury from explosive munitions. J. Trauma. 47, 96–103 (1999).
Melton, S. M., Davis, K. A., Moomey, C. B., Fabian, T. C. & Proctor, K. G. Mediator-dependent secondary injury after unilateral blunt thoracic trauma. Shock 11, 396–402 (1999).
Moss, N. G., Vogel, P. A., Kopple, T. E. & Arendshorst, W. J. Thromboxane-induced renal vasoconstriction is mediated by the ADP-ribosyl cyclase CD38 and superoxide anion. Am. J. Physiol. Ren. Physiol. 305, F830–F838 (2013).
Li, R. et al. Histone deacetylase inhibition and IκB kinase/nuclear factor-κB blockade ameliorate microvascular proinflammatory responses associated with hemorrhagic shock/resuscitation in mice. Crit. Care Med. 43, e567–e580 (2015).
van Meurs, M. et al. Shock-induced stress induces loss of microvascular endothelial Tie2 in the kidney which is not associated with reduced glomerular barrier function. Am. J. Physiol. Ren. Physiol. 297, F272–F281 (2009).
Sheerin, N. S. et al. Synthesis of complement protein C3 in the kidney is an important mediator of local tissue injury. FASEB J. 22, 1065–1072 (2008).
Ganter, M. T. et al. Role of the alternative pathway in the early complement activation following major trauma. Shock 28, 29–34 (2007).
Wan, J.-X. et al. Complement 3 is involved in changing the phenotype of human glomerular mesangial cells. J. Cell. Physiol. 213, 495–501 (2007).
Lovett, D. H., Haensch, G. M., Goppelt, M., Resch, K. & Gemsa, D. Activation of glomerular mesangial cells by the terminal membrane attack complex of complement. J. Immunol. 138, 2473–2480 (1987).
Torbohm, I. et al. C5b-8 and C5b-9 modulate the collagen release of human glomerular epithelial cells. Kidney Int. 37, 1098–1104 (1990).
Huber-Lang, M. et al. Role of C5a in multiorgan failure during sepsis. J. Immunol. 166, 1193–1199 (2001).
Chen, Y. et al. The role of podocyte damage in the etiology of ischemia-reperfusion acute kidney injury and post-injury fibrosis. BMC Nephrol. 20, 106 (2019).
Caron, A., Desrosiers, R. R., Langlois, S. & Béliveau, R. Ischemia-reperfusion injury stimulates gelatinase expression and activity in kidney glomeruli. Can. J. Physiol. Pharmacol. 83, 287–300 (2005).
De Gaudio, A. R., Spina, R., Di Filippo, A. & Feri, M. Glomerular permeability and trauma: a correlation between microalbuminuria and Injury Severity Score. Crit. Care Med. 27, 2105–2108 (1999).
Agrawal, S., Guess, A. J., Chanley, M. A. & Smoyer, W. E. Albumin-induced podocyte injury and protection are associated with regulation of COX-2. Kidney Int. 86, 1150–1160 (2014).
Bosch, X., Poch, E. & Grau, J. M. Rhabdomyolysis and acute kidney injury. N. Engl. J. Med. 361, 62–72 (2009).
Blachar, Y., Fong, J. S., de Chadarévian, J. P. & Drummond, K. N. Muscle extract infusion in rabbits. A new experimental model of the crush syndrome. Circ. Res. 49, 114–124 (1981).
Kitamura, M. & Fine, L. G. The concept of glomerular self-defense. Kidney Int. 55, 1639–1671 (1999).
Racusen, L. C., Fivush, B. A., Li, Y. L., Slatnik, I. & Solez, K. Dissociation of tubular cell detachment and tubular cell death in clinical and experimental ‘acute tubular necrosis’. Lab. Invest. 64, 546–556 (1991).
Thadhani, R., Pascual, M. & Bonventre, J. V. Acute renal failure. N. Engl. J. Med. 334, 1448–1460 (1996).
Thurman, J. M. Altered renal tubular expression of the complement inhibitor Crry permits complement activation after ischemia/reperfusion. J. Clin. Invest. 116, 357–368 (2006).
Zhou, W. et al. Predominant role for C5b-9 in renal ischemia/reperfusion injury. J. Clin. Invest. 105, 1363–1371 (2000).
Thurman, J. M., Lucia, M. S., Ljubanovic, D. & Holers, V. M. Acute tubular necrosis is characterized by activation of the alternative pathway of complement. Kidney Int. 67, 524–530 (2005).
Farrar, C. A. et al. Collectin-11 detects stress-induced L-fucose pattern to trigger renal epithelial injury. J. Clin. Invest. 126, 1911–1925 (2016).
van der Pol, P. et al. Mannan-binding lectin mediates renal ischemia/reperfusion injury independent of complement activation. Am. J. Transpl. 12, 877–887 (2012).
de Vries, B. et al. Complement factor C5a mediates renal ischemia-reperfusion injury independent from neutrophils. J. Immunol. 170, 3883–3889 (2003).
Peng, Q. et al. C3a and C5a promote renal ischemia-reperfusion injury. J. Am. Soc. Nephrol. 23, 1474–1485 (2012).
Ehrnthaller, C. et al. Hemorrhagic shock induces renal complement activation. Eur. J. Trauma Emerg. Surg. https://doi.org/10.1007/s00068-019-01187-1 (2019).
Singbartl, K. & Ley, K. Protection from ischemia-reperfusion induced severe acute renal failure by blocking E-selectin. Crit. Care Med. 28, 2507–2514 (2000).
Ritis, K. et al. A novel C5a receptor-tissue factor cross-talk in neutrophils links innate immunity to coagulation pathways. J. Immunol. 177, 4794–4802 (2006).
Denk, S. et al. Complement C5a functions as a master switch for the pH balance in neutrophils exerting fundamental immunometabolic effects. J. Immunol. 198, 4846–4854 (2017).
Peng, Q. et al. The C5a/C5aR1 axis promotes progression of renal tubulointerstitial fibrosis in a mouse model of renal ischemia/reperfusion injury. Kidney Int. 96, 117–128 (2019).
Gupta, S. & Kaplan, M. J. The role of neutrophils and NETosis in autoimmune and renal diseases. Nat. Rev. Nephrol. 12, 402–413 (2016).
Salazar-Gonzalez, H., Zepeda-Hernandez, A., Melo, Z., Saavedra-Mayorga, D. E. & Echavarria, R. Neutrophil extracellular traps in the establishment and progression of renal diseases. Medicina 55, 431 (2019).
Younan, D., Richman, J., Zaky, A. & Pittet, J.-F. An increasing neutrophil-to-lymphocyte ratio trajectory predicts organ failure in critically-ill male trauma patients. an exploratory study. Healthcare 7, 42 (2019).
Awad, A. S. et al. Compartmentalization of neutrophils in the kidney and lung following acute ischemic kidney injury. Kidney Int. 75, 689–698 (2009).
Block, H. et al. Crucial role of SLP-76 and ADAP for neutrophil recruitment in mouse kidney ischemia-reperfusion injury. J. Exp. Med. 209, 407–421 (2012).
Singbartl, K., Miller, L., Ruiz-Velasco, V. & Kellum, J. A. Reversal of acute kidney injury-induced neutrophil dysfunction: a critical role for resistin. Crit. Care Med. 44, e492–e501 (2016).
Dong, X.-Q. et al. Resistin is associated with mortality in patients with traumatic brain injury. Crit. Care 14, R190 (2010).
Singbartl, K., Formeck, C. L. & Kellum, J. A. Kidney-immune system crosstalk in AKI. Semin. Nephrol. 39, 96–106 (2019).
Miller, L. et al. Resistin directly inhibits bacterial killing in neutrophils. Intensive Care Med. Exp. 7, 30 (2019).
Dodd-o, J. M. et al. Interactive effects of mechanical ventilation and kidney health on lung function in an in vivo mouse model. Am. J. Physiol. Lung Cell. Mol. Physiol. 296, L3–L11 (2009).
Jang, H. R. & Rabb, H. Immune cells in experimental acute kidney injury. Nat. Rev. Nephrol. 11, 88–101 (2015).
Nelson, P. J. et al. The renal mononuclear phagocytic system. J. Am. Soc. Nephrol. 23, 194–203 (2012).
Kurts, C., Ginhoux, F. & Panzer, U. Kidney dendritic cells: fundamental biology and functional roles in health and disease. Nat. Rev. Nephrol. 16, 391–407 (2020).
Tang, P. M.-K., Nikolic-Paterson, D. J. & Lan, H.-Y. Macrophages: versatile players in renal inflammation and fibrosis. Nat. Rev. Nephrol. 15, 144–158 (2019).
De Greef, K. E. et al. Anti-B7-1 blocks mononuclear cell adherence in vasa recta after ischemia. Kidney Int. 60, 1415–1427 (2001).
Williams, T. M., Little, M. H. & Ricardo, S. D. Macrophages in renal development, injury, and repair. Semin. Nephrol. 30, 255–267 (2010).
Li, L. et al. The chemokine receptors CCR2 and CX3CR1 mediate monocyte/macrophage trafficking in kidney ischemia-reperfusion injury. Kidney Int. 74, 1526–1537 (2008).
Huen, S. C. & Cantley, L. G. Macrophage-mediated injury and repair after ischemic kidney injury. Pediatr. Nephrol. 30, 199–209 (2015).
Gueler, F. et al. Statins attenuate ischemia-reperfusion injury by inducing heme oxygenase-1 in infiltrating macrophages. Am. J. Pathol. 170, 1192–1199 (2007).
Han, H. I., Skvarca, L. B., Espiritu, E. B., Davidson, A. J. & Hukriede, N. A. The role of macrophages during acute kidney injury: destruction and repair. Pediatr. Nephrol. 34, 561–569 (2019).
Anders, H.-J. & Ryu, M. Renal microenvironments and macrophage phenotypes determine progression or resolution of renal inflammation and fibrosis. Kidney Int. 80, 915–925 (2011).
Chiba, T. et al. Retinoic acid signaling coordinates macrophage-dependent injury and repair after AKI. J. Am. Soc. Nephrol. 27, 495–508 (2016).
Chen, T., Cao, Q., Wang, Y. & Harris, D. C. H. M2 macrophages in kidney disease: biology, therapies, and perspectives. Kidney Int. 95, 760–773 (2019).
Susnik, N. et al. Ablation of proximal tubular suppressor of cytokine signaling 3 enhances tubular cell cycling and modifies macrophage phenotype during acute kidney injury. Kidney Int. 85, 1357–1368 (2014).
Gunay, Y. et al. A novel mechanism of anti–T-lymphocyte globulin mediated by fractalkine in renal ischemia–reperfusion injury in rats. Transplant. Proc. 45, 2461–2468 (2013).
Dai, H., Thomson, A. W. & Rogers, N. M. Dendritic cells as sensors, mediators, and regulators of ischemic injury. Front. Immunol. 10, 2418 (2019).
Dong, X. et al. Resident dendritic cells are the predominant TNF-secreting cell in early renal ischemia-reperfusion injury. Kidney Int. 71, 619–628 (2007).
Kurts, C., Panzer, U., Anders, H.-J. & Rees, A. J. The immune system and kidney disease: basic concepts and clinical implications. Nat. Rev. Immunol. 13, 738–753 (2013).
Pons, M. et al. Mast cells and MCPT4 chymase promote renal impairment after partial ureteral obstruction. Front. Immunol. 8, 450 (2017).
Tong, F., Luo, L. & Liu, D. Effect of intervention in mast cell function before reperfusion on renal ischemia-reperfusion injury in rats. Kidney Blood Press. Res. 41, 335–344 (2016).
Danelli, L. et al. Early Phase mast cell activation determines the chronic outcome of renal ischemia–reperfusion injury. J. Immunol. 198, 2374–2382 (2017).
Madjene, L. C. et al. Mast cell chymase protects against acute ischemic kidney injury by limiting neutrophil hyperactivation and recruitment. Kidney Int. 97, 516–527 (2019).
Cameron, G. J. M. et al. Emerging therapeutic potential of group 2 innate lymphoid cells in acute kidney injury. J. Pathol. 248, 9–15 (2019).
Cao, Q. et al. Potentiating tissue-resident type 2 innate lymphoid cells by IL-33 to prevent renal ischemia-reperfusion injury. J. Am. Soc. Nephrol. 29, 961–976 (2018).
Rabb, H. et al. Pathophysiological role of T lymphocytes in renal ischemia-reperfusion injury in mice. Am. J. Physiol. Ren. Physiol. 279, F525–F531 (2000).
Burne-Taney, M. J. et al. B cell deficiency confers protection from renal ischemia reperfusion injury. J. Immunol. 171, 3210–3215 (2003).
Cantaluppi, V. et al. Interaction between systemic inflammation and renal tubular epithelial cells. Nephrol. Dial. Transplant. 29, 2004–2011 (2014).
Kim, B. S. et al. Ischemia-repersfusion injury activates innate immunity in rat kidneys. Transplantation 79, 1370–1377 (2005).
Hoke, T. S. et al. Acute renal failure after bilateral nephrectomy is associated with cytokine-mediated pulmonary injury. J. Am. Soc. Nephrol. 18, 155–164 (2007).
Grigoryev, D. N. et al. The local and systemic inflammatory transcriptome after acute kidney injury. J. Am. Soc. Nephrol. 19, 547–558 (2008).
Baek, J.-H. et al. IL-34 mediates acute kidney injury and worsens subsequent chronic kidney disease. J. Clin. Invest. 125, 3198–3214 (2015).
Rosenberger, C. et al. Cellular responses to hypoxia after renal segmental infarction. Kidney Int. 64, 874–886 (2003).
Leelahavanichkul, A. et al. Chronic kidney disease worsens sepsis and sepsis-induced acute kidney injury by releasing high mobility group box protein-1. Kidney Int. 80, 1198–1211 (2011).
Jansen, M. P. B. et al. Mitochondrial DNA is released in urine of SIRS patients with acute kidney injury and correlates with severity of renal dysfunction. Shock 49, 301–310 (2018).
Ferenbach, D. A. & Bonventre, J. V. Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD. Nat. Rev. Nephrol. 11, 264–276 (2015).
Janak, J. C. et al. Urinary biomarkers are associated with severity and mechanism of injury. Shock 47, 593–598 (2017).
Ichimura, T. et al. Kidney injury molecule–1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells. J. Clin. Invest. 118, 1657–1668 (2008).
Yang, L. et al. KIM-1–mediated phagocytosis reduces acute injury to the kidney. J. Clin. Invest. 125, 1620–1636 (2015).
Schunk, S. J. et al. Association between urinary dickkopf-3, acute kidney injury, and subsequent loss of kidney function in patients undergoing cardiac surgery: an observational cohort study. Lancet 394, 488–496 (2019).
Jin, H. et al. Epithelial innate immunity mediates tubular cell senescence after kidney injury. JCI Insight 4, e125490 (2019).
Joannidis, M. et al. Use of cell cycle arrest biomarkers in conjunction with classical markers of acute kidney injury. Crit. Care Med. 47, e820–e826 (2019).
Humphreys, B. D. et al. Repair of injured proximal tubule does not involve specialized progenitors. Proc. Natl Acad. Sci. USA 108, 9226–9231 (2011).
Chen, Y.-T. et al. Platelet-derived growth factor receptor signaling activates pericyte–myofibroblast transition in obstructive and post-ischemic kidney fibrosis. Kidney Int. 80, 1170–1181 (2011).
Henriksen, H. H. et al. Metabolic systems analysis of shock-induced endotheliopathy (SHINE) in trauma: a new research paradigm. Ann. Surg. https://doi.org/10.1097/SLA.0000000000003307 (2019).
Johansson, P. I. et al. Traumatic endotheliopathy: a prospective observational study of 424 severely injured patients. Ann. Surg. 265, 597–603 (2017).
van Nieuw Amerongen, G. P., Musters, R. J. P., Eringa, E. C., Sipkema, P. & van Hinsbergh, V. W. M. Thrombin-induced endothelial barrier disruption in intact microvessels: role of RhoA/Rho kinase-myosin phosphatase axis. Am. J. Physiol. Cell Physiol. 294, C1234–C1241 (2008).
Noiri, E. et al. Oxidative and nitrosative stress in acute renal ischemia. Am. J. Physiol. Ren. Physiol. 281, F948–F957 (2001).
Noiri, E., Peresleni, T., Miller, F. & Goligorsky, M. S. In vivo targeting of inducible NO synthase with oligodeoxynucleotides protects rat kidney against ischemia. J. Clin. Invest. 97, 2377–2383 (1996).
Ratliff, B. B., Rabadi, M. M., Vasko, R., Yasuda, K. & Goligorsky, M. S. Messengers without borders: mediators of systemic inflammatory response in AKI. J. Am. Soc. Nephrol. 24, 529–536 (2013).
Schillemans, M., Karampini, E., Kat, M. & Bierings, R. Exocytosis of Weibel–Palade bodies: how to unpack a vascular emergency kit. J. Thromb. Haemost. 17, 6–18 (2019).
Vogel, S. et al. Platelet-derived HMGB1 is a critical mediator of thrombosis. J. Clin. Invest. 125, 4638–4654 (2015).
Yamamoto, T. et al. Intravital videomicroscopy of peritubular capillaries in renal ischemia. Am. J. Physiol. Ren. Physiol. 282, F1150–F1155 (2002).
Augustin, H. G., Young Koh, G., Thurston, G. & Alitalo, K. Control of vascular morphogenesis and homeostasis through the angiopoietin–Tie system. Nat. Rev. Mol. Cell Biol. 10, 165–177 (2009).
Trieu, M. et al. Vasculotide, an angiopoietin-1 mimetic, restores microcirculatory perfusion and microvascular leakage and decreases fluid resuscitation requirements in hemorrhagic shock. Anesthesiology 128, 361–374 (2018).
Rübig, E. et al. The synthetic Tie2 agonist peptide vasculotide protects renal vascular barrier function in experimental acute kidney injury. Sci. Rep. 6, 22111 (2016).
Jansen, M. P. B. et al. Release of extracellular DNA influences renal ischemia reperfusion injury by platelet activation and formation of neutrophil extracellular traps. Kidney Int. 91, 352–364 (2017).
Lu, C. Y., Winterberg, P. D., Chen, J. & Hartono, J. R. Acute kidney injury: a conspiracy of toll-like receptor 4 on endothelia, leukocytes, and tubules. Pediatr. Nephrol. 27, 1847–1854 (2012).
Patel, N. S. A. et al. Endogenous interleukin-6 enhances the renal injury, dysfunction, and inflammation caused by ischemia/reperfusion. J. Pharmacol. Exp. Ther. 312, 1170–1178 (2005).
Johns, E. J., Kopp, U. C. & DiBona, G. F. Neural control of renal function. in Comprehensive Physiology (ed. Terjung, R.) c100043 (John Wiley & Sons, Inc., 2011).
Fujii, T. et al. The role of renal sympathetic nervous system in the pathogenesis of ischemic acute renal failure. Eur. J. Pharmacol. 481, 241–248 (2003).
Okusa, M. D., Rosin, D. L. & Tracey, K. J. Targeting neural reflex circuits in immunity to treat kidney disease. Nat. Rev. Nephrol. 13, 669–680 (2017).
Levy, G. et al. Parasympathetic stimulation via the vagus nerve prevents systemic organ dysfunction by abrogating gut injury and lymph toxicity in trauma and hemorrhagic shock. Shock 39, 39–44 (2013).
Hering, D. & Winklewski, P. J. R1 autonomic nervous system in acute kidney injury. Clin. Exp. Pharmacol. Physiol. 44, 162–171 (2017).
Inoue, T. et al. Non-canonical cholinergic anti-inflammatory pathway-mediated activation of peritoneal macrophages induces Hes1 and blocks ischemia/reperfusion injury in the kidney. Kidney Int. 95, 563–576 (2019).
Brorsson, C. et al. Adrenal response after trauma is affected by time after trauma and sedative/analgesic drugs. Injury 45, 1149–1155 (2014).
Offner, P. J., Moore, E. E. & Ciesla, D. The adrenal response after severe trauma. Am. J. Surg. 184, 649–653 (2002).
Zager, R. A. & Johnson, A. C. M. Acute kidney injury induces dramatic p21 upregulation via a novel, glucocorticoid-activated, pathway. Am. J. Physiol. Ren. Physiol. 316, F674–F681 (2019).
Baban, B. et al. Glucocorticoid-induced leucine zipper promotes neutrophil and T-cell polarization with protective effects in acute kidney injury. J. Pharmacol. Exp. Ther. 367, 483–493 (2018).
DiBona, G. F. Physiology in perspective: the wisdom of the body. neural control of the kidney. Am. J. Physiol. Regul. Integr. Comp. Physiol. 289, R633–R641 (2005).
Faubel, S. & Edelstein, C. L. Mechanisms and mediators of lung injury after acute kidney injury. Nat. Rev. Nephrol. 12, 48–60 (2016).
Freeman, W. D. & Wadei, H. M. A brain–kidney connection: the delicate interplay of brain and kidney physiology. Neurocrit. Care 22, 173–175 (2015).
Nongnuch, A., Panorchan, K. & Davenport, A. Brain–kidney crosstalk. Crit. Care 18, 225 (2014).
Maesaka, J. K., Imbriano, L. J., Ali, N. M. & Ilamathi, E. Is it cerebral or renal salt wasting? Kidney Int. 76, 934–938 (2009).
Tanaka, S. & Okusa, M. D. Crosstalk between the nervous system and the kidney. Kidney Int. 97, 466–476 (2020).
Liu, M. et al. Acute kidney injury leads to inflammation and functional changes in the brain. J. Am. Soc. Nephrol. 19, 1360–1370 (2008).
Kelly, K. J. Distant effects of experimental renal ischemia/reperfusion injury. J. Am. Soc. Nephrol. 14, 1549–1558 (2003).
Prud’homme, M. et al. Acute kidney injury induces remote cardiac damage and dysfunction through the galectin-3 pathway. JACC Basic Transl Sci. 4, 717–732 (2019).
Hassoun, H. T. et al. Kidney ischemia-reperfusion injury induces caspase-dependent pulmonary apoptosis. Am. J. Physiol. Renal Physiol. 297, F125–F137 (2009).
Kramer, A. A. et al. Renal ischemia/reperfusion leads to macrophage-mediated increase in pulmonary vascular permeability. Kidney Int. 55, 2362–2367 (1999).
Rabb, H. et al. Acute renal failure leads to dysregulation of lung salt and water channels. Kidney Int. 63, 600–606 (2003).
Klein, C. L. et al. Interleukin-6 mediates lung injury following ischemic acute kidney injury or bilateral nephrectomy. Kidney Int. 74, 901–909 (2008).
Doi, K. et al. The high-mobility group protein B1–Toll-like receptor 4 pathway contributes to the acute lung injury induced by bilateral nephrectomy. Kidney Int. 86, 316–326 (2014).
Rossi, M. et al. HO-1 mitigates acute kidney injury and subsequent kidney-lung cross-talk. Free. Radic. Res. 53, 1035–1043 (2019).
Husain-Syed, F., Slutsky, A. S. & Ronco, C. Lung-kidney cross-talk in the critically Ill patient. Am. J. Respir. Crit. Care Med. 194, 402–414 (2016).
Vivino, G. et al. Risk factors for acute renal failure in trauma patients. Intensive Care Med. 24, 808–814 (1998).
Raimundo, M. et al. Low systemic oxygen delivery and BP and Risk of progression of early AKI. Clin. J. Am. Soc. Nephrol. 10, 1340–1349 (2015).
Gosling, P., Sanghera, K. & Dickson, G. Generalized vascular permeability and pulmonary function in patients following serious trauma. J. Trauma. 36, 477–481 (1994).
Park, S. W. et al. Cytokines induce small intestine and liver injury after renal ischemia or nephrectomy. Lab. Invest. 91, 63–84 (2011).
Golab, F. et al. Ischemic and non-ischemic acute kidney injury cause hepatic damage. Kidney Int. 75, 783–792 (2009).
Kim, M., Park, S. W., Kim, M., D’Agati, V. D. & Lee, H. T. Isoflurane activates intestinal sphingosine kinase to protect against renal ischemia-reperfusion-induced liver and intestine injury. Anesthesiology 114, 363–373 (2011).
Gurley, B. J. et al. Extrahepatic ischemia-reperfusion injury reduces hepatic oxidative drug metabolism as determined by serial antipyrine clearance. Pharm. Res. 14, 67–72 (1997).
Lane, K., Dixon, J. J., MacPhee, I. A. M. & Philips, B. J. Renohepatic crosstalk: does acute kidney injury cause liver dysfunction? Nephrol. Dial. Transplant. 28, 1634–1647 (2013).
Hassoun, H. T. et al. Post-injury multiple organ failure: the role of the gut. Shock 15, 1–10 (2001).
Mittal, R. & Coopersmith, C. M. Redefining the gut as the motor of critical illness. Trends Mol. Med. 20, 214–223 (2014).
Vaziri, N. D. et al. Disintegration of colonic epithelial tight junction in uremia: a likely cause of CKD-associated inflammation. Nephrol. Dial. Transpl. 27, 2686–2693 (2012).
Yang, T., Richards, E. M., Pepine, C. J. & Raizada, M. K. The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease. Nat. Rev. Nephrol. 14, 442–456 (2018).
Niwa, T. & Ise, M. Indoxyl sulfate, a circulating uremic toxin, stimulates the progression of glomerular sclerosis. J. Lab. Clin. Med. 124, 96–104 (1994).
Wang, W. et al. Serum indoxyl sulfate is associated with mortality in hospital-acquired acute kidney injury: a prospective cohort study. BMC Nephrol. 20, 57 (2019).
Nakade, Y. et al. Gut microbiota-derived D-serine protects against acute kidney injury. JCI Insight 3, e97957 (2018).
Andrade-Oliveira, V. et al. Gut bacteria products prevent AKI induced by ischemia-reperfusion. J. Am. Soc. Nephrol. 26, 1877–1888 (2015).
Al-Harbi, N. O. et al. Short chain fatty acid, acetate ameliorates sepsis-induced acute kidney injury by inhibition of NADPH oxidase signaling in T cells. Int. Immunopharmacol. 58, 24–31 (2018).
Park, J., Goergen, C. J., HogenEsch, H. & Kim, C. H. Chronically elevated levels of short-chain fatty acids induce T cell-mediated ureteritis and hydronephrosis. J. Immunol. 196, 2388–2400 (2016).
Gigliotti, J. C. & Okusa, M. D. The spleen: the forgotten organ in acute kidney injury of critical illness. Nephron Clin. Pract. 127, 153–157 (2014).
Andrés-Hernando, A. et al. Splenectomy exacerbates lung injury after ischemic acute kidney injury in mice. Am. J. Physiol. Renal Physiol. 301, F907–F916 (2011).
Jiang, H. et al. Splenectomy ameliorates acute multiple organ damage induced by liver warm ischemia reperfusion in rats. Surgery 141, 32–40 (2007).
Inoue, T., Tanaka, S. & Okusa, M. D. Neuroimmune interactions in inflammation and acute kidney injury. Front. Immunol. 8, 945 (2017).
Inoue, T. et al. Vagus nerve stimulation mediates protection from kidney ischemia-reperfusion injury through α7nAChR+ splenocytes. J. Clin. Invest. 126, 1939–1952 (2016).
Demetriades, D. et al. Blunt splenic trauma: splenectomy increases early infectious complications. J. Trauma Acute Care Surg. 72, 229–234 (2012).
Watters, J. M. et al. Splenectomy leads to a persistent hypercoagulable state after trauma. Am. J. Surg. 199, 646–651 (2010).
Wei, K., Yin, Z. & Xie, Y. Roles of the kidney in the formation, remodeling and repair of bone. J. Nephrol. 29, 349–357 (2016).
Porter, C. J. et al. Acute and chronic kidney disease in elderly patients with hip fracture: prevalence, risk factors and outcome with development and validation of a risk prediction model for acute kidney injury. BMC Nephrol. 18, 20 (2017).
Ulucay, C. et al. Risk factors for acute kidney injury after hip fracture surgery in the elderly individuals. Geriatr. Orthop. Surg. Rehabil. 3, 150–156 (2012).
Marty, P. et al. The Doppler renal resistive index for early detection of acute kidney injury after hip fracture. Anaesth. Crit. Care Pain. Med. 35, 377–382 (2016).
Tiansheng, S. et al. Is damage control orthopedics essential for the management of bilateral femoral fractures associated or complicated with shock? An animal study. J. Trauma. 67, 1402–1411 (2009).
Sangkomkamhang, T., Thinkhamrop, W., Thinkhamrop, B. & Laohasiriwong, W. Incidence and risk factors for complications after definitive skeletal fixation of lower extremity in multiple injury patients: a retrospective chart review. F1000Res 7, 612 (2018).
Goldstein, S. L., Jaber, B. L., Faubel, S., Chawla, L. S. & for the Acute Kidney Injury Advisory Group of the American Society of Nephrology. AKI transition of care: a potential opportunity to detect and prevent CKD. Clin. J. Am. Soc. Nephrol. 8, 476–483 (2013).
Moe, S. et al. Definition, evaluation, and classification of renal osteodystrophy: a position statement from kidney disease: improving global outcomes (KDIGO). Kidney Int. 69, 1945–1953 (2006).
Livingston, D. H. et al. Bone marrow failure following severe injury in humans. Ann. Surg. 238, 748–753 (2003).
Chen, D., Xiao, D., Guo, J., Chahan, B. & Wang, Z. Neutrophil-lymphocyte count ratio as a diagnostic marker for acute kidney injury: a systematic review and meta-analysis. Clin. Exp. Nephrol. 24, 126–135 (2020).
Kim, W. H., Park, J. Y., Ok, S.-H., Shin, I.-W. & Sohn, J.-T. Association between the neutrophil/lymphocyte ratio and acute kidney injury after cardiovascular surgery: a retrospective observational study. Medicine 94, e1867 (2015).
Ito, S. et al. Neutrophil/lymphocyte ratio elevation in renal dysfunction is caused by distortion of leukocyte hematopoiesis in bone marrow. Ren. Fail. 41, 284–293 (2019).
Goldstein, S. L. & Chawla, L. S. Renal angina. Clin. J. Am. Soc. Nephrol. 5, 943–949 (2010).
Weiss, R., Meersch, M., Pavenstädt, H.-J. & Zarbock, A. Acute kidney injury. Dtsch. Arztebl. Int. 116, 833–842 (2019).
Kashani, K. et al. Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. Crit. Care 17, R25 (2013).
Sharfuddin, A. A. & Molitoris, B. A. Pathophysiology of ischemic acute kidney injury. Nat. Rev. Nephrol. 7, 189–200 (2011).
Peerapornratana, S., Manrique-Caballero, C. L., Gómez, H. & Kellum, J. A. Acute kidney injury from sepsis: current concepts, epidemiology, pathophysiology, prevention and treatment. Kidney Int. 96, 1083–1099 (2019).
Coccolini, F. et al. Kidney and uro-trauma: WSES-AAST guidelines. World J. Emerg. Surg. 14, 54 (2019).
This review was supported by funding from the German Research Foundation (DFG) to M. H.-L. (CRC 1149, project numbers INST 40/479-2 and INST 40/487-2).
The authors declare no competing interests.
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- Haemorrhagic shock
Life-threatening blood loss with subsequent reduced tissue perfusion and inadequate oxygen supply relative to oxygen requirement.
- Positive end-expiratory pressure
The level of airway pressure in the lungs above ambient pressure at end-expiration.
- Mass transfusion
Transfusion of ≥10 units of packed red blood cells within 24 h.
- Restrictive transfusion
Transfusion initiated when the patient has a total haemoglobin concentration ≤80 g/l and/or the patient develops symptoms of anaemia.
- Liberal transfusion
Transfusion initiated when the patient has a total haemoglobin concentration ≤100 g/l.
- Crush injury
Compression of the limbs and/or torso due to trauma.
Multiple traumatic injuries, of which at least one injury or the combination thereof is life-threatening.
Formation of thrombi initiated by the innate immune response to invading bacteria aimed at local infection control.
- Crush syndrome
Syndrome characterized by degradation of muscle tissue (that is, rhabdomyolysis) accompanied by the accumulation of tissue debris and myoglobin.
- Marginated neutrophils
Neutrophils from the circulating cell pool that attach to surfaces such as the endothelium.
- Post-traumatic abdominal compartment syndrome
Syndrome characterized by post-traumatic intra-abdominal hypertension (that is, intra-abdominal pressure >20 mmHg) and de novo visceral organ dysfunction or failure.
- Neuronal pyknosis
An early hallmark of neuronal cell death characterized by irreversible condensation of chromatin.
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Messerer, D.A.C., Halbgebauer, R., Nilsson, B. et al. Immunopathophysiology of trauma-related acute kidney injury. Nat Rev Nephrol 17, 91–111 (2021). https://doi.org/10.1038/s41581-020-00344-9
Neurocritical Care (2022)
European Journal of Medical Research (2021)
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