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Immunopathophysiology of trauma-related acute kidney injury

Nature Reviews Nephrology volume 17, pages 91–111 (2021)Cite this article

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Abstract

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.

Key points

  • 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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Fig. 1: Frequent trauma sites and complications.
Fig. 2: TRAKI as a hybrid of heterogeneous AKI types.
Fig. 3: Pathophysiological response of TRAKI.
Fig. 4: Innate immune response in the glomerulus during TRAKI.
Fig. 5: Innate immune response in the tubular system during TRAKI.
Fig. 6: Neuroinflammatory axis underlying TRAKI.
Fig. 7: Kidney as target and effector of TRAKI-associated organ crosstalk.

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References

  1. 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).

    Article  PubMed  Google Scholar 

  2. World Health Organization. Injuries and Violence: the Facts. https://www.who.int/violence_injury_prevention/key_facts/en/ (WHO, 2010).

  3. Harrois, A. et al. Prevalence and risk factors for acute kidney injury among trauma patients: a multicenter cohort study. Crit. Care 22, 344 (2018).

    PubMed  PubMed Central  Google Scholar 

  4. 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).

    PubMed  Google Scholar 

  5. 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).

    PubMed  Google Scholar 

  6. 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).

    Google Scholar 

  7. Kim, S.-M. et al. Inflammasome-independent role of NLRP3 mediates mitochondrial regulation in renal injury. Front. Immunol. 9, 2563 (2018).

    PubMed  PubMed Central  Google Scholar 

  8. Huber-Lang, M., Lambris, J. D. & Ward, P. A. Innate immune responses to trauma. Nat. Immunol. 19, 327–341 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 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).

    PubMed  Google Scholar 

  10. Grams, M. E. & Rabb, H. The distant organ effects of acute kidney injury. Kidney Int. 81, 942–948 (2012).

    PubMed  Google Scholar 

  11. Yap, S. C. & Lee, H. T. Acute kidney injury and extrarenal organ dysfunction: new concepts and experimental evidence. Anesthesiology 116, 1139–1148 (2012).

    PubMed  Google Scholar 

  12. 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).

    PubMed  Google Scholar 

  13. Simmons, M. N., Schreiber, M. J. & Gill, I. S. Surgical renal ischemia: a contemporary overview. J. Urol. 180, 19–30 (2008).

    PubMed  Google Scholar 

  14. Gaibi, T. & Ghatak-Roy, A. Approach to acute kidney injuries in the emergency department. Emerg. Med. Clin. North Am. 37, 661–677 (2019).

    PubMed  Google Scholar 

  15. American College of Surgeons & Committee on Trauma. Advanced Trauma Life Support: Student Course Manual (American College of Surgeons, 2018).

  16. 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).

    PubMed  Google Scholar 

  17. Harrois, A., Libert, N. & Duranteau, J. Acute kidney injury in trauma patients. Curr. Opin. Crit. Care 23, 447–456 (2017).

    PubMed  Google Scholar 

  18. Ronco, C., Bellomo, R. & Kellum, J. A. Acute kidney injury. Lancet 394, 1949–1964 (2019).

    CAS  PubMed  Google Scholar 

  19. Semler, M. W. et al. Balanced crystalloids versus saline in critically ill adults. N. Engl. J. Med. 378, 829–839 (2018).

    PubMed  PubMed Central  Google Scholar 

  20. 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).

    PubMed  Google Scholar 

  21. 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).

    CAS  PubMed  Google Scholar 

  22. 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).

    CAS  PubMed  Google Scholar 

  23. 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).

    CAS  PubMed  Google Scholar 

  24. Meißner, A. & Schlenke, P. Massive bleeding and massive transfusion. Transfus. Med. Hemother 39, 73–84 (2012).

    PubMed  PubMed Central  Google Scholar 

  25. Spahn, D. R. et al. The European guideline on management of major bleeding and coagulopathy following trauma: fifth edition. Crit. Care 23, 98 (2019).

    PubMed  PubMed Central  Google Scholar 

  26. Goodnough, L. T., Levy, J. H. & Murphy, M. F. Concepts of blood transfusion in adults. Lancet 381, 1845–1854 (2013).

    PubMed  Google Scholar 

  27. Van Avondt, K., Nur, E. & Zeerleder, S. Mechanisms of haemolysis-induced kidney injury. Nat. Rev. Nephrol. 15, 671–692 (2019).

    PubMed  Google Scholar 

  28. 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).

    CAS  PubMed  Google Scholar 

  29. Wang, L. et al. Labile heme aggravates renal inflammation and complement activation after ischemia reperfusion injury. Front. Immunol. 10, 2975 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 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).

    PubMed  Google Scholar 

  31. Bellomo, R. & Giantomasso, D. D. Noradrenaline and the kidney: friends or foes? Crit. Care 5, 294–298 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Fähling, M., Seeliger, E., Patzak, A. & Persson, P. B. Understanding and preventing contrast-induced acute kidney injury. Nat. Rev. Nephrol. 13, 169–180 (2017).

    PubMed  Google Scholar 

  33. Windpessl, M. & Kronbichler, A. Contrast-associated acute kidney injury (CA-AKI) in children: special considerations. Child. Kidney Dis. 23, 77–85 (2019).

    Google Scholar 

  34. Bihorac, A. et al. Incidence, clinical predictors, genomics, and outcome of acute kidney injury among trauma patients. Ann. Surg. 252, 158–165 (2010).

    PubMed  PubMed Central  Google Scholar 

  35. Perkins, Z. B. et al. Trauma induced acute kidney injury. PLoS ONE 14, e0211001 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Kellum, J. A. Why are patients still getting and dying from acute kidney injury? Curr. Opin. Crit. Care 22, 513–519 (2016).

    PubMed  Google Scholar 

  37. 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).

    PubMed  PubMed Central  Google Scholar 

  38. Kellum, J. A. & Prowle, J. R. Paradigms of acute kidney injury in the intensive care setting. Nat. Rev. Nephrol. 14, 217–230 (2018).

    PubMed  Google Scholar 

  39. Xu, K. et al. Unique transcriptional programs identify subtypes of AKI. J. Am. Soc. Nephrol. 28, 1729–1740 (2017).

    CAS  PubMed  Google Scholar 

  40. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 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).

    PubMed  PubMed Central  Google Scholar 

  42. 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).

    CAS  PubMed  Google Scholar 

  43. Vincent, J.-L. & De Backer, D. Circulatory shock. N. Engl. J. Med. 369, 1726–1734 (2013).

    CAS  PubMed  Google Scholar 

  44. Mizock, B. A. Alterations in fuel metabolism in critical illness: hyperglycaemia. Best. Pract. Res. Clin. Endocrinol. Metab. 15, 533–551 (2001).

    CAS  PubMed  Google Scholar 

  45. Cuthbertson, D. Post-shock metabolic response. Lancet 239, 433–437 (1942).

    Google Scholar 

  46. 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).

    PubMed  PubMed Central  Google Scholar 

  47. 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).

    PubMed  PubMed Central  Google Scholar 

  48. 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).

    PubMed  PubMed Central  Google Scholar 

  49. 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).

    PubMed  Google Scholar 

  50. 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).

    PubMed  Google Scholar 

  51. 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).

    CAS  PubMed  Google Scholar 

  52. 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).

    CAS  PubMed  Google Scholar 

  53. Pfeiffer, L. et al. Endotoxinemia and multiple organ failure after polytrauma. Anaesthesiol. Reanim. 21, 91–96 (1996).

    CAS  PubMed  Google Scholar 

  54. Attanà, P. et al. Endotoxin role in cardiogenic shock: a brief report. Int. J. Cardiol. 167, 3031–3032 (2013).

    PubMed  Google Scholar 

  55. 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).

    PubMed  Google Scholar 

  56. Gentile, L. F. et al. Is there value in plasma cytokine measurements in patients with severe trauma and sepsis? Methods 61, 3–9 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Halbgebauer, R. et al. Hemorrhagic shock drives glycocalyx, barrier and organ dysfunction early after polytrauma. J. Crit. Care 44, 229–237 (2018).

    PubMed  Google Scholar 

  58. 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).

    PubMed  Google Scholar 

  59. Williams, L. R. & Leggett, R. W. Reference values for resting blood flow to organs of man. Clin. Phys. Physiol. Meas. 10, 187–217 (1989).

    CAS  PubMed  Google Scholar 

  60. O’Connor, P. M. Renal oxygen delivery: matching delivery to metabolic demand. Clin. Exp. Pharmacol. Physiol. 33, 961–967 (2006).

    PubMed  Google Scholar 

  61. Cupples, W. A. Interactions contributing to kidney blood flow autoregulation. Curr. Opin. Nephrol. Hypertens. 16, 39–45 (2007).

    PubMed  Google Scholar 

  62. Ricksten, S.-E., Bragadottir, G. & Redfors, B. Renal oxygenation in clinical acute kidney injury. Crit. Care 17, 221 (2013).

    PubMed  PubMed Central  Google Scholar 

  63. 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).

    CAS  PubMed  Google Scholar 

  64. 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).

    CAS  PubMed  Google Scholar 

  65. Legrand, M. & Payen, D. Understanding urine output in critically ill patients. Ann. Intensive Care 1, 13 (2011).

    PubMed  PubMed Central  Google Scholar 

  66. 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).

    CAS  PubMed  Google Scholar 

  67. Riddez, L. et al. Central and regional hemodynamics during acute hypovolemia and volume substitution in volunteers. Crit. Care Med. 25, 635–640 (1997).

    CAS  PubMed  Google Scholar 

  68. 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).

    PubMed  Google Scholar 

  69. Nelimarkka, O., Halkola, L. & Niinikoski, J. Renal hypoxia and lactate metabolism in hemorrhagic shock in dogs. Crit. Care Med. 12, 656–660 (1984).

    CAS  PubMed  Google Scholar 

  70. Zarbock, A., Koyner, J. L., Hoste, E. A. J. & Kellum, J. A. Update on perioperative acute kidney injury. Anesth. Analg. 127, 1236–1245 (2018).

    PubMed  Google Scholar 

  71. Villa, G., Samoni, S., De Rosa, S. & Ronco, C. The pathophysiological hypothesis of kidney damage during intra-abdominal hypertension. Front. Physiol. 7, 55 (2016).

    PubMed  PubMed Central  Google Scholar 

  72. 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).

    PubMed  Google Scholar 

  73. 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).

    CAS  PubMed  Google Scholar 

  74. 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).

    CAS  PubMed  Google Scholar 

  75. Engelmann, B. & Massberg, S. Thrombosis as an intravascular effector of innate immunity. Nat. Rev. Immunol. 13, 34–45 (2013).

    CAS  PubMed  Google Scholar 

  76. 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).

    PubMed  PubMed Central  Google Scholar 

  77. 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).

    CAS  PubMed  Google Scholar 

  78. Zhang, Q. et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464, 104–107 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 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).

    CAS  PubMed  Google Scholar 

  80. Burk, A.-M. et al. Early complementopathy after multiple injuries in humans. Shock 37, 348–354 (2012).

    PubMed  PubMed Central  Google Scholar 

  81. Bihorac, A. et al. Acute kidney injury is associated with early cytokine changes after trauma. J. Trauma Acute Care Surg. 74, 1005–1013 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Frith, D. et al. Definition and drivers of acute traumatic coagulopathy: clinical and experimental investigations. J. Thromb. Haemost. 8, 1919–1925 (2010).

    CAS  PubMed  Google Scholar 

  83. Vulliamy, P. et al. Histone H4 induces platelet ballooning and microparticle release during trauma hemorrhage. Proc. Natl Acad. Sci. USA 116, 17444–17449 (2019).

    CAS  PubMed  Google Scholar 

  84. Denk, S. et al. Role of hemorrhagic shock in experimental polytrauma. Shock 49, 154–163 (2018).

    PubMed  Google Scholar 

  85. Singbartl, K., Green, S. A. & Ley, K. Blocking P-selectin protects from ischemia/reperfusion-induced acute renal failure. FASEB J. 14, 48–54 (2000).

    CAS  PubMed  Google Scholar 

  86. 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).

    CAS  PubMed  Google Scholar 

  87. Zhou, H.-L. et al. Metabolic reprogramming by the S-nitroso-CoA reductase system protects against kidney injury. Nature 565, 96–100 (2019).

    CAS  PubMed  Google Scholar 

  88. 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).

    CAS  PubMed  Google Scholar 

  89. Cernak, I., Savic, J., Ignjatovic, D. & Jevtic, M. Blast injury from explosive munitions. J. Trauma. 47, 96–103 (1999).

    CAS  PubMed  Google Scholar 

  90. 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).

    CAS  PubMed  Google Scholar 

  91. 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).

    CAS  Google Scholar 

  92. 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).

    CAS  PubMed  Google Scholar 

  93. 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).

    Google Scholar 

  94. 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).

    CAS  PubMed  Google Scholar 

  95. Ganter, M. T. et al. Role of the alternative pathway in the early complement activation following major trauma. Shock 28, 29–34 (2007).

    CAS  PubMed  Google Scholar 

  96. 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).

    CAS  PubMed  Google Scholar 

  97. 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).

    CAS  PubMed  Google Scholar 

  98. Torbohm, I. et al. C5b-8 and C5b-9 modulate the collagen release of human glomerular epithelial cells. Kidney Int. 37, 1098–1104 (1990).

    CAS  PubMed  Google Scholar 

  99. Huber-Lang, M. et al. Role of C5a in multiorgan failure during sepsis. J. Immunol. 166, 1193–1199 (2001).

    CAS  PubMed  Google Scholar 

  100. 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).

    PubMed  PubMed Central  Google Scholar 

  101. 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).

    CAS  PubMed  Google Scholar 

  102. 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).

    PubMed  Google Scholar 

  103. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Bosch, X., Poch, E. & Grau, J. M. Rhabdomyolysis and acute kidney injury. N. Engl. J. Med. 361, 62–72 (2009).

    CAS  PubMed  Google Scholar 

  105. 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).

    CAS  PubMed  Google Scholar 

  106. Kitamura, M. & Fine, L. G. The concept of glomerular self-defense. Kidney Int. 55, 1639–1671 (1999).

    CAS  PubMed  Google Scholar 

  107. 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).

    CAS  PubMed  Google Scholar 

  108. Thadhani, R., Pascual, M. & Bonventre, J. V. Acute renal failure. N. Engl. J. Med. 334, 1448–1460 (1996).

    CAS  PubMed  Google Scholar 

  109. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Zhou, W. et al. Predominant role for C5b-9 in renal ischemia/reperfusion injury. J. Clin. Invest. 105, 1363–1371 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 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).

    CAS  PubMed  Google Scholar 

  112. 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).

    PubMed  PubMed Central  Google Scholar 

  113. 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).

    Google Scholar 

  114. de Vries, B. et al. Complement factor C5a mediates renal ischemia-reperfusion injury independent from neutrophils. J. Immunol. 170, 3883–3889 (2003).

    PubMed  Google Scholar 

  115. Peng, Q. et al. C3a and C5a promote renal ischemia-reperfusion injury. J. Am. Soc. Nephrol. 23, 1474–1485 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 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).

    Article  PubMed  Google Scholar 

  117. Singbartl, K. & Ley, K. Protection from ischemia-reperfusion induced severe acute renal failure by blocking E-selectin. Crit. Care Med. 28, 2507–2514 (2000).

    CAS  PubMed  Google Scholar 

  118. 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).

    CAS  PubMed  Google Scholar 

  119. 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).

    CAS  PubMed  Google Scholar 

  120. 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).

    CAS  PubMed  Google Scholar 

  121. Gupta, S. & Kaplan, M. J. The role of neutrophils and NETosis in autoimmune and renal diseases. Nat. Rev. Nephrol. 12, 402–413 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 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).

    PubMed Central  Google Scholar 

  123. 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).

    PubMed Central  Google Scholar 

  124. Awad, A. S. et al. Compartmentalization of neutrophils in the kidney and lung following acute ischemic kidney injury. Kidney Int. 75, 689–698 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Dong, X.-Q. et al. Resistin is associated with mortality in patients with traumatic brain injury. Crit. Care 14, R190 (2010).

    PubMed  PubMed Central  Google Scholar 

  128. Singbartl, K., Formeck, C. L. & Kellum, J. A. Kidney-immune system crosstalk in AKI. Semin. Nephrol. 39, 96–106 (2019).

    CAS  PubMed  Google Scholar 

  129. Miller, L. et al. Resistin directly inhibits bacterial killing in neutrophils. Intensive Care Med. Exp. 7, 30 (2019).

    PubMed  PubMed Central  Google Scholar 

  130. 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).

    CAS  PubMed  Google Scholar 

  131. Jang, H. R. & Rabb, H. Immune cells in experimental acute kidney injury. Nat. Rev. Nephrol. 11, 88–101 (2015).

    CAS  PubMed  Google Scholar 

  132. Nelson, P. J. et al. The renal mononuclear phagocytic system. J. Am. Soc. Nephrol. 23, 194–203 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 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).

    PubMed  Google Scholar 

  134. 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).

    PubMed  Google Scholar 

  135. De Greef, K. E. et al. Anti-B7-1 blocks mononuclear cell adherence in vasa recta after ischemia. Kidney Int. 60, 1415–1427 (2001).

    PubMed  Google Scholar 

  136. Williams, T. M., Little, M. H. & Ricardo, S. D. Macrophages in renal development, injury, and repair. Semin. Nephrol. 30, 255–267 (2010).

    CAS  PubMed  Google Scholar 

  137. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Huen, S. C. & Cantley, L. G. Macrophage-mediated injury and repair after ischemic kidney injury. Pediatr. Nephrol. 30, 199–209 (2015).

    PubMed  Google Scholar 

  139. Gueler, F. et al. Statins attenuate ischemia-reperfusion injury by inducing heme oxygenase-1 in infiltrating macrophages. Am. J. Pathol. 170, 1192–1199 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 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).

    PubMed  Google Scholar 

  141. 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).

    CAS  PubMed  Google Scholar 

  142. Chiba, T. et al. Retinoic acid signaling coordinates macrophage-dependent injury and repair after AKI. J. Am. Soc. Nephrol. 27, 495–508 (2016).

    CAS  PubMed  Google Scholar 

  143. 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).

    CAS  PubMed  Google Scholar 

  144. 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).

    CAS  PubMed  Google Scholar 

  145. 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).

    CAS  PubMed  Google Scholar 

  146. Dai, H., Thomson, A. W. & Rogers, N. M. Dendritic cells as sensors, mediators, and regulators of ischemic injury. Front. Immunol. 10, 2418 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 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).

    CAS  PubMed  Google Scholar 

  148. 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).

    CAS  PubMed  Google Scholar 

  149. Pons, M. et al. Mast cells and MCPT4 chymase promote renal impairment after partial ureteral obstruction. Front. Immunol. 8, 450 (2017).

    PubMed  PubMed Central  Google Scholar 

  150. 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).

    CAS  PubMed  Google Scholar 

  151. Danelli, L. et al. Early Phase mast cell activation determines the chronic outcome of renal ischemia–reperfusion injury. J. Immunol. 198, 2374–2382 (2017).

    CAS  PubMed  Google Scholar 

  152. 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).

    PubMed  Google Scholar 

  153. 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).

    CAS  PubMed  Google Scholar 

  154. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. 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).

    CAS  Google Scholar 

  156. Burne-Taney, M. J. et al. B cell deficiency confers protection from renal ischemia reperfusion injury. J. Immunol. 171, 3210–3215 (2003).

    CAS  PubMed  Google Scholar 

  157. Cantaluppi, V. et al. Interaction between systemic inflammation and renal tubular epithelial cells. Nephrol. Dial. Transplant. 29, 2004–2011 (2014).

    CAS  PubMed  Google Scholar 

  158. Kim, B. S. et al. Ischemia-repersfusion injury activates innate immunity in rat kidneys. Transplantation 79, 1370–1377 (2005).

    PubMed  Google Scholar 

  159. 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).

    CAS  PubMed  Google Scholar 

  160. Grigoryev, D. N. et al. The local and systemic inflammatory transcriptome after acute kidney injury. J. Am. Soc. Nephrol. 19, 547–558 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Baek, J.-H. et al. IL-34 mediates acute kidney injury and worsens subsequent chronic kidney disease. J. Clin. Invest. 125, 3198–3214 (2015).

    PubMed  PubMed Central  Google Scholar 

  162. Rosenberger, C. et al. Cellular responses to hypoxia after renal segmental infarction. Kidney Int. 64, 874–886 (2003).

    PubMed  Google Scholar 

  163. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. 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).

    CAS  PubMed  Google Scholar 

  165. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Janak, J. C. et al. Urinary biomarkers are associated with severity and mechanism of injury. Shock 47, 593–598 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Yang, L. et al. KIM-1–mediated phagocytosis reduces acute injury to the kidney. J. Clin. Invest. 125, 1620–1636 (2015).

    PubMed  PubMed Central  Google Scholar 

  169. 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).

    CAS  PubMed  Google Scholar 

  170. Jin, H. et al. Epithelial innate immunity mediates tubular cell senescence after kidney injury. JCI Insight 4, e125490 (2019).

    PubMed Central  Google Scholar 

  171. 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).

    CAS  PubMed  Google Scholar 

  172. Humphreys, B. D. et al. Repair of injured proximal tubule does not involve specialized progenitors. Proc. Natl Acad. Sci. USA 108, 9226–9231 (2011).

    CAS  PubMed  Google Scholar 

  173. 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).

    CAS  PubMed  Google Scholar 

  174. 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).

    Article  Google Scholar 

  175. Johansson, P. I. et al. Traumatic endotheliopathy: a prospective observational study of 424 severely injured patients. Ann. Surg. 265, 597–603 (2017).

    PubMed  Google Scholar 

  176. 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).

    PubMed  Google Scholar 

  177. Noiri, E. et al. Oxidative and nitrosative stress in acute renal ischemia. Am. J. Physiol. Ren. Physiol. 281, F948–F957 (2001).

    CAS  Google Scholar 

  178. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. 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).

    CAS  PubMed  Google Scholar 

  180. 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).

    CAS  PubMed  Google Scholar 

  181. Vogel, S. et al. Platelet-derived HMGB1 is a critical mediator of thrombosis. J. Clin. Invest. 125, 4638–4654 (2015).

    PubMed  PubMed Central  Google Scholar 

  182. Yamamoto, T. et al. Intravital videomicroscopy of peritubular capillaries in renal ischemia. Am. J. Physiol. Ren. Physiol. 282, F1150–F1155 (2002).

    CAS  Google Scholar 

  183. 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).

    CAS  PubMed  Google Scholar 

  184. 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).

    CAS  PubMed  Google Scholar 

  185. 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).

    PubMed  PubMed Central  Google Scholar 

  186. 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).

    CAS  PubMed  Google Scholar 

  187. 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).

    PubMed  Google Scholar 

  188. 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).

    CAS  PubMed  Google Scholar 

  189. 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).

  190. 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).

    CAS  PubMed  Google Scholar 

  191. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Hering, D. & Winklewski, P. J. R1 autonomic nervous system in acute kidney injury. Clin. Exp. Pharmacol. Physiol. 44, 162–171 (2017).

    CAS  PubMed  Google Scholar 

  194. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Brorsson, C. et al. Adrenal response after trauma is affected by time after trauma and sedative/analgesic drugs. Injury 45, 1149–1155 (2014).

    PubMed  Google Scholar 

  196. Offner, P. J., Moore, E. E. & Ciesla, D. The adrenal response after severe trauma. Am. J. Surg. 184, 649–653 (2002).

    CAS  PubMed  Google Scholar 

  197. 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).

    CAS  Google Scholar 

  198. 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).

    CAS  PubMed  Google Scholar 

  199. 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).

    CAS  PubMed  Google Scholar 

  200. Faubel, S. & Edelstein, C. L. Mechanisms and mediators of lung injury after acute kidney injury. Nat. Rev. Nephrol. 12, 48–60 (2016).

    CAS  PubMed  Google Scholar 

  201. Freeman, W. D. & Wadei, H. M. A brain–kidney connection: the delicate interplay of brain and kidney physiology. Neurocrit. Care 22, 173–175 (2015).

    PubMed  Google Scholar 

  202. Nongnuch, A., Panorchan, K. & Davenport, A. Brain–kidney crosstalk. Crit. Care 18, 225 (2014).

    PubMed  PubMed Central  Google Scholar 

  203. Maesaka, J. K., Imbriano, L. J., Ali, N. M. & Ilamathi, E. Is it cerebral or renal salt wasting? Kidney Int. 76, 934–938 (2009).

    PubMed  Google Scholar 

  204. Tanaka, S. & Okusa, M. D. Crosstalk between the nervous system and the kidney. Kidney Int. 97, 466–476 (2020).

    PubMed  Google Scholar 

  205. Liu, M. et al. Acute kidney injury leads to inflammation and functional changes in the brain. J. Am. Soc. Nephrol. 19, 1360–1370 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. Kelly, K. J. Distant effects of experimental renal ischemia/reperfusion injury. J. Am. Soc. Nephrol. 14, 1549–1558 (2003).

    CAS  PubMed  Google Scholar 

  207. 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).

    PubMed  PubMed Central  Google Scholar 

  208. Hassoun, H. T. et al. Kidney ischemia-reperfusion injury induces caspase-dependent pulmonary apoptosis. Am. J. Physiol. Renal Physiol. 297, F125–F137 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. Kramer, A. A. et al. Renal ischemia/reperfusion leads to macrophage-mediated increase in pulmonary vascular permeability. Kidney Int. 55, 2362–2367 (1999).

    CAS  PubMed  Google Scholar 

  210. Rabb, H. et al. Acute renal failure leads to dysregulation of lung salt and water channels. Kidney Int. 63, 600–606 (2003).

    CAS  PubMed  Google Scholar 

  211. Klein, C. L. et al. Interleukin-6 mediates lung injury following ischemic acute kidney injury or bilateral nephrectomy. Kidney Int. 74, 901–909 (2008).

    CAS  PubMed  Google Scholar 

  212. 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).

    CAS  PubMed  Google Scholar 

  213. Rossi, M. et al. HO-1 mitigates acute kidney injury and subsequent kidney-lung cross-talk. Free. Radic. Res. 53, 1035–1043 (2019).

    CAS  PubMed  Google Scholar 

  214. 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).

    CAS  PubMed  Google Scholar 

  215. Vivino, G. et al. Risk factors for acute renal failure in trauma patients. Intensive Care Med. 24, 808–814 (1998).

    CAS  PubMed  Google Scholar 

  216. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. Gosling, P., Sanghera, K. & Dickson, G. Generalized vascular permeability and pulmonary function in patients following serious trauma. J. Trauma. 36, 477–481 (1994).

    CAS  PubMed  Google Scholar 

  218. Park, S. W. et al. Cytokines induce small intestine and liver injury after renal ischemia or nephrectomy. Lab. Invest. 91, 63–84 (2011).

    CAS  PubMed  Google Scholar 

  219. Golab, F. et al. Ischemic and non-ischemic acute kidney injury cause hepatic damage. Kidney Int. 75, 783–792 (2009).

    CAS  PubMed  Google Scholar 

  220. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  221. 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).

    CAS  PubMed  Google Scholar 

  222. 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).

    PubMed  Google Scholar 

  223. Hassoun, H. T. et al. Post-injury multiple organ failure: the role of the gut. Shock 15, 1–10 (2001).

    CAS  PubMed  Google Scholar 

  224. Mittal, R. & Coopersmith, C. M. Redefining the gut as the motor of critical illness. Trends Mol. Med. 20, 214–223 (2014).

    PubMed  Google Scholar 

  225. 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).

    CAS  Google Scholar 

  226. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  227. Niwa, T. & Ise, M. Indoxyl sulfate, a circulating uremic toxin, stimulates the progression of glomerular sclerosis. J. Lab. Clin. Med. 124, 96–104 (1994).

    CAS  PubMed  Google Scholar 

  228. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  229. Nakade, Y. et al. Gut microbiota-derived D-serine protects against acute kidney injury. JCI Insight 3, e97957 (2018).

    PubMed Central  Google Scholar 

  230. Andrade-Oliveira, V. et al. Gut bacteria products prevent AKI induced by ischemia-reperfusion. J. Am. Soc. Nephrol. 26, 1877–1888 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  231. 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).

    CAS  PubMed  Google Scholar 

  232. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  233. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  234. 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).

    PubMed  PubMed Central  Google Scholar 

  235. Jiang, H. et al. Splenectomy ameliorates acute multiple organ damage induced by liver warm ischemia reperfusion in rats. Surgery 141, 32–40 (2007).

    PubMed  Google Scholar 

  236. Inoue, T., Tanaka, S. & Okusa, M. D. Neuroimmune interactions in inflammation and acute kidney injury. Front. Immunol. 8, 945 (2017).

    PubMed  PubMed Central  Google Scholar 

  237. Inoue, T. et al. Vagus nerve stimulation mediates protection from kidney ischemia-reperfusion injury through α7nAChR+ splenocytes. J. Clin. Invest. 126, 1939–1952 (2016).

    PubMed  PubMed Central  Google Scholar 

  238. Demetriades, D. et al. Blunt splenic trauma: splenectomy increases early infectious complications. J. Trauma Acute Care Surg. 72, 229–234 (2012).

    PubMed  Google Scholar 

  239. Watters, J. M. et al. Splenectomy leads to a persistent hypercoagulable state after trauma. Am. J. Surg. 199, 646–651 (2010).

    PubMed  Google Scholar 

  240. Wei, K., Yin, Z. & Xie, Y. Roles of the kidney in the formation, remodeling and repair of bone. J. Nephrol. 29, 349–357 (2016).

    PubMed  PubMed Central  Google Scholar 

  241. 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).

    PubMed  PubMed Central  Google Scholar 

  242. 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).

    PubMed  PubMed Central  Google Scholar 

  243. 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).

    PubMed  Google Scholar 

  244. 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).

    PubMed  Google Scholar 

  245. 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).

    PubMed  PubMed Central  Google Scholar 

  246. 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).

    CAS  PubMed  Google Scholar 

  247. 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).

    CAS  PubMed  Google Scholar 

  248. Livingston, D. H. et al. Bone marrow failure following severe injury in humans. Ann. Surg. 238, 748–753 (2003).

    PubMed  PubMed Central  Google Scholar 

  249. 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).

    PubMed  Google Scholar 

  250. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  251. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  252. Goldstein, S. L. & Chawla, L. S. Renal angina. Clin. J. Am. Soc. Nephrol. 5, 943–949 (2010).

    PubMed  Google Scholar 

  253. Weiss, R., Meersch, M., Pavenstädt, H.-J. & Zarbock, A. Acute kidney injury. Dtsch. Arztebl. Int. 116, 833–842 (2019).

    PubMed  PubMed Central  Google Scholar 

  254. Kashani, K. et al. Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. Crit. Care 17, R25 (2013).

    PubMed  PubMed Central  Google Scholar 

  255. Sharfuddin, A. A. & Molitoris, B. A. Pathophysiology of ischemic acute kidney injury. Nat. Rev. Nephrol. 7, 189–200 (2011).

    CAS  PubMed  Google Scholar 

  256. 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).

    PubMed  PubMed Central  Google Scholar 

  257. Coccolini, F. et al. Kidney and uro-trauma: WSES-AAST guidelines. World J. Emerg. Surg. 14, 54 (2019).

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

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).

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Authors and Affiliations

  1. Institute of Clinical and Experimental Trauma Immunology, University Hospital Ulm, Ulm, Germany

    David A. C. Messerer, Rebecca Halbgebauer & Markus Huber-Lang

  2. Department of Anaesthesiology and Intensive Care Medicine, University Hospital Ulm, Ulm, Germany

    David A. C. Messerer

  3. Department of Immunology, Genetics and Pathology, Rudbeck Laboratory Uppsala University, Uppsala, Sweden

    Bo Nilsson

  4. Internal Medicine D, University Hospital Muenster, Muenster, Germany

    Hermann Pavenstädt

  5. Institute of Anaesthesiological Pathophysiology and Process Development, University Hospital Ulm, Ulm, Germany

    Peter Radermacher

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  1. David A. C. Messerer
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  2. Rebecca Halbgebauer
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Contributions

D.A.C.M., R.H., B.N. and M.H.-L. made substantial contributions to discussions of the content of the article. D.A.C.M., R.H., P.R. and M.H.-L. researched data for the article. D.A.C.M., R.H., H.P., P.R. and M.H.-L. wrote the manuscript. All authors reviewed or edited the manuscript before submission.

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Correspondence to Markus Huber-Lang.

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Nature Reviews Nephrology thanks the anonymous reviewers for their contribution to the peer review of this work.

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Supplementary information

Glossary

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.

Polytrauma

Multiple traumatic injuries, of which at least one injury or the combination thereof is life-threatening.

Immunothrombosis

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

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