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A review of the role of immune cells in acute kidney injury

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Abstract

Acute kidney injury (AKI) is a systemic disease occurring commonly in patients who are critically ill. Etiologies of AKI can be septic or aseptic (nephrotoxic, or ischemia–reperfusion injury). Recent evidence reveals that innate and adaptive immune responses are involved in mediating damage to renal tubular cells and in recovery from AKI. Dendritic cells, monocytes/macrophages, neutrophils, T lymphocytes, and B lymphocytes all contribute to kidney injury. Conversely, M2 macrophages and regulatory T cells are essential in suppressing inflammation, tissue remodeling and repair following kidney injury. AKI itself confers an increased risk for developing infection owing to increased production and decreased clearance of cytokines, in addition to dysfunction of immune cells themselves. Neutrophils are the predominant cell type rendered dysfunctional by AKI. In this review, we describe the bi-directional interplay between the immune system and AKI and summarize recent developments in this field of research.

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References

  1. Hoste EA, Bagshaw SM, Bellomo R, Cely CM, Colman R, Cruz DN, Edipidis K, Forni LG, Gomersall CD, Govil D, Honoré PM, Joannes-Boyau O, Joannidis M, Korhonen AM, Lavrentieva A, Mehta RL, Palevsky P, Roessler E, Ronco C, Uchino S, Vazquez JA, Vidal Andrade E, Webb S, Kellum JA (2015) Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med 41(8):1411–1423

    Article  PubMed  Google Scholar 

  2. Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, Morgera S, Schetz M, Tan I, Bouman C, Macedo E, Gibney N, Tolwani A, Ronco C, Beginning, Ending Supportive Therapy for the Kidney (BEST Kidney) Investigators (2005) Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA 294(7):813–818

    Article  PubMed  CAS  Google Scholar 

  3. Sutherland SM, Ji J, Sheikhi FH, Widen E, Tian L, Alexander SR, Ling XB (2013) AKI in hospitalized children: epidemiology and clinical associations in a national cohort. Clin J Am Soc Nephrol 8(10):1661–1669

    Article  PubMed  PubMed Central  Google Scholar 

  4. Ball EF, Kara T (2008) Epidemiology and outcome of acute kidney injury in New Zealand children. J Paediatr Child Health 44(11):642–646

    PubMed  Google Scholar 

  5. Singbartl K, Joannidis M (2015) Short-term effects of acute kidney injury. Crit Care Clin 31(4):751–762

    Article  PubMed  Google Scholar 

  6. Kinsey GR, Okusa MD (2014) Expanding role of T cells in acute kidney injury. Curr Opin Nephrol Hypertens 23(1):9–16

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Rogers NM, Ferenbach DA, Isenberg JS, Thomson AW, Hughes J (2014) Dendritic cells and macrophages in the kidney: a spectrum of good and evil. Nat Rev Nephrol 10(11):625–643

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Jang HR, Rabb H (2015) Immune cells in experimental acute kidney injury. Nat Rev Nephrol 11(2):88–101

    Article  PubMed  CAS  Google Scholar 

  9. Nelson PJ, Rees AJ, Griffin MD, Hughes J, Kurts C, Duffield J (2012) The renal mononuclear phagocytic system. J Am Soc Nephrol 23(2):194–203

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Duann P, Lianos EA, Ma J, Lin PH (2016) Autophagy, innate immunity and tissue repair in acute kidney injury. Int J Mol Sci 17(5):662

    Article  PubMed Central  CAS  Google Scholar 

  11. Hauenstein AV, Zhang L, Wu H (2015) The hierarchical structural architecture of inflammasomes, supramolecular inflammatory machines. Curr Opin Struct Biol 31:75–83

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Takada M, Nadeau KC, Shaw GD, Tilney NL (1997) Early cellular and molecular changes in ischemia/reperfusion injury: inhibition by a selectin antagonist, P-selectin glycoprotein ligand-1. Transplant Proc 29(1–2):1324–1325

    Article  PubMed  CAS  Google Scholar 

  13. Li L, Huang L, Sung SS, Vergis AL, Rosin DL, Rose CE Jr, Lobo PI, Okusa MD (2008) The chemokine receptors CCR2 and CX3CR1 mediate monocyte/macrophage trafficking in kidney ischemia-reperfusion injury. Kidney Int 74(12):1526–1537

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Kelly KJ, Williams WW Jr, Colvin RB, Meehan SM, Springer TA, Gutierrez-Ramos JC, Bonventre JV (1996) Intercellular adhesion molecule-1-deficient mice are protected against ischemic renal injury. J Clin Invest 97(4):1056–1063

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Awad AS, Rouse M, Huang L, Vergis AL, Reutershan J, Cathro HP, Linden J, Okusa MD (2009) Compartmentalization of neutrophils in the kidney and lung following acute ischemic kidney injury. Kidney Int 75(7):689–698

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Ysebaert DK, De Greef KE, Vercauteren SR, Ghielli M, Verpooten GA, Eyskens EJ, De Broe ME (2000) Identification and kinetics of leukocytes after severe ischaemia/reperfusion renal injury. Nephrol Dial Transplant 15(10):1562–1574

    Article  PubMed  CAS  Google Scholar 

  17. Huen SC, Cantley LG (2015) Macrophage-mediated injury and repair after ischemic kidney injury. Pediatr Nephrol 30(2):199–209

    Article  PubMed  Google Scholar 

  18. Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM (1998) Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest 101(4):890–898

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Filardy AA, Pires DR, Nunes MP, Takiya CM, Freire-de-Lima CG, Ribeiro-Gomes FL, DosReis GA (2010) Proinflammatory clearance of apoptotic neutrophils induces an IL-12(low)IL-10(high) regulatory phenotype in macrophages. J Immunol 185(4):2044–2050

    Article  PubMed  CAS  Google Scholar 

  20. Lemley KV, Kriz W (1991) Anatomy of the renal interstitium. Kidney Int 39(3):370–381

    Article  PubMed  CAS  Google Scholar 

  21. Soos TJ, Sims TN, Barisoni L, Lin K, Littman DR, Dustin ML, Nelson PJ (2006) CX3CR1+ interstitial dendritic cells form a contiguous network throughout the entire kidney. Kidney Int 70(3):591–596

    Article  PubMed  CAS  Google Scholar 

  22. Aggarwal BB (2003) Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 3(9):745–756

    Article  PubMed  CAS  Google Scholar 

  23. Zhang ZX, Shek K, Wang S, Huang X, Lau A, Yin Z, Sun H, Liu W, Garcia B, Rittling S, Jevnikar AM (2010) Osteopontin expressed in tubular epithelial cells regulates NK cell-mediated kidney ischemia reperfusion injury. J Immunol 185(2):967–973

    Article  PubMed  CAS  Google Scholar 

  24. Rabb H, Daniels F, O'Donnell M, Haq M, Saba SR, Keane W, Tang WW (2000) Pathophysiological role of T lymphocytes in renal ischemia-reperfusion injury in mice. Am J Physiol Renal Physiol 279(3):F525–F531

    Article  PubMed  CAS  Google Scholar 

  25. Burne MJ, Daniels F, El Ghandour A, Mauiyyedi S, Colvin RB, O'Donnell MP, Rabb H (2001) Identification of the CD4(+) T cell as a major pathogenic factor in ischemic acute renal failure. J Clin Invest 108(9):1283–1290

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Wang S, Diao H, Guan Q, Cruikshank WW, Delovitch TL, Jevnikar AM, Du C (2008) Decreased renal ischemia-reperfusion injury by IL-16 inactivation. Kidney Int 73(3):318–326

    Article  PubMed  CAS  Google Scholar 

  27. Ascon M, Ascon DB, Liu M, Cheadle C, Sarkar C, Racusen L, Hassoun HT, Rabb H (2009) Renal ischemia-reperfusion leads to long term infiltration of activated and effector-memory T lymphocytes. Kidney Int 75(5):526–535

    Article  PubMed  CAS  Google Scholar 

  28. Kinsey GR, Sharma R, Huang L, Li L, Vergis AL, Ye H, Ju ST, Okusa MD (2009) Regulatory T cells suppress innate immunity in kidney ischemia-reperfusion injury. J Am Soc Nephrol 20(8):1744–1753

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Linfert D, Chowdhry T, Rabb H (2009) Lymphocytes and ischemia-reperfusion injury. Transplant Rev (Orlando) 23(1):1–10

    Article  Google Scholar 

  30. Jang HR, Gandolfo MT, Ko GJ, Satpute SR, Racusen L, Rabb H (2010) B cells limit repair after ischemic acute kidney injury. J Am Soc Nephrol 21(4):654–665

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Burne-Taney MJ, Ascon DB, Daniels F, Racusen L, Baldwin W, Rabb H (2003) B cell deficiency confers protection from renal ischemia reperfusion injury. J Immunol 171(6):3210–3215

    Article  PubMed  CAS  Google Scholar 

  32. Ramesh G, Reeves WB (2002) TNF-alpha mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity. J Clin Invest 110(6):835–842

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Ramesh G, Reeves WB (2003) TNFR2-mediated apoptosis and necrosis in cisplatin-induced acute renal failure. Am J Physiol Renal Physiol 285(4):F610–F618

    Article  PubMed  CAS  Google Scholar 

  34. Deng J, Kohda Y, Chiao H, Wang Y, Hu X, Hewitt SM, Miyaji T, McLeroy P, Nibhanupudy B, Li S, Star RA (2001) Interleukin-10 inhibits ischemic and cisplatin-induced acute renal injury. Kidney Int 60(6):2118–2128

    Article  PubMed  CAS  Google Scholar 

  35. Tadagavadi RK, Reeves WB (2010) Renal dendritic cells ameliorate nephrotoxic acute kidney injury. J Am Soc Nephrol 21(1):53–63

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Scholz J, Lukacs-Kornek V, Engel DR, Specht S, Kiss E, Eitner F, Floege J, Groene HJ, Kurts C (2008) Renal dendritic cells stimulate IL-10 production and attenuate nephrotoxic nephritis. J Am Soc Nephrol 19(3):527–537

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Faubel S, Lewis EC, Reznikov L, Ljubanovic D, Hoke TS, Somerset H, Oh DJ, Lu L, Klein CL, Dinarello CA, Edelstein CL (2007) Cisplatin-induced acute renal failure is associated with an increase in the cytokines interleukin (IL)-1beta, IL-18, IL-6, and neutrophil infiltration in the kidney. J Pharmacol Exp Ther 322(1):8–15

    Article  PubMed  CAS  Google Scholar 

  38. Kelly KJ, Meehan SM, Colvin RB, Williams WW, Bonventre JV (1999) Protection from toxicant-mediated renal injury in the rat with anti-CD54 antibody. Kidney Int 56(3):922–931

    Article  PubMed  CAS  Google Scholar 

  39. Lu LH, Oh DJ, Dursun B, He Z, Hoke TS, Faubel S, Edelstein CL (2008) Increased macrophage infiltration and fractalkine expression in cisplatin-induced acute renal failure in mice. J Pharmacol Exp Ther 324(1):111–117

    Article  PubMed  CAS  Google Scholar 

  40. Chauhan P, Sodhi A, Shrivastava A (2009) Cisplatin primes murine peritoneal macrophages for enhanced expression of nitric oxide, proinflammatory cytokines, TLRs, transcription factors and activation of MAP kinases upon co-incubation with L929 cells. Immunobiology 214(3):197–209

    Article  PubMed  CAS  Google Scholar 

  41. Liu M, Chien CC, Burne-Taney M, Molls RR, Racusen LC, Colvin RB, Rabb H (2006) A pathophysiologic role for T lymphocytes in murine acute cisplatin nephrotoxicity. J Am Soc Nephrol 17(3):765–774

    Article  PubMed  CAS  Google Scholar 

  42. Moussion C, Ortega N, Girard JP (2008) The IL-1-like cytokine IL-33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo: a novel 'alarmin'? PLoS One 3(10):n3331

    Article  CAS  Google Scholar 

  43. Lüthi AU, Cullen SP, McNeela EA, Duriez PJ, Afonina IS, Sheridan C, Brumatti G, Taylor RC, Kersse K, Vandenabeele P, Lavelle EC, Martin SJ (2009) Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases. Immunity 31(1):84–98

    Article  PubMed  CAS  Google Scholar 

  44. Lee H, Nho D, Chung HS, Shin MK, Kim SH, Bae H (2010) CD4+CD25+ regulatory T cells attenuate cisplatin-induced nephrotoxicity in mice. Kidney Int 78(11):1100–1109

    Article  PubMed  CAS  Google Scholar 

  45. Wan L, Bagshaw SM, Langenberg C, Saotome T, May C, Bellomo R (2008) Pathophysiology of septic acute kidney injury: what do we really know? Crit Care Med 36 [4 Suppl]:S198–S203

    Article  PubMed  Google Scholar 

  46. Gómez H, Kellum JA (2016) Sepsis-induced acute kidney injury. Curr Opin Crit Care 22(6):546–553

    Article  PubMed  PubMed Central  Google Scholar 

  47. Ergin B, Kapucu A, Demirci-Tansel C, Ince C (2015) The renal microcirculation in sepsis. Nephrol Dial Transplant 30(2):169–177

    Article  PubMed  CAS  Google Scholar 

  48. Tyml K, Wang X, Lidington D, Ouellette Y (2001) Lipopolysaccharide reduces intercellular coupling in vitro and arteriolar conducted response in vivo. Am J Physiol Heart Circ Physiol 281(3):H1397–H1406

    Article  PubMed  CAS  Google Scholar 

  49. Cunha FQ, Assreuy J, Moss DW, Rees D, Leal LM, Moncada S, Carrier M, O'Donnell CA, Liew FY (1994) Differential induction of nitric oxide synthase in various organs of the mouse during endotoxaemia: role of TNF-alpha and IL-1-beta. Immunology 81(2):211–215

    PubMed  PubMed Central  CAS  Google Scholar 

  50. Lerolle N, Nochy D, Guérot E, Bruneval P, Fagon JY, Diehl JL, Hill G (2010) Histopathology of septic shock induced acute kidney injury: apoptosis and leukocytic infiltration. Intensive Care Med 36(3):471–478

    Article  PubMed  Google Scholar 

  51. Hotchkiss RS, Karl IE (2003) The pathophysiology and treatment of sepsis. N Engl J Med 348(2):138–150

    Article  PubMed  CAS  Google Scholar 

  52. Maravitsa P, Adamopoulou M, Pistiki A, Netea MG, Louis K, Giamarellos-Bourboulis EJ (2016) Systemic over-release of interleukin-17 in acute kidney injury after septic shock: clinical and experimental evidence. Immunol Lett 178:68–76

    Article  PubMed  CAS  Google Scholar 

  53. Luo CJ, Luo F, Zhang L, Xu Y, Cai GY, Fu B, Feng Z, Sun XF, Chen XM (2016) Knockout of interleukin-17A protects against sepsis-associated acute kidney injury. Ann Intensive Care 6(1):56

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Repine JE, Beehler CJ (1991) Neutrophils and adult respiratory distress syndrome: two interlocking perspectives in 1991. Am Rev Respir Dis 144(2):251–252

    Article  PubMed  CAS  Google Scholar 

  55. Nelson S, Belknap SM, Carlson RW, Dale D, DeBoisblanc B, Farkas S, Fotheringham N, Ho H, Marrie T, Movahhed H, Root R, Wilson J (1998) A randomized controlled trial of filgrastim as an adjunct to antibiotics for treatment of hospitalized patients with community-acquired pneumonia. CAP study group. J Infect Dis 178(4):1075–1080

    Article  PubMed  CAS  Google Scholar 

  56. Boomer JS, To K, Chang KC, Takasu O, Osborne DF, Walton AH, Bricker TL, Jarman SD, Kreisel D, Krupnick AS, Srivastava A, Swanson PE, Green JM, Hotchkiss RS (2011) Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA 306(23):2594–2605

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Pachot A, Monneret G, Brion A, Venet F, Bohé J, Bienvenu J, Mougin B, Lepape A (2005) Messenger RNA expression of major histocompatibility complex class II genes in whole blood from septic shock patients. Crit Care Med 33(1):31–38, discussion 236–237

    Article  PubMed  CAS  Google Scholar 

  58. Thakar CV, Yared JP, Worley S, Cotman K, Paganini EP (2003) Renal dysfunction and serious infections after open-heart surgery. Kidney Int 64(1):239–246

    Article  PubMed  Google Scholar 

  59. De Waele JJ, Hoste EA, Blot SI (2008) Blood stream infections of abdominal origin in the intensive care unit: characteristics and determinants of death. Surg Infect 9(2):171–177

    Article  Google Scholar 

  60. Tumbarello M, Spanu T, Caira M, Trecarichi EM, Laurenti L, Montuori E, Fianchi L, Leone F, Fadda G, Cauda R, Pagano L (2009) Factors associated with mortality in bacteremic patients with hematologic malignancies. Diagn Microbiol Infect Dis 64(3):320–326

    Article  PubMed  Google Scholar 

  61. Thakar CV, Liangos O, Yared JP, Nelson D, Piedmonte MR, Hariachar S, Paganini EP (2003) ARF after open-heart surgery: influence of gender and race. Am J Kidney Dis 41(4):742–751

    Article  PubMed  Google Scholar 

  62. Selby NM, Kolhe NV, McIntyre CW, Monaghan J, Lawson N, Elliott D, Packington R, Fluck RJ (2012) Defining the cause of death in hospitalised patients with acute kidney injury. PLoS One 7(11):e48580

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Hoke TS, Douglas IS, Klein CL, He Z, Fang W, Thurman JM, Tao Y, Dursun B, Voelkel NF, Edelstein CL, Faubel S (2007) Acute renal failure after bilateral nephrectomy is associated with cytokine-mediated pulmonary injury. J Am Soc Nephrol 18(1):155–164

    Article  PubMed  CAS  Google Scholar 

  64. Faubel S, Edelstein CL (2016) Mechanisms and mediators of lung injury after acute kidney injury. Nat Rev Nephrol 12(1):48–60

    Article  PubMed  CAS  Google Scholar 

  65. Zarbock A, Schmolke M, Spieker T, Jurk K, Van Aken H, Singbartl K (2006) Acute uremia but not renal inflammation attenuates aseptic acute lung injury: a critical role for uremic neutrophils. J Am Soc Nephrol 17(11):3124–3131

    Article  PubMed  CAS  Google Scholar 

  66. Singbartl K, Bishop JV, Wen X, Murugan R, Chandra S, Filippi MD, Kellum JA (2011) Differential effects of kidney-lung cross-talk during acute kidney injury and bacterial pneumonia. Kidney Int 80(6):633–644

    Article  PubMed  PubMed Central  Google Scholar 

  67. Rossaint J, Spelten O, Kassens N, Mueller H, Van Aken HK, Singbartl K, Zarbock A (2011) Acute loss of renal function attenuates slow leukocyte rolling and transmigration by interfering with intracellular signaling. Kidney Int 80(5):493–503

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Singbartl K, Miller L, Ruiz-Velasco V, Kellum JA (2016) Reversal of acute kidney injury-induced neutrophil dysfunction: a critical role for resistin. Crit Care Med 44(7):e492–e501

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Cohen G, Ilic D, Raupachova J, Horl WH (2008) Resistin inhibits essential functions of polymorphonuclear leukocytes. J Immunol 181(6):3761–3768

    Article  PubMed  CAS  Google Scholar 

  70. Silva RC, Landgraf MA, Correa-Costa M, Semedo P, Cenedeze MA, Pacheco-Silva A, Landgraf RG, Camara NO (2013) Acute kidney injury reduces phagocytic and microbicidal capacities of alveolar macrophages. Cell Physiol Biochem 31(2–3):179–188

    Article  PubMed  CAS  Google Scholar 

  71. Himmelfarb J, Le P, Klenzak J, Freedman S, McMenamin ME, Ikizler TA, Group P (2004) Impaired monocyte cytokine production in critically ill patients with acute renal failure. Kidney Int 66(6):2354–2360

    Article  PubMed  CAS  Google Scholar 

  72. Rabb H, Griffin MD, McKay DB, Swaminathan S, Pickkers P, Rosner MH, Kellum JA, Ronco C, Acute Dialysis Quality Initiative Consensus XWG (2016) Inflammation in AKI: current understanding, key questions, and knowledge gaps. J Am Soc Nephrol 27(2):371–379

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Anesthesiology and Perioperative Medicine, PennState Health—Milton S. Hershey Medical Center, Hershey, PA, USA

    Anthony Bonavia

  2. Department of Critical Care Medicine, Mayo Clinic, Phoenix, AZ, 85054, USA

    Kai Singbartl

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Correspondence to Kai Singbartl.

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Bonavia, A., Singbartl, K. A review of the role of immune cells in acute kidney injury. Pediatr Nephrol 33, 1629–1639 (2018). https://doi.org/10.1007/s00467-017-3774-5

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