Sepsis pp 127-142 | Cite as

Sepsis-Induced AKI

  • Hernando Gomez
  • Alex Zarbock
  • Raghavan Murugan
  • John A. KellumEmail author
Part of the Respiratory Medicine book series (RM)


Acute kidney injury (AKI) is a common complication in critically ill patients, and is associated with increased morbidity and mortality. Sepsis is the most common cause of AKI in the critically ill. Considerable evidence has shown that AKI can occur in the absence of overt clinical signs of shock, and in the setting of increased renal blood flow. This has challenged the traditional paradigm that renal dysfunction was solely on the basis of hypoperfusion and ischemia. Animal and human data have further shown that sepsis-induced AKI is characterized not by acute tubular necrosis, but by a paucity of apoptosis and necrosis in the context of a very bland histology, by inflammation, by microvascular dysfunction, and cellular bioenergetics adaptive responses. These novel findings suggest that other potential mechanisms centered in these three domains may help explain the pathophysiology of sepsis-induced AKI. Furthermore, the extreme functional changes seen in sepsis-induced AKI and the response of the tubular epithelial cells to inflammation and injury may be adaptive. This chapter focuses on the recent advances in this area and discusses possible therapeutic interventions that might derive from these new insights into the pathogenesis of sepsis-induced AKI.


Acute kidney injury Sepsis Inflammation Microvascular dysfunction Tubular epithelial cells 



The authors declare no conflicts of interest. This work was funded by NIH/NHLBI grant number 1K12HL109068-02 awarded to H.G., and research grant from the German research foundation (ZA428/10-1) and Else-Kröner Fresenius Stiftung awarded to A.Z.


  1. 1.
    Uchino S, Kellum, JA, Bellomo R, Doig GS, Morimatsu H, Morgera S, et al. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA. 2005;294(7):813–8. doi: 10.1001/jama.294.7.813.CrossRefPubMedGoogle Scholar
  2. 2.
    Thakar CV, Christianson A, Freyberg R, Almenoff P, Render ML. Incidence and outcomes of acute kidney injury in intensive care units: a Veterans Administration study. Crit Care Med. 2009;37(9):2552–8. doi: 10.1097/CCM.0b013e3181a5906f.CrossRefPubMedGoogle Scholar
  3. 3.
    Murugan R, Kellum JA. Acute kidney injury: what’s the prognosis? Nat Rev Nephrol. 2011;7(4):209–17. doi: 10.1038/nrneph.2011.13.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Langenberg C, Wan L, Egi M, May CN, Bellomo R. Renal blood flow in experimental septic acute renal failure. Kidney Int. 2006;69(11):1996–2002. doi: 10.1038/ Scholar
  5. 5.
    Prowle JR, Ishikawa K, May CN, Bellomo R. Renal blood flow during acute renal failure in man. Blood Purif. 2009;28(3):216–25. doi: 10.1159/000230813.CrossRefPubMedGoogle Scholar
  6. 6.
    Murugan R, Karajala-Subramanyam V, Lee M, et al. Acute kidney injury in non-severe pneumonia is associated with an increased immune response and lower survival. Kidney Int. 2010;77(6):527–35. doi: 10.1038/ki.2009.502.CrossRefPubMedGoogle Scholar
  7. 7.
    Cantaluppi V, Assenzio B, Pasero D, et al. Polymyxin-B hemoperfusion inactivates circulating proapoptotic factors. Intensive Care Med. 2008;34(9):1638–45. doi: 10.1007/s00134-008-1124-6.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Hotchkiss RS, Swanson PE, Freeman BD, et al. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med. 1999;27(7):1230–51.CrossRefPubMedGoogle Scholar
  9. 9.
    Takasu O, Gaut JP, Watanabe E, et al. Mechanisms of cardiac and renal dysfunction in patients dying of sepsis. Am J Respir Crit Care Med. 2013;187(5):509–17. doi: 10.1164/rccm.201211-1983OC.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Wang Z, Holthoff JH, Seely KA, et al. Development of oxidative stress in the peritubular capillary microenvironment mediates sepsis-induced renal microcirculatory failure and acute kidney injury. AJPA. 2012;180(2):505–16. doi: 10.1016/j.ajpath.2011.10.011.Google Scholar
  11. 11.
    Seely KA, Holthoff JH, Burns ST, et al. Hemodynamic changes in the kidney in a pediatric rat model of sepsis-induced acute kidney injury. Am J Physiol Renal Physiol. 2011;301(1):F209–17. doi: 10.1152/ajprenal.00687.2010.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    De Backer D, Creteur J, Preiser J-C, Dubois M-J, Vincent J-L. Microvascular blood flow is altered in patients with sepsis. Am J Respir Crit Care Med. 2002;166(1):98–104.CrossRefPubMedGoogle Scholar
  13. 13.
    Singer M, De Santis V, Vitale D, Jeffcoate W. Multiorgan failure is an adaptive, endocrine-mediated, metabolic response to overwhelming systemic inflammation. Lancet. 2004;364(9433):545–8. doi: 10.1016/S0140-6736(04)16815-3.CrossRefPubMedGoogle Scholar
  14. 14.
    KDIGO. Section 2: AKI definition. Kidney Int Suppl. 2012;2(1):19–36. doi: 10.1038/kisup.2011.32.CrossRefGoogle Scholar
  15. 15.
    Hoste EAJ, Schurgers M. Epidemiology of acute kidney injury: how big is the problem? Crit Care Med. 2008;36(4 Suppl):S146–51. doi: 10.1097/CCM.0b013e318168c590.CrossRefPubMedGoogle Scholar
  16. 16.
    Hoste EAJ, Bagshaw SM, Bellomo R, et al. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med. 2015;41(8):1411–23. doi: 10.1007/s00134-015-3934-7.CrossRefPubMedGoogle Scholar
  17. 17.
    Spronk PE, Ince C, Gardien MJ, Mathura KR, Oudemans-van Straaten HM, Zandstra DF. Nitroglycerin in septic shock after intravascular volume resuscitation. Lancet. 2002;360(9343):1395–6.CrossRefPubMedGoogle Scholar
  18. 18.
    De Backer D, Donadello K, Taccone FS, Ospina-Tascon G, Salgado D, Vincent J-L. Microcirculatory alterations: potential mechanisms and implications for therapy. Ann Intensive Care. 2011;1(1):27. doi: 10.1186/2110-5820-1-27.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Tiwari MM, Brock RW, Megyesi JK, Kaushal GP, Mayeux PR. Disruption of renal peritubular blood flow in lipopolysaccharide-induced renal failure: role of nitric oxide and caspases. Am J Physiol Renal Physiol. 2005;289(6):F1324–32. doi: 10.1152/ajprenal.00124.2005.CrossRefPubMedGoogle Scholar
  20. 20.
    Holthoff JH, Wang Z, Seely KA, Gokden N, Mayeux PR. Resveratrol improves renal microcirculation, protects the tubular epithelium, and prolongs survival in a mouse model of sepsis-induced acute kidney injury. Kidney Int. 2012;81(4):370–8. doi: 10.1038/ki.2011.347.CrossRefPubMedGoogle Scholar
  21. 21.
    Bezemer R, Legrand M, Klijn E, et al. Real-time assessment of renal cortical microvascular perfusion heterogeneities using near-infrared laser speckle imaging. Opt Express. 2010;18(14):15054–61. doi: 10.1364/OE.18.015054.CrossRefPubMedGoogle Scholar
  22. 22.
    Dyson A, Bezemer R, Legrand M, Balestra G, Singer M, Ince C. Microvascular and interstitial oxygen tension in the renal cortex and medulla studied in a 4-h rat model of LPS-induced endotoxemia. Shock. 2011;36(1):83–9. doi: 10.1097/SHK.0b013e3182169d5a.CrossRefPubMedGoogle Scholar
  23. 23.
    Almac E, Siegemund M, Demirci C, Ince C. Microcirculatory recruitment maneuvers correct tissue CO2 abnormalities in sepsis. Minerva Anestesiol. 2006;72(6):507–19.PubMedGoogle Scholar
  24. 24.
    Tyml K, Wang X, Lidington D, Ouellette Y. Lipopolysaccharide reduces intercellular coupling in vitro and arteriolar conducted response in vivo. Am J Physiol Heart Circ Physiol. 2001;281(3):H1397–406.PubMedGoogle Scholar
  25. 25.
    Prowle JR, Echeverri JE, Ligabo EV, Ronco C, Bellomo R. Fluid balance and acute kidney injury. Nat Rev Nephrol. 2010;6(2):107–15. doi: 10.1038/nrneph.2009.213.CrossRefPubMedGoogle Scholar
  26. 26.
    Bagshaw SM, Brophy PD, Cruz D, Ronco C. Fluid balance as a biomarker: impact of fluid overload on outcome in critically ill patients with acute kidney injury. Crit Care. 2008;12(4):169. doi: 10.1186/cc6948.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Hollenberg SM, Ahrens TS, Annane D, et al. Practice parameters for hemodynamic support of sepsis in adult patients: 2004 update. Crit Care Med. 2004;32(9):1928–48.CrossRefPubMedGoogle Scholar
  28. 28.
    Prowle JR, Kirwan CJ, Bellomo R. Fluid management for the prevention and attenuation of acute kidney injury. Nat Rev Nephrol. 2013;10(1):37–47. doi: 10.1038/nrneph.2013.232.CrossRefPubMedGoogle Scholar
  29. 29.
    Rajendram R, Prowle JR. Venous congestion: are we adding insult to kidney injury in sepsis? Crit Care. 2014;18(1):104. doi: 10.1186/cc13709.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Sprague AH, Khalil RA. Inflammatory cytokines in vascular dysfunction and vascular disease. Biochem Pharmacol. 2009;78(6):539–52. doi: 10.1016/j.bcp.2009.04.029.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Cunha FQ, Assreuy J, Moss DW, et al. Differential induction of nitric oxide synthase in various organs of the mouse during endotoxaemia: role of TNF-alpha and IL-1-beta. Immunology. 1994;81(2):211–5.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Trzeciak S, Cinel I, Phillip Dellinger R, et al. Resuscitating the microcirculation in sepsis: the central role of nitric oxide, emerging concepts for novel therapies, and challenges for clinical trials. Acad Emerg Med. 2008;15(5):399–413. doi: 10.1111/j.1553-2712.2008.00109.x.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Chauhan SD, Seggara G, Vo PA, Macallister RJ, Hobbs AJ, Ahluwalia A. Protection against lipopolysaccharide-induced endothelial dysfunction in resistance and conduit vasculature of iNOS knockout mice. FASEB J. 2003;17(6):773–5. doi: 10.1096/fj.02-0668fje.PubMedGoogle Scholar
  34. 34.
    Heemskerk S, Masereeuw R, Russel FGM, Pickkers P. Selective iNOS inhibition for the treatment of sepsis-induced acute kidney injury. Nat Rev Nephrol. 2009;5(11):629–40. doi: 10.1038/nrneph.2009.155.CrossRefPubMedGoogle Scholar
  35. 35.
    Rabelink TJ, van Zonneveld A-J. Coupling eNOS uncoupling to the innate immune response. Arterioscler Thromb Vasc Biol. 2006;26(12):2585–7. doi: 10.1161/01.ATV.0000250932.24151.50.CrossRefPubMedGoogle Scholar
  36. 36.
    Weinbaum S, Tarbell JM, Damiano ER. The structure and function of the endothelial glycocalyx layer. Annu Rev Biomed Eng. 2007;9(1):121–67. doi: 10.1146/annurev.bioeng.9.060906.151959.CrossRefPubMedGoogle Scholar
  37. 37.
    Goddard CM, Allard MF, Hogg JC, Herbertson MJ, Walley KR. Prolonged leukocyte transit time in coronary microcirculation of endotoxemic pigs. Am J Physiol. 1995;269(4 Pt 2):H1389–97.PubMedGoogle Scholar
  38. 38.
    Wu L, Tiwari MM, Messer KJ, et al. Peritubular capillary dysfunction and renal tubular epithelial cell stress following lipopolysaccharide administration in mice. Am J Physiol Renal Physiol. 2007;292(1):F261–8. doi: 10.1152/ajprenal.00263.2006.CrossRefPubMedGoogle Scholar
  39. 39.
    Wu X, Guo R, Wang Y, Cunningham PN. The role of ICAM-1 in endotoxin-induced acute renal failure. Am J Physiol Renal Physiol. 2007;293(4):F1262–71. doi: 10.1152/ajprenal.00445.2006.CrossRefPubMedGoogle Scholar
  40. 40.
    Payen D, Lukaszewicz AC, Legrand M, et al. A multicentre study of acute kidney injury in severe sepsis and septic shock: association with inflammatory phenotype and HLA genotype. PLoS One. 2012;7(6):e35838. doi: 10.1371/journal.pone.0035838.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013;369(9):840–51. doi: 10.1056/NEJMra1208623.CrossRefPubMedGoogle Scholar
  42. 42.
    Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. 2010;140(6):805–20. doi: 10.1016/j.cell.2010.01.022.CrossRefPubMedGoogle Scholar
  43. 43.
    Chan JK, Roth J, Oppenheim JJ, et al. Alarmins: awaiting a clinical response. J Clin Invest. 2012;122(8):2711–9. doi: 10.1172/JCI62423.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Herter JM, Rossaint J, Spieker T, Zarbock A. Adhesion molecules involved in neutrophil recruitment during sepsis-induced acute kidney injury. J Innate Immun. 2014;6(5):597–606. doi: 10.1159/000358238.CrossRefPubMedGoogle Scholar
  45. 45.
    Singbartl K, Bishop JV, Wen X, et al. Differential effects of kidney-lung cross-talk during acute kidney injury and bacterial pneumonia. Kidney Int. 2011;80(6):633–44. doi: 10.1038/ki.2011.201.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Gomez H, Ince C, De Backer D, et al. A unified theory of sepsis-induced acute kidney injury: inflammation, microcirculatory dysfunction, bioenergetics, and the tubular cell adaptation to injury. Shock. 2014;41(1):3–11. doi: 10.1097/SHK.0000000000000052.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Brown KA, Brain SD, Pearson JD, Edgeworth JD, Lewis SM, Treacher DF. Neutrophils in development of multiple organ failure in sepsis. Lancet. 2006;368(9530):157–69. doi: 10.1016/S0140-6736(06)69005-3.CrossRefPubMedGoogle Scholar
  48. 48.
    Zarbock A, Ley K. Mechanisms and consequences of neutrophil interaction with the endothelium. AJPA. 2008;172(1):1–7. doi: 10.2353/ajpath.2008.070502.Google Scholar
  49. 49.
    El-Achkar TM, Hosein M, Dagher PC. Pathways of renal injury in systemic gram-negative sepsis. Eur J Clin Invest. 2008;38:39–44. doi: 10.1111/j.1365-2362.2008.02007.x.CrossRefPubMedGoogle Scholar
  50. 50.
    Krüger B, Krick S, Dhillon N, et al. Donor Toll-like receptor 4 contributes to ischemia and reperfusion injury following human kidney transplantation. Proc Natl Acad Sci U S A. 2009;106(9):3390–5. doi: 10.1073/pnas.0810169106.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Kalakeche R, Hato T, Rhodes G, et al. Endotoxin uptake by S1 proximal tubular segment causes oxidative stress in the downstream S2 segment. J Am Soc Nephrol. 2011;22(8):1505–16. doi: 10.1681/ASN.2011020203.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Mudaliar H, Pollock C, Komala MG, Chadban S, Wu H, Panchapakesan U. The role of Toll-like receptor proteins (TLR) 2 and 4 in mediating inflammation in proximal tubules. Am J Physiol Renal Physiol. 2013;305(2):F143–54. doi: 10.1152/ajprenal.00398.2012.CrossRefPubMedGoogle Scholar
  53. 53.
    Lin M, Yiu WH, Wu HJ, et al. Toll-like receptor 4 promotes tubular inflammation in diabetic nephropathy. J Am Soc Nephrol. 2012;23(1):86–102. doi: 10.1681/ASN.2010111210.CrossRefPubMedGoogle Scholar
  54. 54.
    Ferraro E, Cecconi F. Autophagic and apoptotic response to stress signals in mammalian cells. Arch Biochem Biophys. 2007;462(2):210–9. doi: 10.1016/ Scholar
  55. 55.
    Singer M. The role of mitochondrial dysfunction in sepsis-induced multi-organ failure. Virulence. 2014;5(1):66–72. doi: 10.4161/viru.26907.CrossRefPubMedGoogle Scholar
  56. 56.
    Hochachka PW, Buck LT, Doll CJ, Land SC. Unifying theory of hypoxia tolerance: molecular/metabolic defense and rescue mechanisms for surviving oxygen lack. Proc Natl Acad Sci U S A. 1996;93(18):9493–8.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    May CN, Ishikawa K, Wan L, et al. Renal bioenergetics during early gram-negative mammalian sepsis and angiotensin II infusion. Intensive Care Med. 2012;38(5):886–93. doi: 10.1007/s00134-012-2487-2.CrossRefPubMedGoogle Scholar
  58. 58.
    Carchman EH, Rao J, Loughran PA, Rosengart MR, Zuckerbraun BS. Heme oxygenase-1-mediated autophagy protects against hepatocyte cell death and hepatic injury from infection/sepsis in mice. Hepatology. 2011;53(6):2053–62. doi: 10.1002/hep.24324.CrossRefPubMedGoogle Scholar
  59. 59.
    Brealey D, Karyampudi S, Jacques TS, et al. Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure. Am J Physiol Regul Integr Comp Physiol. 2004;286(3):R491–7. doi: 10.1152/ajpregu.00432.2003.CrossRefPubMedGoogle Scholar
  60. 60.
    Schmidt C, Höcherl K, Schweda F, Bucher M. Proinflammatory cytokines cause down-regulation of renal chloride entry pathways during sepsis. Crit Care Med. 2007;35(9):2110–9.CrossRefPubMedGoogle Scholar
  61. 61.
    Mandel LJ, Balaban RS. Stoichiometry and coupling of active transport to oxidative metabolism in epithelial tissues. Am J Physiol. 1981;240(5):F357–71.PubMedGoogle Scholar
  62. 62.
    Gupta A, Rhodes GJ, Berg DT, Gerlitz B, Molitoris BA, Grinnell BW. Activated protein C ameliorates LPS-induced acute kidney injury and downregulates renal INOS and angiotensin 2. Am J Physiol Renal Physiol. 2007;293(1):F245–54. doi: 10.1152/ajprenal.00477.2006.CrossRefPubMedGoogle Scholar
  63. 63.
    Good DW, George T, Watts BA. Lipopolysaccharide directly alters renal tubule transport through distinct TLR4-dependent pathways in basolateral and apical membranes. Am J Physiol Renal Physiol. 2009;297(4):F866–74. doi: 10.1152/ajprenal.00335.2009.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Hsiao H-W, Tsai K-L, Wang L-F, et al. The decline of autophagy contributes to proximal tubular dysfunction during sepsis. Shock. 2012;37(3):289–96. doi: 10.1097/SHK.0b013e318240b52a.CrossRefPubMedGoogle Scholar
  65. 65.
    Carré JE, Singer M. Cellular energetic metabolism in sepsis: the need for a systems approach. Biochim Biophys Acta. 2008;1777(7–8):763–71. doi: 10.1016/j.bbabio.2008.04.024.CrossRefPubMedGoogle Scholar
  66. 66.
    Vanhorebeek I, Gunst J, Derde S, et al. Mitochondrial fusion, fission, and biogenesis in prolonged critically ill patients. J Clin Endocrinol Metab. 2012;97(1):E59–64. doi: 10.1210/jc.2011-1760.CrossRefPubMedGoogle Scholar
  67. 67.
    Green DR, Galluzzi L, Kroemer G. Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science. 2011;333(6046):1109–12. doi: 10.1126/science.1201940.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Waltz P, Carchman EH, Young AC, et al. Lipopolysaccaride induces autophagic signaling in macrophages via a TLR4, heme oxygenase-1 dependent pathway. Autophagy. 2011;7(3):315–20. doi: 10.4161/auto.7.3.14044.CrossRefPubMedGoogle Scholar
  69. 69.
    Frank M, Duvezin-Caubet S, Koob S, et al. Mitophagy is triggered by mild oxidative stress in a mitochondrial fission dependent manner. Biochim Biophys Acta. 2012;1823(12):2297–310. doi: 10.1016/j.bbamcr.2012.08.007.CrossRefPubMedGoogle Scholar
  70. 70.
    Wang Y, Nartiss Y, Steipe B, McQuibban GA, Kim PK. ROS-induced mitochondrial depolarization initiates PARK2/PARKIN-dependent mitochondrial degradation by autophagy. Autophagy. 2012;8(10):1462–76. doi: 10.4161/auto.21211.CrossRefPubMedGoogle Scholar
  71. 71.
    Gunst J, Derese I, Aertgeerts A, et al. Insufficient autophagy contributes to mitochondrial dysfunction, organ failure, and adverse outcome in an animal model of critical illness. Crit Care Med. 2013;41(1):182–94. doi: 10.1097/CCM.0b013e3182676657.CrossRefPubMedGoogle Scholar
  72. 72.
    Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature. 2008;451(7182):1069–75. doi: 10.1038/nature06639.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Levine B, Yuan J. Autophagy in cell death: an innocent convict? J Clin Invest. 2005;115(10):2679–88. doi: 10.1172/JCI26390.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Ciechomska IA, Goemans CG, Tolkovsky AM. Molecular links between autophagy and apoptosis. Methods Mol Biol. 2008;445(Chapter 12):175–193. doi: 10.1007/978-1-59745-157-4_12.
  75. 75.
    Finkel T, Hwang PM. The Krebs cycle meets the cell cycle: mitochondria and the G1-S transition. Proc Natl Acad Sci U S A. 2009;106(29):11825–6. doi: 10.1073/pnas.0906430106.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Mitra K, Wunder C, Roysam B, Lin G, Lippincott-Schwartz J. A hyperfused mitochondrial state achieved at G1-S regulates cyclin E buildup and entry into S phase. Proc Natl Acad Sci U S A. 2009;106(29):11960–5. doi: 10.1073/pnas.0904875106.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Schieke SM, McCoy JP, Finkel T. Coordination of mitochondrial bioenergetics with G1 phase cell cycle progression. Cell Cycle. 2008;7(12):1782–7.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Mandal S, Guptan P, Owusu-Ansah E, Banerjee U. Mitochondrial regulation of cell cycle progression during development as revealed by the tenured mutation in Drosophila. Dev Cell. 2005;9(6):843–54. doi: 10.1016/j.devcel.2005.11.006.CrossRefPubMedGoogle Scholar
  79. 79.
    Yang Q-H, Liu D-W, Long Y, Liu H-Z, Chai W-Z, Wang X-T. Acute renal failure during sepsis: potential role of cell cycle regulation. J Infect. 2009;58(6):459–64. doi: 10.1016/j.jinf.2009.04.003.CrossRefPubMedGoogle Scholar
  80. 80.
    Meersch M, Schmidt C, Van Aken H, et al. Urinary TIMP-2 and IGFBP7 as early biomarkers of acute kidney injury and renal recovery following cardiac surgery. PLoS One. 2014;9(3):e93460. doi: 10.1371/journal.pone.0093460.t005.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Bihorac A, Chawla LS, Shaw AD, et al. Validation of cell-cycle arrest biomarkers for acute kidney injury using clinical adjudication. Am J Respir Crit Care Med. 2014;189(8):932–9. doi: 10.1164/rccm.201401-0077OC.CrossRefPubMedGoogle Scholar
  82. 82.
    Kashani K, Al-Khafaji A, Ardiles T, et al. Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. Crit Care. 2013;17(1):R25. doi: 10.1186/cc12503.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Kellum JA, Venkataraman R, Powner D, Elder M, Hergenroeder G, Carter M. Feasibility study of cytokine removal by hemoadsorption in brain-dead humans. Crit Care Med. 2008;36(1):268–72. doi: 10.1097/01.CCM.0000291646.34815.BB.CrossRefPubMedGoogle Scholar
  84. 84.
    Peng Z-Y, Wang H-Z, Carter MJ, et al. Acute removal of common sepsis mediators does not explain the effects of extracorporeal blood purification in experimental sepsis. Kidney Int. 2012;81(4):363–9. doi: 10.1038/ki.2011.320.CrossRefPubMedGoogle Scholar
  85. 85.
    Heemskerk S, Masereeuw R, Moesker O, et al. Alkaline phosphatase treatment improves renal function in severe sepsis or septic shock patients. Crit Care Med. 2009;37(2):417–23–e1. doi: 10.1097/CCM.0b013e31819598af.CrossRefGoogle Scholar
  86. 86.
    Pickkers P, Heemskerk S, Schouten J, et al. Alkaline phosphatase for treatment of sepsis-induced acute kidney injury: a prospective randomized double-blind placebo-controlled trial. Crit Care. 2012;16(1):R14. doi: 10.1186/cc11159.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Susantitaphong P, Perianayagam MC, Tighiouart H, Liangos O, Bonventre JV, Jaber BL. Tumor necrosis factor alpha promoter polymorphism and severity of acute kidney injury. Nephron Clin Pract. 2013;123(1–2):67–73. doi: 10.1159/000351684.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Boerma EC, Koopmans M, Konijn A, et al. Effects of nitroglycerin on sublingual microcirculatory blood flow in patients with severe sepsis/septic shock after a strict resuscitation protocol: a double-blind randomized placebo controlled trial. Crit Care Med. 2010;38(1):93–100. doi: 10.1097/CCM.0b013e3181b02fc1.CrossRefPubMedGoogle Scholar
  89. 89.
    Liakopoulos OJ, Choi Y-H, Haldenwang PL, et al. Impact of preoperative statin therapy on adverse postoperative outcomes in patients undergoing cardiac surgery: a meta-analysis of over 30,000 patients. Eur Heart J. 2008;29(12):1548–59. doi: 10.1093/eurheartj/ehn198.CrossRefPubMedGoogle Scholar
  90. 90.
    Song YR, Lee T, You SJ, et al. Prevention of acute kidney injury by erythropoietin in patients undergoing coronary artery bypass grafting: a pilot study. Am J Nephrol. 2009;30(3):253–60. doi: 10.1159/000223229.CrossRefPubMedGoogle Scholar
  91. 91.
    Asfar P, Meziani F, Hamel J-F, et al. High versus low blood-pressure target in patients with septic shock. N Engl J Med. 2014;370(17):1583–93. doi: 10.1056/NEJMoa1312173.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Hernando Gomez
    • 1
    • 2
  • Alex Zarbock
    • 3
  • Raghavan Murugan
    • 1
    • 2
  • John A. Kellum
    • 1
    • 2
    Email author
  1. 1.The Center for Critical Care NephrologyUniversity of PittsburghPittsburghUSA
  2. 2.The CRISMA Center, Department of Critical Care MedicineUniversity of PittsburghPittsburghUSA
  3. 3.Department of Anesthesiology, Intensive Care and Pain MedicineUniversity of MünsterMünsterGermany

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