Sepsis-Associated Acute Kidney Injury: Making Progress Against a Lethal Syndrome

  • Rajit K. BasuEmail author


Sepsis and acute kidney injury (AKI) are disease processes that increase morbidity and mortality in hospitalized patients. Though separate entities, sepsis and AKI carry considerable pathophysiologic overlap and significantly worsen patient outcomes when concurrent. Sepsis is the most commonly associated condition with AKI in critically ill patients (S-AKI). Despite a multitude of epidemiologic data describing prevalence and associated outcomes, understanding of the complicated pathophysiology driving S-AKI is only superficial, appreciation of the disease phenotype is lacking, and current diagnostics are outdated. Ultimately, these shortcomings contribute to a large knowledge gap, resulting in a paucity of focused and effective therapeutic options. This chapter will detail available data, delineate the current paradigm and describe limitations, and then create a narrative describing a path necessary to follow in order to better manage S-AKI. Clinicians and researchers must move past the status quo, challenge assumptions, and simultaneously innovate, collaborate, and advocate for their patients suffering from this lethal condition.


Sepsis AKI Risk stratification Phenotype Targeted therapeutics 


  1. 1.
    Jawad I, Luksic I, Rafnsson SB. Assessing available information on the burden of sepsis: global estimates of incidence, prevalence and mortality. J Glob Health. 2012;2(1):010404.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Martin GS, et al. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003;348(16):1546–54.CrossRefPubMedGoogle Scholar
  3. 3.
    Gaieski DF, et al. Benchmarking the incidence and mortality of severe sepsis in the United States. Crit Care Med. 2013;41(5):1167–74.CrossRefPubMedGoogle Scholar
  4. 4.
    Annane D, et al. Current epidemiology of septic shock: the CUB-Rea network. Am J Respir Crit Care Med. 2003;168(2):165–72.CrossRefPubMedGoogle Scholar
  5. 5.
    Angus DC, et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29(7):1303–10.CrossRefPubMedGoogle Scholar
  6. 6.
    Martin CM, et al. A prospective, observational registry of patients with severe sepsis: the Canadian Sepsis treatment and response registry. Crit Care Med. 2009;37(1):81–8.CrossRefPubMedGoogle Scholar
  7. 7.
    Karlsson S, et al. Incidence, treatment, and outcome of severe sepsis in ICU-treated adults in Finland: the Finnsepsis study. Intensive Care Med. 2007;33(3):435–43.CrossRefPubMedGoogle Scholar
  8. 8.
    de Mendonca A, et al. Acute renal failure in the ICU: risk factors and outcome evaluated by the SOFA score. Intensive Care Med. 2000;26(7):915–21.CrossRefPubMedGoogle Scholar
  9. 9.
    Uchino S, et al. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA. 2005;294(7):813–8.CrossRefPubMedGoogle Scholar
  10. 10.
    Bagshaw SM, et al. Changes in the incidence and outcome for early acute kidney injury in a cohort of Australian intensive care units. Crit Care. 2007;11(3):R68.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Ostermann M, Chang RW. Acute kidney injury in the intensive care unit according to RIFLE. Crit Care Med. 2007;35(8):1837–43. quiz 1852CrossRefPubMedGoogle Scholar
  12. 12.
    Bagshaw SM, et al. A multi-Centre evaluation of the RIFLE criteria for early acute kidney injury in critically ill patients. Nephrol Dial Transplant. 2008;23(4):1203–10.CrossRefPubMedGoogle Scholar
  13. 13.
    Andrikos E, et al. Epidemiology of acute renal failure in ICUs: a multi-center prospective study. Blood Purif. 2009;28(3):239–44.CrossRefPubMedGoogle Scholar
  14. 14.
    Thakar CV, et al. Incidence and outcomes of acute kidney injury in intensive care units: a veterans administration study. Crit Care Med. 2009;37(9):2552–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Medve L, et al. Epidemiology of acute kidney injury in Hungarian intensive care units: a multicenter, prospective, observational study. BMC Nephrol. 2011;12:43.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Piccinni P, et al. Prospective multicenter study on epidemiology of acute kidney injury in the ICU: a critical care nephrology Italian collaborative effort (NEFROINT). Minerva Anestesiol. 2011;77(11):1072–83.PubMedGoogle Scholar
  17. 17.
    Nisula S, et al. Incidence, risk factors and 90-day mortality of patients with acute kidney injury in Finnish intensive care units: the FINNAKI study. Intensive Care Med. 2013;39(3):420–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Poukkanen M, et al. Acute kidney injury in patients with severe sepsis in Finnish intensive care units. Acta Anaesthesiol Scand. 2013;57(7):863–72.CrossRefPubMedGoogle Scholar
  19. 19.
    Bailey D, et al. Risk factors of acute renal failure in critically ill children: a prospective descriptive epidemiological study. Pediatr Crit Care Med. 2007;8(1):29–35.CrossRefGoogle Scholar
  20. 20.
    Schneider J, et al. Serum creatinine as stratified in the RIFLE score for acute kidney injury is associated with mortality and length of stay for children in the pediatric intensive care unit. Crit Care Med. 2010;38(3):933–9.CrossRefPubMedGoogle Scholar
  21. 21.
    Vachvanichsanong P, et al. Childhood acute renal failure: 22-year experience in a university hospital in southern Thailand. Pediatrics. 2006;118(3):e786–91.CrossRefPubMedGoogle Scholar
  22. 22.
    Kellum JA, Angus DC. Patients are dying of acute renal failure. Crit Care Med. 2002;30(9):2156–7.CrossRefPubMedGoogle Scholar
  23. 23.
    Bagshaw SM, et al. Early acute kidney injury and sepsis: a multicentre evaluation. Crit Care. 2008;12(2):R47.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Bagshaw SM, et al. Septic acute kidney injury in critically ill patients: clinical characteristics and outcomes. Clin J Am Soc Nephrol. 2007;2(3):431–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Kolhe NV, et al. Case mix, outcome and activity for patients with severe acute kidney injury during the first 24 hours after admission to an adult, general critical care unit: application of predictive models from a secondary analysis of the ICNARC case mix Programme database. Crit Care. 2008;12(Suppl 1):S2.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Daher EF, et al. Acute kidney injury in an infectious disease intensive care unit – an assessment of prognostic factors. Swiss Med Wkly. 2008;138(9–10):128–33.PubMedGoogle Scholar
  27. 27.
    Alkandari O, et al. Acute kidney injury is an independent risk factor for pediatric intensive care unit mortality, longer length of stay and prolonged mechanical ventilation in critically ill children: a two-center retrospective cohort study. Crit Care. 2011;15(3):R146.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Pundziene B, Dobiliene D, Rudaitis S. Acute kidney injury in pediatric patients: experience of a single center during an 11-year period. Medicina (Kaunas). 2010;46(8):511–5.CrossRefGoogle Scholar
  29. 29.
    Duzova A, et al. Etiology and outcome of acute kidney injury in children. Pediatr Nephrol. 2010;25(8):1453–61.CrossRefPubMedGoogle Scholar
  30. 30.
    Mehta P, et al. Incidence of acute kidney injury in hospitalized children. Indian Pediatr. 2012;49(7):537–42.CrossRefPubMedGoogle Scholar
  31. 31.
    Lopes JA, et al. Acute kidney injury in patients with sepsis: a contemporary analysis. Int J Infect Dis. 2009;13(2):176–81.CrossRefPubMedGoogle Scholar
  32. 32.
    Plotz FB, et al. Effect of acute renal failure on outcome in children with severe septic shock. Pediatr Nephrol. 2005;20(8):1177–81.CrossRefPubMedGoogle Scholar
  33. 33.
    Parrillo JE. Pathogenetic mechanisms of septic shock. N Engl J Med. 1993;328(20):1471–7.CrossRefPubMedGoogle Scholar
  34. 34.
    Schrier RW, Wang W. Acute renal failure and sepsis. N Engl J Med. 2004;351(2):159–69.CrossRefPubMedGoogle Scholar
  35. 35.
    Ceneviva G, et al. Hemodynamic support in fluid-refractory pediatric septic shock. Pediatrics. 1998;102(2):e19.CrossRefPubMedGoogle Scholar
  36. 36.
    Riley C, et al. Pediatric sepsis: preparing for the future against a global scourge. Curr Infect Dis Rep. 2012;14(5):503–11.CrossRefPubMedGoogle Scholar
  37. 37.
    Gotts JE, Matthay MA. Sepsis: pathophysiology and clinical management. BMJ. 2016;353:i1585.CrossRefPubMedGoogle Scholar
  38. 38.
    Gomez H, 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.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Chawla LS. Disentanglement of the acute kidney injury syndrome. Curr Opin Crit Care. 2012;18(6):579–84.CrossRefPubMedGoogle Scholar
  40. 40.
    Liu VX, et al. The timing of early antibiotics and hospital mortality in Sepsis. Am J Respir Crit Care Med. 2017;196(7):856–63.CrossRefPubMedGoogle Scholar
  41. 41.
    Prowle JR. Sepsis-associated AKI. Clin J Am Soc Nephrol. 2018;13(2):339–42.CrossRefPubMedGoogle Scholar
  42. 42.
    Schneider AG, et al. Choice of renal replacement therapy modality and dialysis dependence after acute kidney injury: a systematic review and meta-analysis. Intensive Care Med. 2013;39(6):987–97.CrossRefPubMedGoogle Scholar
  43. 43.
    Wald R, et al. The association between renal replacement therapy modality and long-term outcomes among critically ill adults with acute kidney injury: a retrospective cohort study*. Crit Care Med. 2014;42(4):868–77.CrossRefPubMedGoogle Scholar
  44. 44.
    Ronco C, et al. Effects of different doses in continuous veno-venous haemofiltration on outcomes of acute renal failure: a prospective randomised trial. Lancet. 2000;356(9223):26–30.CrossRefPubMedGoogle Scholar
  45. 45.
    Network, V.N.A.R.F.T, et al. Intensity of renal support in critically ill patients with acute kidney injury. N Engl J Med. 2008;359(1):7–20.CrossRefGoogle Scholar
  46. 46.
    Investigators, R.R.T.S, et al. Intensity of continuous renal-replacement therapy in critically ill patients. N Engl J Med. 2009;361(17):1627–38.CrossRefGoogle Scholar
  47. 47.
    Joannes-Boyau O, et al. High-volume versus standard-volume haemofiltration for septic shock patients with acute kidney injury (IVOIRE study): a multicentre randomized controlled trial. Intensive Care Med. 2013;39(9):1535–46.CrossRefPubMedGoogle Scholar
  48. 48.
    Feltes CM, Van Eyk J, Rabb H. Distant-organ changes after acute kidney injury. Nephron Physiol. 2008;109(4):p80–4.CrossRefPubMedGoogle Scholar
  49. 49.
    Shiao CC, et al. Long-term remote organ consequences following acute kidney injury. Crit Care. 2015;19:438.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Yap SC, Lee HT. Acute kidney injury and extrarenal organ dysfunction: new concepts and experimental evidence. Anesthesiology. 2012;116(5):1139–48.CrossRefPubMedGoogle Scholar
  51. 51.
    Shin YJ, et al. Age-related differences in kidney injury biomarkers induced by cisplatin. Environ Toxicol Pharmacol. 2014;37(3):1028–39.CrossRefPubMedGoogle Scholar
  52. 52.
    Vandijck DM, et al. Severe infection, sepsis and acute kidney injury. Acta Clin Belg. 2007;62(Suppl 2):332–6.CrossRefPubMedGoogle Scholar
  53. 53.
    Langenberg C, et al. Renal blood flow in sepsis. Crit Care. 2005;9(4):R363–74.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Langenberg C, et al. Renal blood flow in experimental septic acute renal failure. Kidney Int. 2006;69(11):1996–2002.CrossRefPubMedGoogle Scholar
  55. 55.
    Scicluna BP, et al. Classification of patients with sepsis according to blood genomic endotype: a prospective cohort study. Lancet Respir Med. 2017;5(10):816–26.CrossRefPubMedGoogle Scholar
  56. 56.
    Wong HR, et al. Improved risk stratification in pediatric septic shock using both protein and mRNA biomarkers. PERSEVERE-XP. Am J Respir Crit Care Med. 2017;196(4):494–501.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Langenberg C, et al. The histopathology of septic acute kidney injury: a systematic review. Crit Care. 2008;12(2):R38.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Zarbock A, Gomez H, Kellum JA. Sepsis-induced acute kidney injury revisited: pathophysiology, prevention and future therapies. Curr Opin Crit Care. 2014;20(6):588–95.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Chvojka J, et al. Renal haemodynamic, microcirculatory, metabolic and histopathological responses to peritonitis-induced septic shock in pigs. Crit Care. 2008;12(6):R164.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Doi K, et al. Animal models of sepsis and sepsis-induced kidney injury. J Clin Invest. 2009;119(10):2868–78.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Goldstein SL, Chawla LS. Renal angina. Clin J Am Soc Nephrol. 2010;5(5):943–9.CrossRefPubMedGoogle Scholar
  62. 62.
    Basu RK, et al. Derivation and validation of the renal angina index to improve the prediction of acute kidney injury in critically ill children. Kidney Int. 2014;85(3):659–67.CrossRefPubMedGoogle Scholar
  63. 63.
    Hoste EA, et al. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med. 2015;41(8):1411–23.CrossRefPubMedGoogle Scholar
  64. 64.
    Kaddourah A, et al. Epidemiology of acute kidney injury in critically ill children and young adults. N Engl J Med. 2017;376(1):11–20.CrossRefPubMedGoogle Scholar
  65. 65.
    Fitzgerald JC, et al. Acute kidney injury in pediatric severe Sepsis: an independent risk factor for death and new disability. Crit Care Med. 2016;44(12):2241–50.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Kellum JA, et al. Classifying AKI by urine output versus serum creatinine level. J Am Soc Nephrol. 2015;26(9):2231–8.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Chen S. Retooling the creatinine clearance equation to estimate kinetic GFR when the plasma creatinine is changing acutely. J Am Soc Nephrol. 2013;24(6):877–88.CrossRefPubMedGoogle Scholar
  68. 68.
    Bagshaw SM, et al. Plasma and urine neutrophil gelatinase-associated lipocalin in septic versus non-septic acute kidney injury in critical illness. Intensive Care Med. 2010;36(3):452–61.CrossRefPubMedGoogle Scholar
  69. 69.
    Kim H, et al. Plasma neutrophil gelatinase-associated lipocalin as a biomarker for acute kidney injury in critically ill patients with suspected sepsis. Clin Biochem. 2013;46(15):1414–8.CrossRefPubMedGoogle Scholar
  70. 70.
    Tu Y, et al. Urinary netrin-1 and KIM-1 as early biomarkers for septic acute kidney injury. Ren Fail. 2014;36(10):1559–63.CrossRefPubMedGoogle Scholar
  71. 71.
    Basu RK, et al. Incorporation of biomarkers with the renal angina index for prediction of severe AKI in critically ill children. Clin J Am Soc Nephrol. 2014;9(4):654–62.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Powell TC, et al. Association of inflammatory and endothelial cell activation biomarkers with acute kidney injury after sepsis. Spring. 2014;3:207.CrossRefGoogle Scholar
  73. 73.
    Kashani K, et al. Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. Crit Care. 2013;17(1):R25.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Devarajan P. Genomic and proteomic characterization of acute kidney injury. Nephron. 2015;131(2):85–91.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Chawla LS, et al. Development and standardization of a furosemide stress test to predict the severity of acute kidney injury. Crit Care. 2013;17(5):R207.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Solomon R, Goldstein S. Real-time measurement of glomerular filtration rate. Curr Opin Crit Care. 2017;23(6):470–4.CrossRefPubMedGoogle Scholar
  77. 77.
    Gaudry S, et al. Initiation strategies for renal-replacement therapy in the intensive care unit. N Engl J Med. 2016;375(2):122–33.CrossRefPubMedGoogle Scholar
  78. 78.
    Zarbock A, et al. Effect of early vs delayed initiation of renal replacement therapy on mortality in critically ill patients with acute kidney injury: the ELAIN randomized clinical trial. JAMA. 2016;315(20):2190–9.CrossRefPubMedGoogle Scholar
  79. 79.
    Smith OM, et al. Standard versus accelerated initiation of renal replacement therapy in acute kidney injury (STARRT-AKI): study protocol for a randomized controlled trial. Trials. 2013;14:320.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Lee SY, et al. Distinct pathophysiologic mechanisms of septic acute kidney injury: role of immune suppression and renal tubular cell apoptosis in murine model of septic acute kidney injury. Crit Care Med. 2012;40(11):2997–3006.CrossRefPubMedGoogle Scholar
  81. 81.
    Homsi E, Janino P, de Faria JB. Role of caspases on cell death, inflammation, and cell cycle in glycerol-induced acute renal failure. Kidney Int. 2006;69(8):1385–92.CrossRefPubMedGoogle Scholar
  82. 82.
    Wang W, et al. Ghrelin protects mice against endotoxemia-induced acute kidney injury. Am J Physiol Renal Physiol. 2009;297(4):F1032–7.CrossRefPubMedGoogle Scholar
  83. 83.
    Simon F, et al. Comparison of cardiac, hepatic, and renal effects of arginine vasopressin and noradrenaline during porcine fecal peritonitis: a randomized controlled trial. Crit Care. 2009;13(4):R113.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Lee HT, et al. A3 adenosine receptor activation decreases mortality and renal and hepatic injury in murine septic peritonitis. Am J Physiol Regul Integr Comp Physiol. 2006;291(4):R959–69.CrossRefPubMedGoogle Scholar
  85. 85.
    Bahlmann FH, Fliser D. Erythropoietin and renoprotection. Curr Opin Nephrol Hypertens. 2009;18(1):15–20.CrossRefPubMedGoogle Scholar
  86. 86.
    Pathak E, MacMillan-Crow LA, Mayeux PR. Role of mitochondrial oxidants in an in vitro model of sepsis-induced renal injury. J Pharmacol Exp Ther. 2012;340(1):192–201.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Pickkers P, 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.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Pediatric Critical Care, Children’s Healthcare of Atlanta, Department of PediatricsEmory UniversityAtlantaUSA

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