Intensive Care Medicine

, Volume 33, Issue 7, pp 1285–1296

Urinary biomarkers in septic acute kidney injury

  • Sean M. Bagshaw
  • Christoph Langenberg
  • Michael Haase
  • Li Wan
  • Clive N. May
  • Rinaldo Bellomo
Systematic Review



To appraise the literature on the value of urinary biomarkers in septic acute kidney injury (AKI).


Systematic review.


Academic medical centre.

Patients and participants

Human studies of urinary biomarkers.



Measurements and results

Fourteen articles fulfilled inclusion criteria. Most studies were small, single-centre, and included mixed medical/surgical adult populations. Few focused solely on septic AKI and all had notable limitations. Retrieved articles included data on low-molecular-weight proteins (β2-microglobulin, α1-microglobulin, adenosine deaminase binding protein, retinol binding protein, cystatin C, renal tubular epithelial antigen-1), enzymes (N-acetyl-β-glucosaminidase, alanine-aminopeptidase, alkaline phosphatase; lactate dehydrogenase, α/π-glutathione-S-transferase, γ-glutamyl transpeptidase), cytokines [platelet activating factor (PAF), interleukin-18 (IL-18)] and other biomarkers [kidney injury molecule-1, Na/H exchanger isoform-3 (NHE3)]. Increased PAF, IL-18, and NHE3 were detected early in septic AKI and preceded overt kidney failure. Several additional biomarkers were evident early in AKI; however, their diagnostic value in sepsis remains unknown. In one study, IL-18 excretion was higher in septic than in non-septic AKI. IL-18 also predicted deterioration in kidney function, with increased values preceding clinically significant kidney failure by 24–48 h. Detection of cystatin C, α1-microglobulin, and IL-18 predicted need for renal replacement therapy (RRT).


Few clinical studies of urinary biomarkers in AKI have included septic patients. However, there is promising evidence that selected biomarkers may aid in the early detection of AKI in sepsis and may have value for predicting subsequent deterioration in kidney function. Additional prospective studies are needed to accurately describe their diagnostic and prognostic value in septic AKI.


Acute kidney injury Acute renal failure Sepsis Urinary biomarkers Renal replacement therapy Interleukin-18 


  1. 1.
    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 (2005) Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA 294:813–818PubMedCrossRefGoogle Scholar
  2. 2.
    Hoste EA, Clermont G, Kersten A, Venkataraman R, Angus DC, De Bacquer D, Kellum JA (2006) RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: a cohort analysis. Crit Care 10:R73PubMedCrossRefGoogle Scholar
  3. 3.
    Bagshaw SM, Laupland KB, Doig CJ, Mortis G, Fick GH, Mucenski M, Godinez-Luna T, Svenson LW, Rosenal T (2005) Prognosis for long-term survival and renal recovery in critically ill patients with severe acute renal failure: a population-based study. Crit Care 9:R700–R709PubMedCrossRefGoogle Scholar
  4. 4.
    Cole L, Bellomo R, Silvester W, Reeves JH (2000) A prospective, multicenter study of the epidemiology, management, and outcome of severe acute renal failure in a “closed” ICU system. Am J Respir Crit Care Med 162:191–196PubMedGoogle Scholar
  5. 5.
    Silvester W, Bellomo R, Cole L (2001) Epidemiology, management, and outcome of severe acute renal failure of critical illness in Australia. Crit Care Med 29:1910–1915PubMedCrossRefGoogle Scholar
  6. 6.
    Yegenaga I, Hoste E, Van Biesen W, Vanholder R, Benoit D, Kantarci G, Dhondt A, Colardyn F, Lameire N (2004) Clinical characteristics of patients developing ARF due to sepsis/systemic inflammatory response syndrome: results of a prospective study. Am J Kidney Dis 43:817–824PubMedCrossRefGoogle Scholar
  7. 7.
    Neveu H, Kleinknecht D, Brivet F, Loirat P, Landais P (1996) Prognostic factors in acute renal failure due to sepsis. Results of a prospective multicentre study. The French Study Group on Acute Renal Failure. Nephrol Dial Transplant 11:293–299PubMedGoogle Scholar
  8. 8.
    Hoste EA, Lameire NH, Vanholder RC, Benoit DD, Decruyenaere JM, Colardyn FA (2003) Acute renal failure in patients with sepsis in a surgical ICU: predictive factors, incidence, comorbidity, and outcome. J Am Soc Nephrol 14:1022–1030PubMedCrossRefGoogle Scholar
  9. 9.
    Bellomo R, Kellum JA, Ronco C (2004) Defining acute renal failure: physiological principles. Intensive Care Med 30:33–37PubMedCrossRefGoogle Scholar
  10. 10.
    Rabb H (1998) Evaluation of urinary markers in acute renal failure. Curr Opin Nephrol Hypertens 7:681–685PubMedGoogle Scholar
  11. 11.
    Han WK, Bonventre JV (2004) Biologic markers for the early detection of acute kidney injury. Curr Opin Crit Care 10:476–482PubMedCrossRefGoogle Scholar
  12. 12.
    Trof RJ, Di Maggio F, Leemreis J, Groeneveld AB (2006) Biomarkers of acute renal injury and renal failure. Shock 26:245–253PubMedCrossRefGoogle Scholar
  13. 13.
    Chew SL, Lins RL, Daelemans R, Nuyts GD, De Broe ME (1993) Urinary enzymes in acute renal failure. Nephrol Dial Transplant 8:507–511PubMedGoogle Scholar
  14. 14.
    Herget-Rosenthal S, Poppen D, Husing J, Marggraf G, Pietruck F, Jakob HG, Philipp T, Kribben A (2004) Prognostic value of tubular proteinuria and enzymuria in nonoliguric acute tubular necrosis. Clin Chem 50:552–558PubMedCrossRefGoogle Scholar
  15. 15.
    Han WK, Bailly V, Abichandani R, Thadhani R, Bonventre JV (2002) Kidney Injury Molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury. Kidney Int 62:237–244PubMedCrossRefGoogle Scholar
  16. 16.
    Westhuyzen J, Endre ZH, Reece G, Reith DM, Saltissi D, Morgan TJ (2003) Measurement of tubular enzymuria facilitates early detection of acute renal impairment in the intensive care unit. Nephrol Dial Transplant 18:543–551PubMedCrossRefGoogle Scholar
  17. 17.
    Mehta KP, Ali US, Shankar L, Tirthani D, Ambadekar M (1997) Renal dysfunction detected by beta-2 microglobulinuria in sick neonates. Indian Pediatr 34:107–111PubMedGoogle Scholar
  18. 18.
    Cabrera J, Arroyo V, Ballesta AM, Rimola A, Gual J, Elena M, Rodes J (1982) Aminoglycoside nephrotoxicity in cirrhosis. Value of urinary beta 2-microglobulin to discriminate functional renal failure from acute tubular damage. Gastroenterology 82:97–105PubMedGoogle Scholar
  19. 19.
    Gordjani N, Burghard R, Muller D, Mathai H, Mergehenn G, Leititis JU, Brandis M (1995) Urinary excretion of adenosine deaminase binding protein in neonates treated with tobramycin. Pediatr Nephrol 9:419–422PubMedCrossRefGoogle Scholar
  20. 20.
    Tolkoff-Rubin NE, Thompson RE, Piper DJ, Hansen WP, Bander NH, Cordon-Cardo C, Finstad CJ, Klotz LH, Old LJ, Rubin RH (1987) Diagnosis of renal proximal tubular injury by urinary immunoassay for a proximal tubular antigen, the adenosine deaminase binding protein. Nephrol Dial Transplant 2:143–148PubMedGoogle Scholar
  21. 21.
    Tolkoff-Rubin NE, Cosimi AB, Delmonico FL, Russell PS, Thompson RE, Piper DJ (1988) Diagnosis of tubular injury in renal transplant patients by a urinary assay for a proximal tubular antigen, the adenosine-deaminase binding protein. Transplantation 41:593–597CrossRefGoogle Scholar
  22. 22.
    Du Cheyron D, Daubin C, Poggioli J, Ramakers M, Houillier P, Charbonneau P, Paillard M (2003) Urinary measurement of Na+/H+ exchanger isoform 3 (NHE3) protein as new marker of tubule injury in critically ill patients with ARF. Am J Kidney Dis 42:497–506PubMedCrossRefGoogle Scholar
  23. 23.
    Herget-Rosenthal S, Feldkamp T, Volbracht L, Kribben A (2004) Measurement of urinary cystatin C by particle-enhanced nephelometric immunoassay: precision, interferences, stability and reference range. Ann Clin Biochem 41:111–118PubMedCrossRefGoogle Scholar
  24. 24.
    Zager RA, Rubin NT, Ebert T, Maslov N (1980) Rapid radioimmunoassay for diagnosing acute tubular necrosis. Nephron 26:7–12PubMedCrossRefGoogle Scholar
  25. 25.
    Ehrich JH, Kirschstein M, Kehring N, Wurster U, Volkmann A, Kulpmann WR (1993) [Proteinuria and enzymuria as leading symptoms of renal and extrarenal diseases in childhood]. Monatsschr Kinderheilkd 141:59–69PubMedGoogle Scholar
  26. 26.
    Tessin I, Trollfors B, Thiringer K, Bergmark J, Hultberg B (1988) Enzymuria in neonates during treatment with tobramycin or ceftazidime. Pediatr Infect Dis J 7:142–143PubMedCrossRefGoogle Scholar
  27. 27.
    Tolins JP, Vercellotti GM, Wilkowske M, Ha B, Jacob HS, Raij L (1989) Role of platelet activating factor in endotoxemic acute renal failure in the male rat. J Lab Clin Med 113:316–324PubMedGoogle Scholar
  28. 28.
    Mariano F, Guida G, Donati D, Tetta C, Cavalli PL, Verzetti G, Piccoli G, Camussi G (1999) Production of platelet-activating factor in patients with sepsis-associated acute renal failure. Nephrol Dial Transplant 14:1150–1157PubMedCrossRefGoogle Scholar
  29. 29.
    Melnikov VY, Ecder T, Fantuzzi G, Siegmund B, Lucia MS, Dinarello CA, Schrier RW, Edelstein CL (2001) Impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute renal failure. J Clin Invest 107:1145–1152PubMedGoogle Scholar
  30. 30.
    Melnikov VY, Faubel S, Siegmund B, Lucia MS, Ljubanovic D, Edelstein CL (2002) Neutrophil-independent mechanisms of caspase-1- and IL-18-mediated ischemic acute tubular necrosis in mice. J Clin Invest 110:1083–1091PubMedCrossRefGoogle Scholar
  31. 31.
    Parikh CR, Jani A, Melnikov VY, Faubel S, Edelstein CL (2004) Urinary interleukin-18 is a marker of human acute tubular necrosis. Am J Kidney Dis 43:405–414PubMedCrossRefGoogle Scholar
  32. 32.
    Parikh CR, Mishra J, Thiessen-Philbrook H, Dursun B, Ma Q, Kelly C, Dent C, Devarajan P, Edelstein CL (2006) Urinary IL-18 is an early predictive biomarker of acute kidney injury after cardiac surgery. Kidney Int 70:199–203PubMedCrossRefGoogle Scholar
  33. 33.
    Parikh CR, Abraham E, Ancukiewicz M, Edelstein CL (2005) Urine IL-18 is an early diagnostic marker for acute kidney injury and predicts mortality in the intensive care unit. J Am Soc Nephrol 16:3046–3052PubMedCrossRefGoogle Scholar
  34. 34.
    Ichimura T, Bonventre JV, Bailly V, Wei H, Hession CA, Cate RL, Sanicola M (1998) Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury. J Biol Chem 273:4135–4142PubMedCrossRefGoogle Scholar
  35. 35.
    Ichimura T, Hung CC, Yang SA, Stevens JL, Bonventre JV (2004) Kidney injury molecule-1: a tissue and urinary biomarker for nephrotoxicant-induced renal injury. Am J Physiol Renal Physiol 286:F552–563PubMedCrossRefGoogle Scholar
  36. 36.
    Vaidya VS, Ramirez V, Ichimura T, Bobadilla NA, Bonventre JV (2006) Urinary kidney injury molecule-1: a sensitive quantitative biomarker for early detection of kidney tubular injury. Am J Physiol Renal Physiol 290:F517–529PubMedCrossRefGoogle Scholar
  37. 37.
    Mishra J, Dent C, Tarabishi R, Mitsnefes MM, Ma Q, Kelly C, Ruff SM, Zahedi K, Shao M, Bean J, Mori K, Barasch J, Devarajan P (2005) Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet 365:1231–1238PubMedCrossRefGoogle Scholar
  38. 38.
    Mishra J, Ma Q, Prada A, Mitsnefes M, Zahedi K, Yang J, Barasch J, Devarajan P (2003) Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury. J Am Soc Nephrol 14:2534–2543PubMedCrossRefGoogle Scholar
  39. 39.
    Mishra J, Mori K, Ma Q, Kelly C, Barasch J, Devarajan P (2004) Neutrophil gelatinase-associated lipocalin: a novel early urinary biomarker for cisplatin nephrotoxicity. Am J Nephrol 24:307–315PubMedCrossRefGoogle Scholar
  40. 40.
    Muramatsu Y, Tsujie M, Kohda Y, Pham B, Perantoni AO, Zhao H, Jo SK, Yuen PS, Craig L, Hu X, Star RA (2002) Early detection of cysteine rich protein 61 (CYR61, CCN1) in urine following renal ischemic reperfusion injury. Kidney Int 62:1601–1610PubMedCrossRefGoogle Scholar
  41. 41.
    Li B, Hartono C, Ding R, Sharma VK, Ramaswamy R, Qian B, Serur D, Mouradian J, Schwartz JE, Suthanthiran M (2001) Noninvasive diagnosis of renal-allograft rejection by measurement of messenger RNA for perforin and granzyme B in urine. N Engl J Med 344:947–954PubMedCrossRefGoogle Scholar
  42. 42.
    Hu H, Aizenstein BD, Puchalski A, Burmania JA, Hamawy MM, Knechtle SJ (2004) Elevation of CXCR3-binding chemokines in urine indicates acute renal-allograft dysfunction. Am J Transplant 4:432–437PubMedCrossRefGoogle Scholar
  43. 43.
    Zahedi K, Wang Z, Barone S, Prada AE, Kelly CN, Casero RA, Yokota N, Porter CW, Rabb H, Soleimani M (2003) Expression of SSAT, a novel biomarker of tubular cell damage, increases in kidney ischemia–reperfusion injury. Am J Physiol Renal Physiol 284:F1046–1055PubMedGoogle Scholar
  44. 44.
    Rector F, Goyal S, Rosenberg IK, Lucas CE (1972) Renal hyperemia in associated with clinical sepsis. Surg Forum 23:51–53PubMedGoogle Scholar
  45. 45.
    Brenner M, Schaer GL, Mallory DL, Suffredini AF, Parrillo JE (1990) Detection of renal blood flow abnormalities in septic and critically ill patients using a newly designed indwelling thermodilution renal vein catheter. Chest 98:170–179PubMedGoogle Scholar
  46. 46.
    Langenberg C, Bellomo R, May C, Wan L, Egi M, Morgera S (2005) Renal blood flow in sepsis. Crit Care 9:R363–374PubMedCrossRefGoogle Scholar
  47. 47.
    Langenberg C, Wan L, Egi M, May CN, Bellomo R (2006) Renal blood flow in experimental septic acute renal failure. Kidney Int 69:1996–2002PubMedCrossRefGoogle Scholar
  48. 48.
    Wan L, Bellomo R, Di Giantomasso D, Ronco C (2003) The pathogenesis of septic acute renal failure. Curr Opin Crit Care 9:496–502PubMedCrossRefGoogle Scholar
  49. 49.
    Bouman CSC, Oudemans-van Straaten HM, Tijssen JGP, Zandstra DF, Kesecioglu J (2002) Effects of early high-volume continuous venovenous hemofiltration on survival and recovery of renal function in intensive care patients with acute renal failure: A prospective, randomized trial. Critical Care Medicine 30:2205–2211PubMedCrossRefGoogle Scholar
  50. 50.
    Oudemans-van Straaten HM, Bosman RJ, van der Spoel JI, Zandstra DF (1999) Outcome of critically ill patients treated with intermittent high-volume haemofiltration: a prospective cohort analysis. Intensive Care Med 25:814–821PubMedCrossRefGoogle Scholar
  51. 51.
    Ratanarat R, Brendolan A, Piccinni P, Dan M, Salvatori G, Ricci Z, Ronco C (2005) Pulse high-volume haemofiltration for treatment of severe sepsis: effects on hemodynamics and survival. Crit Care 9:R294–302PubMedCrossRefGoogle Scholar
  52. 52.
    Gettings LG, Reynolds HN, Scalea T (1999) Outcome in post-traumatic acute renal failure when continuous renal replacement therapy is applied early vs. late. Intensive Care Med 25:805–813PubMedCrossRefGoogle Scholar
  53. 53.
    Langenberg C, Wan L, Bagshaw SM, Egi M, May CN, Bellomo R (2006) Urinary biochemistry in experimental septic acute renal failure. Nephrol Dial Transplant 21(12):3389–3397PubMedCrossRefGoogle Scholar
  54. 54.
    Jung K, Schulze G, Reinholdt C (1986) Different diuresis-dependent excretions of urinary enzymes: N-acetyl-beta-D-glucosaminidase, alanine aminopeptidase, alkaline phosphatase, and gamma-glutamyltransferase. Clin Chem 32:529–532PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Sean M. Bagshaw
    • 1
    • 2
  • Christoph Langenberg
    • 2
    • 3
  • Michael Haase
    • 2
  • Li Wan
    • 2
    • 3
  • Clive N. May
    • 3
  • Rinaldo Bellomo
    • 2
    • 4
  1. 1.Division of Critical Care MedicineUniversity of Alberta HospitalEdmontonCanada
  2. 2.Department of Intensive Care MedicineAustin HospitalHeidelbergAustralia
  3. 3.Howard Florey InstituteUniversity of MelbourneSouth CarltonAustralia
  4. 4.Department of MedicineMelbourne UniversityMelbourneAustralia

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