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Investigational biomarkers and the evaluation of acute tubular necrosis

Uta Erdbruegger, MD
Mark D Okusa, MD
Section Editor
Paul M Palevsky, MD
Deputy Editor
Alice M Sheridan, MD


Acute kidney injury (AKI), previously called acute renal failure (ARF), is a common clinical problem [1-7]. Although measurement of the serum creatinine concentration is widely used for the detection of AKI, it does not permit early diagnosis of acute tubular necrosis (ATN), since tubular injury precedes a significant rise in serum creatinine. Investigational biomarkers have been evaluated in patients with possible ATN in an attempt to detect tubular injury at an earlier stage. The US Food and Drug Administration (FDA) has approved use of the first platform measuring tissue inhibitor of metalloproteinases-2/insulin-like growth factor-binding protein 7 (TIMP-2/IGFBP7) to assess for the development of AKI.

We discuss here biomarkers that are being studied for the diagnosis of ATN. The pathophysiology, etiology, clinical presentation, and evaluation and diagnosis of prerenal disease and ATN are discussed elsewhere. (See "Etiology and diagnosis of prerenal disease and acute tubular necrosis in acute kidney injury in adults".)

The diagnostic approach to patients with acute or chronic kidney disease (CKD), the possible prevention and management of ATN, and renal and patient outcomes after ATN are also discussed elsewhere. (See "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting" and "Possible prevention and therapy of ischemic acute tubular necrosis" and "Kidney and patient outcomes after acute kidney injury in adults".)


The loss of kidney function in acute kidney injury (AKI) is most easily detected by measurement of the serum creatinine, which is used to estimate the glomerular filtration rate (GFR). Although the serum creatinine is widely used in diagnosing the presence of AKI, it is a suboptimal biomarker. It is a lagging marker of change in kidney function; therefore, it has poor sensitivity for the early diagnosis of AKI, and, as a marker of glomerular filtration, it is unable to differentiate among the various causes of AKI [8]. As an example, the rise in serum creatinine is slow following the onset of AKI. By the time a change is observed in the serum creatinine, a critical therapeutic window may have been missed, particularly among those with ATN. (See "Assessment of kidney function".)

Thus, different urinary and serum proteins have been intensively investigated as possible biomarkers for the early diagnosis of ATN. There are promising candidate biomarkers that report on kidney and tubule function, detect an early and graded increase in tubular epithelial cell injury, and distinguish prerenal disease from ATN [8-11]. These novel biomarkers have therefore the potential to reflect physiologic and pathophysiologic processes of the injured kidney. Some biomarkers are detected in the urine of patients without a diagnostic increase in serum creatinine, which defines a group of patients with "subclinical AKI" who are at risk for adverse outcomes [12]. Biomarkers are used in clinical investigation to facilitate early randomization to different treatment arms [13]. These vanguard studies using biomarkers may lead to the identification of new therapies and the practical use of biomarkers in routine patient care [8,9,14-16]. Future studies are also needed to investigate whether biomarker profiles can be matched to unique injuries. For instance, sepsis-associated AKI may have a biomarker profile that is distinctly different from that of nephrotoxin-associated AKI.

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Literature review current through: Nov 2017. | This topic last updated: May 10, 2017.
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  1. Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract 2012; 120:c179.
  2. Lameire N, Van Biesen W, Vanholder R. Acute renal failure. Lancet 2005; 365:417.
  3. Hsu CY, McCulloch CE, Fan D, et al. Community-based incidence of acute renal failure. Kidney Int 2007; 72:208.
  4. Waikar SS, Curhan GC, Wald R, et al. Declining mortality in patients with acute renal failure, 1988 to 2002. J Am Soc Nephrol 2006; 17:1143.
  5. Xue JL, Daniels F, Star RA, et al. Incidence and mortality of acute renal failure in Medicare beneficiaries, 1992 to 2001. J Am Soc Nephrol 2006; 17:1135.
  6. Uchino S, Kellum JA, Bellomo R, et al. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA 2005; 294:813.
  7. Liangos O, Wald R, O'Bell JW, et al. Epidemiology and outcomes of acute renal failure in hospitalized patients: a national survey. Clin J Am Soc Nephrol 2006; 1:43.
  8. Bonventre JV. Diagnosis of acute kidney injury: from classic parameters to new biomarkers. Contrib Nephrol 2007; 156:213.
  9. Trof RJ, Di Maggio F, Leemreis J, Groeneveld AB. Biomarkers of acute renal injury and renal failure. Shock 2006; 26:245.
  10. Vanmassenhove J, Vanholder R, Nagler E, Van Biesen W. Urinary and serum biomarkers for the diagnosis of acute kidney injury: an in-depth review of the literature. Nephrol Dial Transplant 2013; 28:254.
  11. Charlton JR, Portilla D, Okusa MD. A basic science view of acute kidney injury biomarkers. Nephrol Dial Transplant 2014; 29:1301.
  12. Haase M, Devarajan P, Haase-Fielitz A, et al. The outcome of neutrophil gelatinase-associated lipocalin-positive subclinical acute kidney injury: a multicenter pooled analysis of prospective studies. J Am Coll Cardiol 2011; 57:1752.
  13. Endre ZH, Walker RJ, Pickering JW, et al. Early intervention with erythropoietin does not affect the outcome of acute kidney injury (the EARLYARF trial). Kidney Int 2010; 77:1020.
  14. Bagshaw SM, Langenberg C, Haase M, et al. Urinary biomarkers in septic acute kidney injury. Intensive Care Med 2007; 33:1285.
  15. Devarajan P. Emerging biomarkers of acute kidney injury. Contrib Nephrol 2007; 156:203.
  16. Nguyen MT, Devarajan P. Biomarkers for the early detection of acute kidney injury. Pediatr Nephrol 2008; 23:2151.
  17. Ralib AM, Pickering JW, Shaw GM, et al. Test characteristics of urinary biomarkers depend on quantitation method in acute kidney injury. J Am Soc Nephrol 2012; 23:322.
  18. Herget-Rosenthal S, Poppen D, Hüsing J, et al. Prognostic value of tubular proteinuria and enzymuria in nonoliguric acute tubular necrosis. Clin Chem 2004; 50:552.
  19. Uchida K, Gotoh A. Measurement of cystatin-C and creatinine in urine. Clin Chim Acta 2002; 323:121.
  20. Herget-Rosenthal S. One step forward in the early detection of acute renal failure. Lancet 2005; 365:1205.
  21. Kjeldsen L, Johnsen AH, Sengeløv H, Borregaard N. Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase. J Biol Chem 1993; 268:10425.
  22. Mishra J, Ma Q, Prada A, et al. Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury. J Am Soc Nephrol 2003; 14:2534.
  23. Mishra J, Mori K, Ma Q, et al. Amelioration of ischemic acute renal injury by neutrophil gelatinase-associated lipocalin. J Am Soc Nephrol 2004; 15:3073.
  24. Mori K, Lee HT, Rapoport D, et al. Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury. J Clin Invest 2005; 115:610.
  25. Mishra J, Dent C, Tarabishi R, et al. Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet 2005; 365:1231.
  26. Wagener G, Jan M, Kim M, et al. Association between increases in urinary neutrophil gelatinase-associated lipocalin and acute renal dysfunction after adult cardiac surgery. Anesthesiology 2006; 105:485.
  27. Zappitelli M, Washburn KK, Arikan AA, et al. Urine neutrophil gelatinase-associated lipocalin is an early marker of acute kidney injury in critically ill children: a prospective cohort study. Crit Care 2007; 11:R84.
  28. Bennett M, Dent CL, Ma Q, et al. Urine NGAL predicts severity of acute kidney injury after cardiac surgery: a prospective study. Clin J Am Soc Nephrol 2008; 3:665.
  29. Nickolas TL, O'Rourke MJ, Yang J, et al. Sensitivity and specificity of a single emergency department measurement of urinary neutrophil gelatinase-associated lipocalin for diagnosing acute kidney injury. Ann Intern Med 2008; 148:810.
  30. Wagener G, Gubitosa G, Wang S, et al. Urinary neutrophil gelatinase-associated lipocalin and acute kidney injury after cardiac surgery. Am J Kidney Dis 2008; 52:425.
  31. Han WK, Wagener G, Zhu Y, et al. Urinary biomarkers in the early detection of acute kidney injury after cardiac surgery. Clin J Am Soc Nephrol 2009; 4:873.
  32. Siew ED, Ware LB, Gebretsadik T, et al. Urine neutrophil gelatinase-associated lipocalin moderately predicts acute kidney injury in critically ill adults. J Am Soc Nephrol 2009; 20:1823.
  33. Koyner JL, Vaidya VS, Bennett MR, et al. Urinary biomarkers in the clinical prognosis and early detection of acute kidney injury. Clin J Am Soc Nephrol 2010; 5:2154.
  34. Haase M, Haase-Fielitz A, Bellomo R, Mertens PR. Neutrophil gelatinase-associated lipocalin as a marker of acute renal disease. Curr Opin Hematol 2011; 18:11.
  35. Paragas N, Qiu A, Zhang Q, et al. The Ngal reporter mouse detects the response of the kidney to injury in real time. Nat Med 2011; 17:216.
  36. Ralib AM, Pickering JW, Shaw GM, et al. The clinical utility window for acute kidney injury biomarkers in the critically ill. Crit Care 2014; 18:601.
  37. Vaidya VS, Ramirez V, Ichimura T, et al. Urinary kidney injury molecule-1: a sensitive quantitative biomarker for early detection of kidney tubular injury. Am J Physiol Renal Physiol 2006; 290:F517.
  38. Steiner RW. Interpreting the fractional excretion of sodium. Am J Med 1984; 77:699.
  39. Han WK, Bailly V, Abichandani R, et al. Kidney Injury Molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury. Kidney Int 2002; 62:237.
  40. Han WK, Waikar SS, Johnson A, et al. Urinary biomarkers in the early diagnosis of acute kidney injury. Kidney Int 2008; 73:863.
  41. Vaidya VS, Ford GM, Waikar SS, et al. A rapid urine test for early detection of kidney injury. Kidney Int 2009; 76:108.
  42. Zhou H, Hewitt SM, Yuen PS, Star RA. Acute Kidney Injury Biomarkers - Needs, Present Status, and Future Promise. Nephrol Self Assess Program 2006; 5:63.
  43. Parikh CR, Mishra J, Thiessen-Philbrook H, et al. Urinary IL-18 is an early predictive biomarker of acute kidney injury after cardiac surgery. Kidney Int 2006; 70:199.
  44. Parikh CR, Abraham E, Ancukiewicz M, Edelstein CL. Urine IL-18 is an early diagnostic marker for acute kidney injury and predicts mortality in the intensive care unit. J Am Soc Nephrol 2005; 16:3046.
  45. Haase M, Bellomo R, Story D, et al. Urinary interleukin-18 does not predict acute kidney injury after adult cardiac surgery: a prospective observational cohort study. Crit Care 2008; 12:R96.
  46. Nisula S, Yang R, Poukkanen M, et al. Predictive value of urine interleukin-18 in the evolution and outcome of acute kidney injury in critically ill adult patients. Br J Anaesth 2015; 114:460.
  47. Kamijo A, Sugaya T, Hikawa A, et al. Urinary excretion of fatty acid-binding protein reflects stress overload on the proximal tubules. Am J Pathol 2004; 165:1243.
  48. Susantitaphong P, Siribamrungwong M, Doi K, et al. Performance of urinary liver-type fatty acid-binding protein in acute kidney injury: a meta-analysis. Am J Kidney Dis 2013; 61:430.
  49. Liangos O, Tighiouart H, Perianayagam MC, et al. Comparative analysis of urinary biomarkers for early detection of acute kidney injury following cardiopulmonary bypass. Biomarkers 2009; 14:423.
  50. Haase-Fielitz A, Bellomo R, Devarajan P, et al. Novel and conventional serum biomarkers predicting acute kidney injury in adult cardiac surgery--a prospective cohort study. Crit Care Med 2009; 37:553.
  51. Hall IE, Coca SG, Perazella MA, et al. Risk of poor outcomes with novel and traditional biomarkers at clinical AKI diagnosis. Clin J Am Soc Nephrol 2011; 6:2740.
  52. Nickolas TL, Schmidt-Ott KM, Canetta P, et al. Diagnostic and prognostic stratification in the emergency department using urinary biomarkers of nephron damage: a multicenter prospective cohort study. J Am Coll Cardiol 2012; 59:246.
  53. Endre ZH, Pickering JW, Walker RJ, et al. Improved performance of urinary biomarkers of acute kidney injury in the critically ill by stratification for injury duration and baseline renal function. Kidney Int 2011; 79:1119.
  54. McCullough PA, Shaw AD, Haase M, et al. Diagnosis of acute kidney injury using functional and injury biomarkers: workgroup statements from the tenth Acute Dialysis Quality Initiative Consensus Conference. Contrib Nephrol 2013; 182:13.
  55. Basu RK, Wong HR, Krawczeski CD, et al. Combining functional and tubular damage biomarkers improves diagnostic precision for acute kidney injury after cardiac surgery. J Am Coll Cardiol 2014; 64:2753.
  56. Ho J, Lucy M, Krokhin O, et al. Mass spectrometry-based proteomic analysis of urine in acute kidney injury following cardiopulmonary bypass: a nested case-control study. Am J Kidney Dis 2009; 53:584.
  57. Weiss RH, Kim K. Metabolomics in the study of kidney diseases. Nat Rev Nephrol 2011; 8:22.
  58. Wei Q, Xiao X, Fogle P, Dong Z. Changes in metabolic profiles during acute kidney injury and recovery following ischemia/reperfusion. PLoS One 2014; 9:e106647.
  59. Erdbrügger U, Le TH. Extracellular Vesicles in Renal Diseases: More than Novel Biomarkers? J Am Soc Nephrol 2016; 27:12.
  60. Lorenzen JM, Kielstein JT, Hafer C, et al. Circulating miR-210 predicts survival in critically ill patients with acute kidney injury. Clin J Am Soc Nephrol 2011; 6:1540.
  61. Aguado-Fraile E, Ramos E, Conde E, et al. A Pilot Study Identifying a Set of microRNAs As Precise Diagnostic Biomarkers of Acute Kidney Injury. PLoS One 2015; 10:e0127175.
  62. Zhang WR, Garg AX, Coca SG, et al. Plasma IL-6 and IL-10 Concentrations Predict AKI and Long-Term Mortality in Adults after Cardiac Surgery. J Am Soc Nephrol 2015; 26:3123.
  63. Greenberg JH, Whitlock R, Zhang WR, et al. Interleukin-6 and interleukin-10 as acute kidney injury biomarkers in pediatric cardiac surgery. Pediatr Nephrol 2015; 30:1519.
  64. Ramesh G, Krawczeski CD, Woo JG, et al. Urinary netrin-1 is an early predictive biomarker of acute kidney injury after cardiac surgery. Clin J Am Soc Nephrol 2010; 5:395.
  65. Yamamoto T, Noiri E, Ono Y, et al. Renal L-type fatty acid--binding protein in acute ischemic injury. J Am Soc Nephrol 2007; 18:2894.
  66. Liu KD, Glidden DV, Eisner MD, et al. Predictive and pathogenetic value of plasma biomarkers for acute kidney injury in patients with acute lung injury. Crit Care Med 2007; 35:2755.
  67. Zhou H, Cheruvanky A, Hu X, et al. Urinary exosomal transcription factors, a new class of biomarkers for renal disease. Kidney Int 2008; 74:613.
  68. Munshi R, Johnson A, Siew ED, et al. MCP-1 gene activation marks acute kidney injury. J Am Soc Nephrol 2011; 22:165.
  69. Alge JL, Karakala N, Neely BA, et al. Urinary angiotensinogen and risk of severe AKI. Clin J Am Soc Nephrol 2013; 8:184.
  70. Alge JL, Karakala N, Neely BA, et al. Association of elevated urinary concentration of renin-angiotensin system components and severe AKI. Clin J Am Soc Nephrol 2013; 8:2043.
  71. Soto K, Papoila AL, Coelho S, et al. Plasma NGAL for the diagnosis of AKI in patients admitted from the emergency department setting. Clin J Am Soc Nephrol 2013; 8:2053.
  72. Witzgall R, Brown D, Schwarz C, Bonventre JV. Localization of proliferating cell nuclear antigen, vimentin, c-Fos, and clusterin in the postischemic kidney. Evidence for a heterogenous genetic response among nephron segments, and a large pool of mitotically active and dedifferentiated cells. J Clin Invest 1994; 93:2175.
  73. Yang QH, Liu DW, Long Y, et al. Acute renal failure during sepsis: potential role of cell cycle regulation. J Infect 2009; 58:459.
  74. 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:R25.
  75. Koyner JL, Shaw AD, Chawla LS, et al. Tissue Inhibitor Metalloproteinase-2 (TIMP-2)⋅IGF-Binding Protein-7 (IGFBP7) Levels Are Associated with Adverse Long-Term Outcomes in Patients with AKI. J Am Soc Nephrol 2015; 26:1747.
  76. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Int Suppl 2012; 2:1.
  77. 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; 189:932.