Advertisement

Biomarkers in AKI

  • Kelly R. McMahon
  • Michael Zappitelli
Chapter

Abstract

Current acute kidney injury (AKI) clinical diagnosis is based on detecting an acute rise in serum creatinine or decrease in urine output. These biomarkers of AKI are suboptimal since they reflect decreased kidney function and do not directly reflect kidney tissue damage. Moreover, they are delayed diagnostic tests of AKI. These limitations have led to delays in developing AKI therapeutic interventions. New AKI biomarkers are mainly proteins that reflect structural kidney injury, many of which are upregulated in response to kidney tissue damage. These novel biomarkers may also inform on the cause and location of kidney injury and provide earlier AKI diagnosis than current diagnostic tests. New AKI biomarkers may also improve prediction of AKI prognosis and risk stratification. In the last two decades, a large amount of research on new AKI biomarkers has been performed. Bringing these biomarkers to use in clinical care has the potential to improve patient management and clinical outcomes. This chapter summarizes novel AKI biomarkers with particular emphasis on pediatric research performed to date. Readers will gain appreciation for utility of novel AKI biomarkers and direct applicability potential in clinical care.

Keywords

Acute renal failure Diagnostic test Children Critical illness Renal angina 

References

  1. 1.
    Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int. 2012;2(1):1–138.CrossRefGoogle Scholar
  2. 2.
    Zappitelli M, Parvex P, Joseph L, Paradis G, Grey V, Lau S, et al. Derivation and validation of cystatin C-based prediction equations for GFR in children. Am J Kidney Dis. 2006;48(2):221–30.CrossRefPubMedGoogle Scholar
  3. 3.
    Hoek FJ, Kemperman FA, Krediet RT. A comparison between cystatin C, plasma creatinine and the Cockcroft and gault formula for the estimation of glomerular filtration rate. Nephrol Dial Transplant. 2003;18(10):2024–31.CrossRefPubMedGoogle Scholar
  4. 4.
    Zhang Z, Lu B, Sheng X, Jin N. Cystatin C in prediction of acute kidney injury: a systemic review and meta-analysis. Am J Kidney Dis. 2011;58(3):356–65.CrossRefPubMedGoogle Scholar
  5. 5.
    Lagos-Arevalo P, Palijan A, Vertullo L, Devarajan P, Bennett MR, Sabbisetti V, et al. Cystatin C in acute kidney injury diagnosis: early biomarker or alternative to serum creatinine? Pediatr Nephrol. 2015;30(4):665–76.CrossRefPubMedGoogle Scholar
  6. 6.
    McCaffrey J, Coupes B, Chaloner C, Webb NJ, Barber R, Lennon R. Towards a biomarker panel for the assessment of AKI in children receiving intensive care. Pediatr Nephrol. 2015;30(10):1861–71.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Volpon LC, Sugo EK, Carlotti AP. Diagnostic and prognostic value of serum cystatin C in critically ill children with acute kidney injury. Pediatr Crit Care Med. 2015;16(5):e125–31.CrossRefPubMedGoogle Scholar
  8. 8.
    Peco-Antic A, Ivanisevic I, Vulicevic I, Kotur-Stevuljevic J, Ilic S, Ivanisevic J, et al. Biomarkers of acute kidney injury in pediatric cardiac surgery. Clin Biochem. 2013;46(13–14):1244–51.CrossRefPubMedGoogle Scholar
  9. 9.
    Di Nardo M, Ficarella A, Ricci Z, Luciano R, Stoppa F, Picardo S, et al. Impact of severe sepsis on serum and urinary biomarkers of acute kidney injury in critically ill children: an observational study. Blood Purif. 2013;35(1–3):172–6.CrossRefPubMedGoogle Scholar
  10. 10.
    Lau L, Al-Ismaili Z, Harel-Sterling M, Pizzi M, Caldwell JS, Piccioni M, et al. Serum cystatin C for acute kidney injury evaluation in children treated with aminoglycosides. Pediatr Nephrol. 2017;32(1):163–71.CrossRefPubMedGoogle Scholar
  11. 11.
    Westhuyzen J, Endre ZH, Reece G, Reith DM, Saltissi D, Morgan TJ. Measurement of tubular enzymuria facilitates early detection of acute renal impairment in the intensive care unit. Nephrol Dial Transplant. 2003;18(3):543–51.CrossRefPubMedGoogle Scholar
  12. 12.
    Han WK, Waikar SS, Johnson A, Betensky RA, Dent CL, Devarajan P, et al. Urinary biomarkers in the early diagnosis of acute kidney injury. Kidney Int. 2008;73(7):863–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Liangos O, Tighiouart H, Perianayagam MC, Kolyada A, Han WK, Wald R, et al. Comparative analysis of urinary biomarkers for early detection of acute kidney injury following cardiopulmonary bypass. Biomarkers. 2009;14(6):423–31.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Zheng J, Xiao Y, Yao Y, Xu G, Li C, Zhang Q, et al. Comparison of urinary biomarkers for early detection of acute kidney injury after cardiopulmonary bypass surgery in infants and young children. Pediatr Cardiol. 2013;34(4):880–6.CrossRefPubMedGoogle Scholar
  15. 15.
    Mohammadi-Karakani A, Asgharzadeh-Haghighi S, Ghazi-Khansari M, Seyed-Ebrahimi A, Ghasemi A, Jabari E. Enzymuria determination in children treated with aminoglycosides drugs. Hum Exp Toxicol. 2008;27(12):879–82.CrossRefPubMedGoogle Scholar
  16. 16.
    Herget-Rosenthal S, Poppen D, Husing J, Marggraf G, Pietruck F, Jakob HG, et al. Prognostic value of tubular proteinuria and enzymuria in nonoliguric acute tubular necrosis. Clin Chem. 2004;50(3):552–8.CrossRefPubMedGoogle Scholar
  17. 17.
    Kashani K, Al-Khafaji A, Ardiles T, Artigas A, Bagshaw SM, Bell M, et al. Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. Crit Care. 2013;17(1):R25.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Koyner JL, Vaidya VS, Bennett MR, Ma Q, Worcester E, Akhter SA, et al. Urinary biomarkers in the clinical prognosis and early detection of acute kidney injury. Clin J Am Soc Nephrol. 2010;5(12):2154–65.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Walshe CM, Odejayi F, Ng S, Marsh B. Urinary glutathione S-transferase as an early marker for renal dysfunction in patients admitted to intensive care with sepsis. Crit Care Resusc. 2009;11(3):204–9.PubMedGoogle Scholar
  20. 20.
    Askenazi DJ, Koralkar R, Patil N, Halloran B, Ambalavanan N, Griffin R. Acute kidney injury urine biomarkers in very low-birth-weight infants. Clin J Am Soc Nephrol. 2016;11(9):1527–35.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Du Y, Zappitelli M, Mian A, Bennett M, Ma Q, Devarajan P, et al. Urinary biomarkers to detect acute kidney injury in the pediatric emergency center. Pediatr Nephrol. 2011;26(2):267–74.CrossRefPubMedGoogle Scholar
  22. 22.
    Bernard AM, Moreau D, Lauwerys R. Comparison of retinol-binding protein and beta 2-microglobulin determination in urine for the early detection of tubular proteinuria. Clin Chim Acta. 1982;126(1):1–7.CrossRefPubMedGoogle Scholar
  23. 23.
    du Cheyron D, Daubin C, Poggioli J, Ramakers M, Houillier P, Charbonneau P, et al. 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. 2003;42(3):497–506.CrossRefPubMedGoogle Scholar
  24. 24.
    Che M, Xie B, Xue S, Dai H, Qian J, Ni Z, et al. Clinical usefulness of novel biomarkers for the detection of acute kidney injury following elective cardiac surgery. Nephron Clin Pract. 2010;115(1):c66–72.CrossRefPubMedGoogle Scholar
  25. 25.
    Roberts DS, Haycock GB, Dalton RN, Turner C, Tomlinson P, Stimmler L, et al. Prediction of acute renal failure after birth asphyxia. Arch Dis Child. 1990;65(Spec 10):1021–8.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Aydogdu M, Gursel G, Sancak B, Yeni S, Sari G, Tasyurek S, et al. The use of plasma and urine neutrophil gelatinase associated lipocalin (NGAL) and cystatin C in early diagnosis of septic acute kidney injury in critically ill patients. Dis Markers. 2013;34(4):237–46.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Askenazi DJ, Koralkar R, Hundley HE, Montesanti A, Parwar P, Sonjara S, et al. Urine biomarkers predict acute kidney injury in newborns. J Pediatr. 2012;161(2):270–5.e1.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Hazle MA, Gajarski RJ, Aiyagari R, Yu S, Abraham A, Donohue J, et al. Urinary biomarkers and renal near-infrared spectroscopy predict intensive care unit outcomes after cardiac surgery in infants younger than 6 months of age. J Thorac Cardiovasc Surg. 2013;146(4):861–7.e1.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Schley G, Koberle C, Manuilova E, Rutz S, Forster C, Weyand M, et al. Comparison of plasma and urine biomarker performance in acute kidney injury. PLoS One. 2015;10(12):e0145042.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Ware LB, Johnson AC, Zager RA. Renal cortical albumin gene induction and urinary albumin excretion in response to acute kidney injury. Am J Physiol Renal Physiol. 2011;300(3):F628–38.CrossRefPubMedGoogle Scholar
  31. 31.
    Parikh CR, Thiessen-Philbrook H, Garg AX, Kadiyala D, Shlipak MG, Koyner JL, et al. Performance of kidney injury molecule-1 and liver fatty acid-binding protein and combined biomarkers of AKI after cardiac surgery. Clin J Am Soc Nephrol. 2013;8(7):1079–88.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Mishra J, Dent C, Tarabishi R, Mitsnefes MM, Ma Q, Kelly C, et al. Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet. 2005;365(9466):1231–8.CrossRefGoogle Scholar
  33. 33.
    Krawczeski CD, Goldstein SL, Woo JG, Wang Y, Piyaphanee N, Ma Q, et al. Temporal relationship and predictive value of urinary acute kidney injury biomarkers after pediatric cardiopulmonary bypass. J Am Coll Cardiol. 2011;58(22):2301–9.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Meersch M, Schmidt C, Van Aken H, Rossaint J, Gorlich D, Stege D, et al. Validation of cell-cycle arrest biomarkers for acute kidney injury after pediatric cardiac surgery. PLoS One. 2014;9(10):e110865.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Parikh CR, Devarajan P, Zappitelli M, Sint K, Thiessen-Philbrook H, Li S, et al. Postoperative biomarkers predict acute kidney injury and poor outcomes after pediatric cardiac surgery. J Am Soc Nephrol. 2011;22(9):1737–47.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Zappitelli M, Washburn KK, Arikan AA, Loftis L, Ma Q, Devarajan P, 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(4):R84.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Zwiers AJ, de Wildt SN, van Rosmalen J, de Rijke YB, Buijs EA, Tibboel D, et al. Urinary neutrophil gelatinase-associated lipocalin identifies critically ill young children with acute kidney injury following intensive care admission: a prospective cohort study. Crit Care. 2015;19:181.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Sterling M, Al-Ismaili Z, McMahon KR, Piccioni M, Pizzi M, Mottes T, et al. Urine biomarkers of acute kidney injury in noncritically ill, hospitalized children treated with chemotherapy. Pediatr Blood Cancer. 2017;64:10.CrossRefGoogle Scholar
  39. 39.
    Haase M, Bellomo R, Devarajan P, Schlattmann P, Haase-Fielitz A, Group NM-aI. Accuracy of neutrophil gelatinase-associated lipocalin (NGAL) in diagnosis and prognosis in acute kidney injury: a systematic review and meta-analysis. Am J Kidney Dis. 2009;54(6):1012–24.CrossRefPubMedGoogle Scholar
  40. 40.
    Haase M, Devarajan P, Haase-Fielitz A, Bellomo R, Cruz DN, Wagener G, 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(17):1752–61.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Wheeler DS, Devarajan P, Ma Q, Harmon K, Monaco M, Cvijanovich N, et al. Serum neutrophil gelatinase-associated lipocalin (NGAL) as a marker of acute kidney injury in critically ill children with septic shock. Crit Care Med. 2008;36(4):1297–303.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Han WK, Bailly V, Abichandani R, Thadhani R, Bonventre JV. Kidney Injury Molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury. Kidney Int. 2002;62(1):237–44.CrossRefPubMedGoogle Scholar
  43. 43.
    Carvalho Pedrosa D, Macedo de Oliveira Neves F, Cavalcante Meneses G, Pinheiro Gomes Wirtzbiki G, da Costa Moraes CA, Costa Martins AM, et al. Urinary KIM-1 in children undergoing nephrotoxic antineoplastic treatment: a prospective cohort study. Pediatr Nephrol. 2015;30(12):2207–13.CrossRefPubMedGoogle Scholar
  44. 44.
    McWilliam SJ, Antoine DJ, Sabbisetti V, Turner MA, Farragher T, Bonventre JV, et al. Mechanism-based urinary biomarkers to identify the potential for aminoglycoside-induced nephrotoxicity in premature neonates: a proof-of-concept study. PLoS One. 2012;7(8):e43809.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    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(10):3046–52.CrossRefPubMedGoogle Scholar
  46. 46.
    Washburn KK, Zappitelli M, Arikan AA, Loftis L, Yalavarthy R, Parikh CR, et al. Urinary interleukin-18 is an acute kidney injury biomarker in critically ill children. Nephrol Dial Transplant. 2008;23(2):566–72.CrossRefPubMedGoogle Scholar
  47. 47.
    Doi K, Noiri E, Maeda-Mamiya R, Ishii T, Negishi K, Hamasaki Y, et al. Urinary L-type fatty acid-binding protein as a new biomarker of sepsis complicated with acute kidney injury. Crit Care Med. 2010;38(10):2037–42.CrossRefPubMedGoogle Scholar
  48. 48.
    Menon S, Goldstein SL, Mottes T, Fei L, Kaddourah A, Terrell T, et al. Urinary biomarker incorporation into the renal angina index early in intensive care unit admission optimizes acute kidney injury prediction in critically ill children: a prospective cohort study. Nephrol Dial Transplant. 2016;31(4):586–94.CrossRefPubMedGoogle Scholar
  49. 49.
    Bihorac A, Chawla LS, Shaw AD, Al-Khafaji A, Davison DL, Demuth GE, 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.CrossRefPubMedGoogle Scholar
  50. 50.
    Hoste EA, McCullough PA, Kashani K, Chawla LS, Joannidis M, Shaw AD, et al. Derivation and validation of cutoffs for clinical use of cell cycle arrest biomarkers. Nephrol Dial Transplant. 2014;29(11):2054–61.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Mayer T, Bolliger D, Scholz M, Reuthebuch O, Gregor M, Meier P, et al. Urine biomarkers of tubular renal cell damage for the prediction of acute kidney injury after cardiac surgery-a pilot study. J Cardiothorac Vasc Anesth. 2017;31:2072.CrossRefPubMedGoogle Scholar
  52. 52.
    Kimmel M, Shi J, Latus J, Wasser C, Kitterer D, Braun N, et al. Association of renal stress/damage and filtration biomarkers with subsequent AKI during hospitalization among patients presenting to the emergency department. Clin J Am Soc Nephrol. 2016;11(6):938–46.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Westhoff JH, Tonshoff B, Waldherr S, Poschl J, Teufel U, Westhoff TH, et al. Urinary tissue inhibitor of Metalloproteinase-2 (TIMP-2) * insulin-like growth factor-binding protein 7 (IGFBP7) predicts adverse outcome in pediatric acute kidney injury. PLoS One. 2015;10(11):e0143628.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Kwon O, Ahn K, Zhang B, Lockwood T, Dhamija R, Anderson D, et al. Simultaneous monitoring of multiple urinary cytokines may predict renal and patient outcome in ischemic AKI. Ren Fail. 2010;32(6):699–708.CrossRefPubMedGoogle Scholar
  55. 55.
    Seibert FS, Pagonas N, Arndt R, Heller F, Dragun D, Persson P, et al. Calprotectin and neutrophil gelatinase-associated lipocalin in the differentiation of pre-renal and intrinsic acute kidney injury. Acta Physiol (Oxf). 2013;207(4):700–8.CrossRefGoogle Scholar
  56. 56.
    Westhoff JH, Fichtner A, Waldherr S, Pagonas N, Seibert FS, Babel N, et al. Urinary biomarkers for the differentiation of prerenal and intrinsic pediatric acute kidney injury. Pediatr Nephrol. 2016;31(12):2353–63.CrossRefPubMedGoogle Scholar
  57. 57.
    Westhoff JH, Seibert FS, Waldherr S, Bauer F, Tonshoff B, Fichtner A, et al. Urinary calprotectin, kidney injury molecule-1, and neutrophil gelatinase-associated lipocalin for the prediction of adverse outcome in pediatric acute kidney injury. Eur J Pediatr. 2017;176(6):745–55.CrossRefPubMedGoogle Scholar
  58. 58.
    Ho J, Lucy M, Krokhin O, Hayglass K, Pascoe E, Darroch G, 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(4):584–95.CrossRefPubMedGoogle Scholar
  59. 59.
    Ho J, Reslerova M, Gali B, Gao A, Bestland J, Rush DN, et al. Urinary hepcidin-25 and risk of acute kidney injury following cardiopulmonary bypass. Clin J Am Soc Nephrol. 2011;6(10):2340–6.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Garimella PS, Jaber BL, Tighiouart H, Liangos O, Bennett MR, Devarajan P, et al. Association of Preoperative Urinary Uromodulin with AKI after cardiac surgery. Clin J Am Soc Nephrol. 2017;12(1):10–8.CrossRefPubMedGoogle Scholar
  61. 61.
    Wai K, Soler-Garcia AA, Perazzo S, Mattison P, Ray PE. A pilot study of urinary fibroblast growth factor-2 and epithelial growth factor as potential biomarkers of acute kidney injury in critically ill children. Pediatr Nephrol. 2013;28(11):2189–98.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Goldstein SL, Chawla LS. Renal angina. Clin J Am Soc Nephrol. 2010;5(5):943–9.CrossRefPubMedGoogle Scholar
  63. 63.
    Basu RK, Chawla LS, Wheeler DS, Goldstein SL. Renal angina: an emerging paradigm to identify children at risk for acute kidney injury. Pediatr Nephrol. 2012;27(7):1067–78.CrossRefPubMedGoogle Scholar
  64. 64.
    Basu RK, Zappitelli M, Brunner L, Wang Y, Wong HR, Chawla LS, 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
  65. 65.
    Basu RK, Kaddourah A, Goldstein SL. Assessment of a renal angina index for prediction of severe acute kidney injury in critically ill children: a multicentre, multinational, prospective observational study. Lancet Child Adolesc Health. 2017;2:112–20.CrossRefGoogle Scholar
  66. 66.
    Basu RK, Wang Y, Wong HR, Chawla LS, Wheeler DS, Goldstein SL. 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
  67. 67.
    Zappitelli M, Coca SG, Garg AX, Krawczeski CD, Thiessen Heather P, Sint K, et al. The association of albumin/creatinine ratio with postoperative AKI in children undergoing cardiac surgery. Clin J Am Soc Nephrol. 2012;7(11):1761–9.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    McCullough PA, Bouchard J, Waikar SS, Siew ED, Endre ZH, Goldstein SL, et al. Implementation of novel biomarkers in the diagnosis, prognosis, and management of acute kidney injury: executive summary from the tenth consensus conference of the acute Dialysis quality initiative (ADQI). Contrib Nephrol. 2013;182:5–12.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pediatrics, Division of Pediatric Nephrology, Montreal Children’s HospitalMcGill University Health CentreMontrealCanada
  2. 2.Department of Pediatrics, Division of NephrologyToronto Hospital for Sick Children, University of TorontoTorontoCanada

Personalised recommendations