Pediatric Nephrology

, 23:1317 | Cite as

Urinary aprotinin as a predictor of acute kidney injury after cardiac surgery in children receiving aprotinin therapy

  • Mai T. Nguyen
  • Catherine L. Dent
  • Gary F. Ross
  • Nathan Harris
  • Peter B. Manning
  • Mark M. Mitsnefes
  • Prasad Devarajan
Original Article

Abstract

Proteomic analysis has revealed potential early biomarkers of acute kidney injury (AKI) in children undergoing cardiopulmonary bypass (CPB), the most prominent one with a mass-to-charge ratio of 6.4 kDa. The objective of this study was to identify this protein and test its utility as a biomarker of AKI. Trypsin-digested protein bands were analyzed by tandem mass spectrometry (MS/MS) to identify the protein in urine samples. Surface-enhanced laser desorption/ionization time-of-flight analysis and a functional activity assay were performed to quantify urinary levels in a pilot study of 106 pediatric patients undergoing CPB. The protein was identified as aprotinin. Urinary aprotinin levels 2 h after initiation of CPB were predictive of AKI (for functional assay: 92% sensitivity, 96% specificity, area under the curve of 0.98). By multivariate analysis, the urinary aprotinin level 2 h after CPB was an independent predictor of AKI (β = 0.001, P < 0.0001). The 2 h urinary aprotinin level correlated with serum creatinine, duration of AKI, and length of hospital stay. We concluded that urinary aprotinin levels 2 h after initiation of CPB predict the development of AKI and adverse clinical outcomes.

Keywords

Acute renal failure Acute kidney injury Biomarker Cardiac surgery Aprotinin 

References

  1. 1.
    Albert MA, Antman EM (2003) Preoperative evaluation for cardiac surgery. In: Cohn LH, Edmunds LH Jr (eds) Cardiac surgery in the adult. New York, McGraw-Hill, pp 235–248Google Scholar
  2. 2.
    Haase M, Haase-Fielitz A, Bagshaw SM, Ronco C, Bellomo R (2007) Cardiopulmonary bypass-associated acute kidney injury: a pigment nephropathy? Contrib Nephrol 156:340–353PubMedGoogle Scholar
  3. 3.
    Rosner MH, Okusa MD (2006) Acute kidney injury associated with cardiac surgery. Clin J Am Soc Nephrol 1:19–32PubMedCrossRefGoogle Scholar
  4. 4.
    Chertow GM, Levy EM, Hammermeister KE, Grover F, Daley J (1998) Independent association between acute renal failure and mortality following cardiac surgery. Am J Med 104:343–348PubMedCrossRefGoogle Scholar
  5. 5.
    Lassning A, Schmidlin D, Mouhieddine M, Bachmann LM, Druml W, Bauer P, Hiesmayr M (2004) Minimal changes of serum creatinine predict prognosis in patients after cardiothoracic surgery: a prospective cohort study. J Am Soc Nephrol 15:1597–1605CrossRefGoogle Scholar
  6. 6.
    Thakar CV, Worley S, Arrigain S, Yared J-P, Paganini EP (2005) Influence of renal dysfunction on mortality after cardiac surgery: modifying effect of preoperative renal function. Kidney Int 67:1112–1119PubMedCrossRefGoogle Scholar
  7. 7.
    Mangano CM, Diamondstone LS, Ramsay JG, Aggarwal A, Herskowitz A, Mangano DT (1998) Renal dysfunction after myocardial revascularization: risk factors, adverse outcomes, and hospital resource utilization. The Multicenter Study of Perioperative Ischemia Research Group. Ann Intern Med 128:194–203PubMedGoogle Scholar
  8. 8.
    Lok CE, Austin PC, Wanh H, Tu JV (2004) Impact of renal insufficiency on short- and long-term outcomes after cardiac surgery. Am Heart J 148:430–438PubMedCrossRefGoogle Scholar
  9. 9.
    Loef BG, Epema AH, Smilde TB, Henning RH, Ebels T, Navis G, Stegemean CA (2005) Immediate postoperative renal function deterioration in cardiac surgical patients predicts in-hospital mortality and long-term survival. J Am Soc Nephrol 16:195–200PubMedCrossRefGoogle Scholar
  10. 10.
    Sorof JM, Stromberg D, Brewer ED, Feltes TF, Fraser CD Jr (1999) Early initiation of peritoneal dialysis after surgical repair of congenital heart disease. Pediatr Nephrol 13:641–645PubMedCrossRefGoogle Scholar
  11. 11.
    Mehta RL (2005) Acute renal failure and cardiac surgery: marching in place or moving ahead? J Am Soc Nephrol 16:12–14PubMedCrossRefGoogle Scholar
  12. 12.
    Thakar CV, Arrigain S, Worley S, Yared J-P, Paganini EP (2005) A clinical score to predict acute renal failure after cardiac surgery. J Am Soc Nephrol 16:162–168PubMedCrossRefGoogle Scholar
  13. 13.
    Mehta RH, Grab JD, O’Brien SM, Bridges CR, Gammie JS, Haan CK, Ferguson TB, Peterson ED, the Society of Thoracic Surgeons National Cardiac Surgery Database Investigators (2006) Bedside tool for predicting the risk of postoperative dialysis in patients undergoing cardiac surgery. Circulation 114:2208–2216PubMedCrossRefGoogle Scholar
  14. 14.
    Wijeysundera DN, Karkouti K, Dupuis JY, Rao V, Chan CT, Granton JT, Beattie WS (2007) Derivation and validation of a simplified predictive index for renal replacement therapy after cardiac surgery. JAMA 297:1801–1809PubMedCrossRefGoogle Scholar
  15. 15.
    Devarajan P (2006) Update on mechanisms of ischemic acute kidney injury. J Am Soc Nephrol 17:1503–1520PubMedCrossRefGoogle Scholar
  16. 16.
    Jo SK, Rosner MH, Okusa MD (2007) Pharmacologic treatment of acute kidney injury: why drugs haven’t worked and what is on the horizon. Clin J Am Soc Nephrol 2:356–365PubMedCrossRefGoogle Scholar
  17. 17.
    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
  18. 18.
    Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P (2004) Acute renal failure—definition, outcome measures, animal models, fluid therapy and information technology needs: The Second International Concensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 8:R204–R212PubMedCrossRefGoogle Scholar
  19. 19.
    Nguyen MT, Ross GF, Dent CL, Devarajan P (2005) Early prediction of acute renal injury using urinary proteomics. Am J Nephrol 25:318–326PubMedCrossRefGoogle Scholar
  20. 20.
    Jenkins KJ, Gauvreau K, Newburger JW, Spray TL, Moller JH, Iezzoni LI (2002) Consensus-based method for risk adjustment for surgery for congenital heart disease. J Thorac Cardiovasc Surg 123:110–118PubMedCrossRefGoogle Scholar
  21. 21.
    Wernovsky G, Wypij D, Jonas RA, Mayer JE Jr, Hanley FL, Hickey PR, Walsh AZ, Chang AC, Castaneda AR, Newburger JW, Wessel DL (1995) Postoperative course and hemodynamic profile after the arterial switch operation in neonates and infants: a comparison of low-flow cardiopulmonary bypass and circulatory arrest. Circulation 92:2226–2235PubMedGoogle Scholar
  22. 22.
    Kulik TJ, Moler FW, Palmisano JM, Custer JR, Mosca RS, Bove EL, Bartlett RH (1996) Outcome-associated factors in pediatric patients treated with extracorporeal membrane oxygenator after cardiac surgery. Circulation 94 [Suppl II]:63–68Google Scholar
  23. 23.
    Cardigan RA, Mackie IJ, Gippner-Steppert C, Jochum M, Royston D, Gallimore MJ (2001) Determination of plasma aprotinin levels by functional and immunologic assays. Blood Coagul Fibrinolysis 12:37–42PubMedCrossRefGoogle Scholar
  24. 24.
    Devarajan P (2007) Emerging biomarkers of acute kidney injury. Contrib Nephrol 156:203–212PubMedCrossRefGoogle Scholar
  25. 25.
    Royston D, van Haaften N, De Vooght P (2007) Aprotinin; friend or foe? A review of recent medical literature. Eur J Anaesthesiol 24:6–14PubMedCrossRefGoogle Scholar
  26. 26.
    Henry DA, Moxey AJ, Carless PA, O’Connell D, McClelland B, Henderson KM, Sly K, Laupacis A, Fergusson D (2001) Anti-fibrinolytic use for minimizing perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 1:CD001886PubMedGoogle Scholar
  27. 27.
    Sedrakyan A, Treasure T, Elefteriades JA (2004) Effect of aprotinin on clinical outcomes in coronary artery bypass graft surgery: a systematic review and meta-analysis of randomized clinical trials. J Thorac Cardiovasc Surg 128:442–448PubMedCrossRefGoogle Scholar
  28. 28.
    Fauli A, Gomar C, Campistol JM, Alvarez L, Manig AM, Matute P (2005) Kidney-specific proteins in patients receiving aprotinin at high- and low-dose regimens during coronary artery bypass graft with cardiopulmonary bypass. Eur J Anaesthesiol 22:666–671PubMedCrossRefGoogle Scholar
  29. 29.
    Karkouti K, Beattie WS, Dattilo KM, McCluskey SA, Ghannam M, Hamdy A, Wijeysundara DM, Fedorko L, Yau TM (2006) A propensity score case-control comparison of aprotinin and tranexamic acid in high-transfusion-risk cardiac surgery. Transfusion 46:327–338PubMedCrossRefGoogle Scholar
  30. 30.
    Mangano DT, Tudor IC, Dietzel C (2006) The risk associated with aprotinin in cardiac surgery. N Engl J Med 354:353–365PubMedCrossRefGoogle Scholar
  31. 31.
    Mangano DT, Miao Y, Vuylsteke A, Tudor IC, Juneja R, Filipescu D, Hoeft A, Fontes ML, Hillel Z, Ott E, Titov T, Dietzel C, Levin J (2007) Mortality associated with aprotinin during 5 years following coronary artery bypass graft surgery. JAMA 297:471–479PubMedCrossRefGoogle Scholar
  32. 32.
    Hunter D (2006) First, gather the data. N Engl J Med 354:329–331PubMedCrossRefGoogle Scholar
  33. 33.
    Vlahakes GJ (2006) The value of phase 4 clinical testing. N Engl J Med 354:413–415PubMedCrossRefGoogle Scholar
  34. 34.
    Ferraris VA, Bridges CR, Anderson RP (2006) Aprotinin in cardiac surgery. N Engl J Med 354:1953–1954PubMedCrossRefGoogle Scholar
  35. 35.
    Levy JH, Ramsay JG, Guyton RA (2006) Aprotinin in cardiac surgery. N Engl J Med 354:1956Google Scholar
  36. 36.
    D’Ambra MN (2006) Aprotinin in cardiac surgery. N Engl J Med 354:1956Google Scholar
  37. 37.
    Brown J, Birkmeyer N, O’Connor J (2006) Aprotinin in cardiac surgery. N Engl J Med 354:1954–1955CrossRefGoogle Scholar
  38. 38.
    Rieves RD, Weiss KD (2006) Aprotinin in cardiac surgery. N Engl J Med 355:2262PubMedGoogle Scholar

Copyright information

© IPNA 2008

Authors and Affiliations

  • Mai T. Nguyen
    • 1
  • Catherine L. Dent
    • 2
  • Gary F. Ross
    • 3
  • Nathan Harris
    • 4
  • Peter B. Manning
    • 5
  • Mark M. Mitsnefes
    • 1
  • Prasad Devarajan
    • 1
    • 6
  1. 1.Department of Pediatrics, Division of Nephrology and Hypertension, Cincinnati Children’s Hospital Medical CenterUniversity of Cincinnati College of MedicineCincinnatiUSA
  2. 2.Department of Pediatrics, Division of Cardiology, Cincinnati Children’s Hospital Medical CenterUniversity of Cincinnati College of MedicineCincinnatiUSA
  3. 3.Bio-Rad LaboratoriesHerculesUSA
  4. 4.Ciphergen BiosystemsFremontUSA
  5. 5.Department of Surgery, Division of Cardiothoracic Surgery, Cincinnati Children’s Hospital Medical CenterUniversity of Cincinnati College of MedicineCincinnatiUSA
  6. 6.MLC 7022CincinnatiUSA

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