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Vol. 28, No. 4, 2008
Issue release date: June 2008
Am J Nephrol 2008;28:576–582

Increased Incidence of Acute Kidney Injury with Aprotinin Use during Cardiac Surgery Detected with Urinary NGAL

Wagener G. · Gubitosa G. · Wang S. · Borregaard N. · Kim M. · Lee H.T.
aDepartment of Anesthesiology, College of Physicians and Surgeons, and bDepartment of Biostatistics, Mailman School of Public Heath, Columbia University, New York, N.Y., USA; cDepartment of Hematology, Rigshospitalet, Copenhagen, Denmark

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Background: Use of aprotinin has been associated with acute kidney injury after cardiac surgery. Neutrophil gelatinase-associated lipocalin (NGAL) is a novel, very sensitive marker for renal injury. Urinary NGAL may be able to detect renal injury caused by aprotinin. This study determined if the use of aprotinin is associated with an increased incidence of acute kidney injury and increased levels of urinary NGAL. Methods: In this prospective, observational study 369 patients undergoing cardiac surgery were enrolled. 205 patients received aprotinin and 164 received epsilon amino-caproic acid intraoperatively. Urinary NGAL was measured before and immediately after cardiac surgery and 3, 18 and 24 h later. The association of aprotinin use with the incidence of acute kidney injury (increase of serum creatinine >0.5 mg/dl) and NGAL levels was determined using logistic and linear regression models. Results: 51 of 205 patients (25%) who received aprotinin developed acute kidney injury compared to 19 of 164 patients (12%) who received epsilon amino-caproic acid (p = 0.0013). Aprotinin use was associated with a two-fold higher risk of acute kidney injury when adjusted for potential confounders (age, Parsonnet score, preoperative serum creatinine, cardiopulmonary bypass and cross-clamp times; multiple logistic regression: OR = 2.164; CI (95%) = 1.102 to 4.249; p = 0.0249. Urinary NGAL was 19 times higher immediately after cardiopulmonary bypass and 18 times higher 3 h later in patients who had received aprotinin (postoperative: 19.23; CI (95%) = 12.60 to 29.33; p < 0.0001; 3 h post-cardiopulmonary bypass 18.67; CI (95%) = 11.45 to 30.43; p < 0.0001). Conclusions: Postoperative urinary NGAL – a novel marker for renal injury – is increased in cardiac surgical patients receiving aprotinin compared to patients receiving epsilon amino-caproic acid. These results further support the hypothesis that aprotinin may cause renal injury. The substantial rise of urinary NGAL associated with aprotinin use may in part be due to aprotinin blocking the uptake of NGAL by megalin/gp330 receptors in the proximal tubules.

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Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
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  1. Alajmo F, Calamai G, Perna AM, Melissano G, Pretelli P, Palmarini MF, Carbonetto F, Noferi D, Boddi V, Palminiello A, et al: High-dose aprotinin: hemostatic effects in open heart operations. Ann Thorac Surg 1989;48:536–539.
  2. Henry DA, Moxey AJ, Carless PA, O’Connell D, McClelland B, Henderson KM, Sly K, Laupacis A, Fergusson D: Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2001:CD001886.
  3. Sedrakyan A, Treasure T, Elefteriades JA: 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 2004;128:442–448.
  4. Mangano DT, Tudor IC, Dietzel C: The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006;354:353–365.
  5. 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: Mortality associated with aprotinin during 5 years following coronary artery bypass graft surgery. JAMA 2007;297:471–479.
  6. Wagener G, Jan M, Kim M, Mori K, Barasch JM, Sladen RN, Lee HT: Association between increases in urinary neutrophil gelatinase-associated lipocalin and acute renal dysfunction after adult cardiac surgery. Anesthesiology 2006;105:485–491.
  7. 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: Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet 2005;365:1231–1238.
  8. Suen WS, Mok CK, Chiu SW, Cheung KL, Lee WT, Cheung D, Das SR, He GW: Risk factors for development of acute renal failure (ARF) requiring dialysis in patients undergoing cardiac surgery. Angiology 1998;49:789–800.
  9. Lawrence DR, Valencia O, Smith EE, Murday A, Treasure T: Parsonnet score is a good predictor of the duration of intensive care unit stay following cardiac surgery. Heart 2000;83:429–432.
  10. Parsonnet V, Dean D, Bernstein AD: A method of uniform stratification of risk for evaluating the results of surgery in acquired adult heart disease. Circulation 1989;79:I3–I12.
  11. Kjeldsen L, Koch C, Arnljots K, Borregaard N: Characterization of two ELISAs for NGAL, a newly described lipocalin in human neutrophils. J Immunol Methods 1996;198:155–164.
  12. Shah BR, Laupacis A, Hux JE, Austin PC : Propensity score methods gave similar results to traditional regression modeling in observational studies: a systematic review. J Clin Epidemiol 2005;58:550–559.
  13. Harrell FE Jr, Lee KL, Mark DB: Multivariable prognostic models: Issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Stat Med 1996;15:361–387.
  14. Harrell FE Jr, Lee KL, Matchar DB, Reichert TA: Regression models for prognostic prediction: advantages, problems, and suggested solutions. Cancer Treat Rep 1985;69:1071–1077.

    External Resources

  15. Peduzzi P, Concato J, Kemper E, Holford TR, Feinstein AR: A simulation study of the number of events per variable in logistic regression analysis. J Clin Epidemiol 1996;49:1373–1379.
  16. Mishra J, Ma Q, Prada A, Mitsnefes M, Zahedi K, Yang J, Barasch J, Devarajan P: Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury. J Am Soc Nephrol 2003;14:2534–2543.
  17. Mori K, Lee HT, Rapoport D, Drexler IR, Foster K, Yang J, Schmidt-Ott KM, Chen X, Li JY, Weiss S, Mishra J, Cheema FH, Markowitz G, Suganami T, Sawai K, Mukoyama M, Kunis C, D’Agati V, Devarajan P, Barasch J: Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury. J Clin Invest 2005;115:610–621.
  18. Schmidt-Ott KM, Mori K, Li JY, Kalandadze A, Cohen DJ, Devarajan P, Barasch J: Dual action of neutrophil gelatinase-associated lipocalin. J Am Soc Nephrol 2007;18:407–413.
  19. Tong Z, Wu X, Ovcharenko D, Zhu J, Chen CS, Kehrer JP: Neutrophil gelatinase-associated lipocalin as a survival factor. Biochem J 2005;391:441–448.
  20. Gaudino M, Luciani N, Giungi S, Caradonna E, Nasso G, Schiavello R, Luciani G, Possati G: Different profiles of patients who require dialysis after cardiac surgery. Ann Thorac Surg 2005;79:825–829; author reply 829–830.
  21. Nguyen MT, Devarajan P: Biomarkers for the early detection of acute kidney injury. Pediatr Nephrol 2007;in press.
  22. Moestrup SK, Cui S, Vorum H, Bregengard C, Bjorn SE, Norris K, Gliemann J, Christensen EI: Evidence that epithelial glycoprotein 330/megalin mediates uptake of polybasic drugs. J Clin Invest 1995;96:1404–1413.
  23. Hvidberg V, Jacobsen C, Strong RK, Cowland JB, Moestrup SK, Borregaard N: The endocytic receptor megalin binds the iron transporting neutrophil-gelatinase-associated lipocalin with high affinity and mediates its cellular uptake. FEBS Lett 2005;579:773–777.
  24. Borregaard N, Cowland JB: Neutrophil gelatinase-associated lipocalin, a siderophore-binding eukaryotic protein. Biometals 2006;19:211–215.

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