Official reprint from UpToDate®
www.uptodate.com ©2018 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Possible prevention and therapy of ischemic acute tubular necrosis

Tushar A Chopra, MD
Mark D Okusa, MD
Section Editor
Paul M Palevsky, MD
Deputy Editor
Alice M Sheridan, MD


Acute kidney injury (AKI) due to ischemic acute tubular necrosis (ATN) typically lasts 7 to 21 days [1], with most patients returning to or near their previous baseline level of renal function as the necrotic tubular cells regenerate.

Possible preventive and therapeutic measures for ischemic ATN will be reviewed here.

The pathogenesis and prognosis of ATN are discussed separately. (See "Kidney and patient outcomes after acute kidney injury in adults" and "Pathogenesis and etiology of ischemic acute tubular necrosis".)


AKI is characterized by an acute reduction of glomerular filtration rate (GFR) and defined by a rise in the serum creatinine concentration or a decline in urine output that has developed within hours to days (table 1). (See "Definition and staging criteria of acute kidney injury in adults".)

AKI is commonly, though not always, caused by ATN, particularly among critically ill hospitalized patients.

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Dec 2017. | This topic last updated: Jan 05, 2018.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2018 UpToDate, Inc.
  1. Myers BD, Moran SM. Hemodynamically mediated acute renal failure. N Engl J Med 1986; 314:97.
  2. Rosner MH, Okusa MD. Acute kidney injury associated with cardiac surgery. Clin J Am Soc Nephrol 2006; 1:19.
  3. Billings FT 4th, Pretorius M, Schildcrout JS, et al. Obesity and oxidative stress predict AKI after cardiac surgery. J Am Soc Nephrol 2012; 23:1221.
  4. Onorati F, Presta P, Fuiano G, et al. A randomized trial of pulsatile perfusion using an intra-aortic balloon pump versus nonpulsatile perfusion on short-term changes in kidney function during cardiopulmonary bypass during myocardial reperfusion. Am J Kidney Dis 2007; 50:229.
  5. Thakar CV, Arrigain S, Worley S, et al. A clinical score to predict acute renal failure after cardiac surgery. J Am Soc Nephrol 2005; 16:162.
  6. Berns AS. Nephrotoxicity of contrast media. Kidney Int 1989; 36:730.
  7. James MT, Hemmelgarn BR, Wiebe N, et al. Glomerular filtration rate, proteinuria, and the incidence and consequences of acute kidney injury: a cohort study. Lancet 2010; 376:2096.
  8. Girman CJ, Kou TD, Brodovicz K, et al. Risk of acute renal failure in patients with Type 2 diabetes mellitus. Diabet Med 2012; 29:614.
  9. Oezkur M, Wagner M, Weismann D, et al. Chronic hyperglycemia is associated with acute kidney injury in patients undergoing CABG surgery--a cohort study. BMC Cardiovasc Disord 2015; 15:41.
  10. Candela-Toha A, Elías-Martín E, Abraira V, et al. Predicting acute renal failure after cardiac surgery: external validation of two new clinical scores. Clin J Am Soc Nephrol 2008; 3:1260.
  11. Sinha Ray A, Haikal A, Hammoud KA, Yu AS. Vancomycin and the Risk of AKI: A Systematic Review and Meta-Analysis. Clin J Am Soc Nephrol 2016; 11:2132.
  12. Burgess LD, Drew RH. Comparison of the incidence of vancomycin-induced nephrotoxicity in hospitalized patients with and without concomitant piperacillin-tazobactam. Pharmacotherapy 2014; 34:670.
  13. Brienza N, Giglio MT, Marucci M, Fiore T. Does perioperative hemodynamic optimization protect renal function in surgical patients? A meta-analytic study. Crit Care Med 2009; 37:2079.
  14. Mahmood A, Gosling P, Vohra RK. Randomized clinical trial comparing the effects on renal function of hydroxyethyl starch or gelatine during aortic aneurysm surgery. Br J Surg 2007; 94:427.
  15. Ragaller MJ, Theilen H, Koch T. Volume replacement in critically ill patients with acute renal failure. J Am Soc Nephrol 2001; 12 Suppl 17:S33.
  16. Boldt J, Brenner T, Lehmann A, et al. Influence of two different volume replacement regimens on renal function in elderly patients undergoing cardiac surgery: comparison of a new starch preparation with gelatin. Intensive Care Med 2003; 29:763.
  17. Stallwood MI, Grayson AD, Mills K, Scawn ND. Acute renal failure in coronary artery bypass surgery: independent effect of cardiopulmonary bypass. Ann Thorac Surg 2004; 77:968.
  18. Chawla LS, Zhao Y, Lough FC, et al. Off-pump versus on-pump coronary artery bypass grafting outcomes stratified by preoperative renal function. J Am Soc Nephrol 2012; 23:1389.
  19. Wijeysundera DN, Beattie WS, Djaiani G, et al. Off-pump coronary artery surgery for reducing mortality and morbidity: meta-analysis of randomized and observational studies. J Am Coll Cardiol 2005; 46:872.
  20. Straka Z, Widimsky P, Jirasek K, et al. Off-pump versus on-pump coronary surgery: final results from a prospective randomized study PRAGUE-4. Ann Thorac Surg 2004; 77:789.
  21. Tang AT, Knott J, Nanson J, et al. A prospective randomized study to evaluate the renoprotective action of beating heart coronary surgery in low risk patients. Eur J Cardiothorac Surg 2002; 22:118.
  22. Chukwuemeka A, Weisel A, Maganti M, et al. Renal dysfunction in high-risk patients after on-pump and off-pump coronary artery bypass surgery: a propensity score analysis. Ann Thorac Surg 2005; 80:2148.
  23. Seabra VF, Alobaidi S, Balk EM, et al. Off-pump coronary artery bypass surgery and acute kidney injury: a meta-analysis of randomized controlled trials. Clin J Am Soc Nephrol 2010; 5:1734.
  24. Di Mauro M, Gagliardi M, Iacò AL, et al. Does off-pump coronary surgery reduce postoperative acute renal failure? The importance of preoperative renal function. Ann Thorac Surg 2007; 84:1496.
  25. Lamy A, Devereaux PJ, Prabhakaran D, et al. Off-pump or on-pump coronary-artery bypass grafting at 30 days. N Engl J Med 2012; 366:1489.
  26. Garg AX, Devereaux PJ, Yusuf S, et al. Kidney function after off-pump or on-pump coronary artery bypass graft surgery: a randomized clinical trial. JAMA 2014; 311:2191.
  27. Lassnigg A, Donner E, Grubhofer G, et al. Lack of renoprotective effects of dopamine and furosemide during cardiac surgery. J Am Soc Nephrol 2000; 11:97.
  28. Ho KM, Sheridan DJ. Meta-analysis of frusemide to prevent or treat acute renal failure. BMJ 2006; 333:420.
  29. Mahesh B, Yim B, Robson D, et al. Does furosemide prevent renal dysfunction in high-risk cardiac surgical patients? Results of a double-blinded prospective randomised trial. Eur J Cardiothorac Surg 2008; 33:370.
  30. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Int Suppl 2012; 2:8.
  31. Hanley MJ, Davidson K. Prior mannitol and furosemide infusion in a model of ischemic acute renal failure. Am J Physiol 1981; 241:F556.
  32. Schrier RW, Arnold PE, Gordon JA, Burke TJ. Protection of mitochondrial function by mannitol in ischemic acute renal failure. Am J Physiol 1984; 247:F365.
  33. Escalante B, Erlij D, Falck JR, McGiff JC. Effect of cytochrome P450 arachidonate metabolites on ion transport in rabbit kidney loop of Henle. Science 1991; 251:799.
  34. Luke RG, Briggs JD, Allison ME, Kennedy AC. Factors determining response to mannitol in acute renal failure. Am J Med Sci 1970; 259:168.
  35. Graziani G, Cantaluppi A, Casati S, et al. Dopamine and frusemide in oliguric acute renal failure. Nephron 1984; 37:39.
  36. Szerlip HM. Renal-dose dopamine: fact and fiction. Ann Intern Med 1991; 115:153.
  37. Nisula S, Kaukonen KM, Vaara ST, et al. Incidence, risk factors and 90-day mortality of patients with acute kidney injury in Finnish intensive care units: the FINNAKI study. Intensive Care Med 2013; 39:420.
  38. Marenzi G, Ferrari C, Marana I, et al. Prevention of contrast nephropathy by furosemide with matched hydration: the MYTHOS (Induced Diuresis With Matched Hydration Compared to Standard Hydration for Contrast Induced Nephropathy Prevention) trial. JACC Cardiovasc Interv 2012; 5:90.
  39. Briguori C, Visconti G, Focaccio A, et al. Renal Insufficiency After Contrast Media Administration Trial II (REMEDIAL II): RenalGuard System in high-risk patients for contrast-induced acute kidney injury. Circulation 2011; 124:1260.
  40. Barbanti M, Gulino S, Capranzano P, et al. Acute Kidney Injury With the RenalGuard System in Patients Undergoing Transcatheter Aortic Valve Replacement: The PROTECT-TAVI Trial (PROphylactic effecT of furosEmide-induCed diuresis with matched isotonic intravenous hydraTion in Transcatheter Aortic Valve Implantation). JACC Cardiovasc Interv 2015; 8:1595.
  41. Friedrich JO, Adhikari N, Herridge MS, Beyene J. Meta-analysis: low-dose dopamine increases urine output but does not prevent renal dysfunction or death. Ann Intern Med 2005; 142:510.
  42. Marik PE, Iglesias J. Low-dose dopamine does not prevent acute renal failure in patients with septic shock and oliguria. NORASEPT II Study Investigators. Am J Med 1999; 107:387.
  43. Bellomo R, Chapman M, Finfer S, et al. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet 2000; 356:2139.
  44. Lauschke A, Teichgräber UK, Frei U, Eckardt KU. 'Low-dose' dopamine worsens renal perfusion in patients with acute renal failure. Kidney Int 2006; 69:1669.
  45. Baldwin L, Henderson A, Hickman P. Effect of postoperative low-dose dopamine on renal function after elective major vascular surgery. Ann Intern Med 1994; 120:744.
  46. Argalious M, Motta P, Khandwala F, et al. "Renal dose" dopamine is associated with the risk of new-onset atrial fibrillation after cardiac surgery. Crit Care Med 2005; 33:1327.
  47. Hoffman TM, Bush DM, Wernovsky G, et al. Postoperative junctional ectopic tachycardia in children: incidence, risk factors, and treatment. Ann Thorac Surg 2002; 74:1607.
  48. Friedewald JJ, Rabb H. Inflammatory cells in ischemic acute renal failure. Kidney Int 2004; 66:486.
  49. Noiri E, Gailit J, Sheth D, et al. Cyclic RGD peptides ameliorate ischemic acute renal failure in rats. Kidney Int 1994; 46:1050.
  50. Ranucci M, Soro G, Barzaghi N, et al. Fenoldopam prophylaxis of postoperative acute renal failure in high-risk cardiac surgery patients. Ann Thorac Surg 2004; 78:1332.
  51. Bove T, Landoni G, Calabrò MG, et al. Renoprotective action of fenoldopam in high-risk patients undergoing cardiac surgery: a prospective, double-blind, randomized clinical trial. Circulation 2005; 111:3230.
  52. Brienza N, Malcangi V, Dalfino L, et al. A comparison between fenoldopam and low-dose dopamine in early renal dysfunction of critically ill patients. Crit Care Med 2006; 34:707.
  53. Morelli A, Ricci Z, Bellomo R, et al. Prophylactic fenoldopam for renal protection in sepsis: a randomized, double-blind, placebo-controlled pilot trial. Crit Care Med 2005; 33:2451.
  54. Landoni G, Biondi-Zoccai GG, Tumlin JA, et al. Beneficial impact of fenoldopam in critically ill patients with or at risk for acute renal failure: a meta-analysis of randomized clinical trials. Am J Kidney Dis 2007; 49:56.
  55. Roasio A, Lobreglio R, Santin A, et al. Fenoldopam reduces the incidence of renal replacement therapy after cardiac surgery. J Cardiothorac Vasc Anesth 2008; 22:23.
  56. Zangrillo A, Biondi-Zoccai GG, Frati E, et al. Fenoldopam and acute renal failure in cardiac surgery: a meta-analysis of randomized placebo-controlled trials. J Cardiothorac Vasc Anesth 2012; 26:407.
  57. Bove T, Zangrillo A, Guarracino F, et al. Effect of fenoldopam on use of renal replacement therapy among patients with acute kidney injury after cardiac surgery: a randomized clinical trial. JAMA 2014; 312:2244.
  58. Gillies MA, Kakar V, Parker RJ, et al. Fenoldopam to prevent acute kidney injury after major surgery-a systematic review and meta-analysis. Crit Care 2015; 19:449.
  59. Nigwekar SU, Hix JK. The role of natriuretic peptide administration in cardiovascular surgery-associated renal dysfunction: a systematic review and meta-analysis of randomized controlled trials. J Cardiothorac Vasc Anesth 2009; 23:151.
  60. Nigwekar SU, Navaneethan SD, Parikh CR, Hix JK. Atrial natriuretic peptide for preventing and treating acute kidney injury. Cochrane Database Syst Rev 2009; :CD006028.
  61. Nigwekar SU, Navaneethan SD, Parikh CR, Hix JK. Atrial natriuretic peptide for management of acute kidney injury: a systematic review and meta-analysis. Clin J Am Soc Nephrol 2009; 4:261.
  62. Sezai A, Hata M, Niino T, et al. Results of low-dose human atrial natriuretic peptide infusion in nondialysis patients with chronic kidney disease undergoing coronary artery bypass grafting: the NU-HIT (Nihon University working group study of low-dose HANP Infusion Therapy during cardiac surgery) trial for CKD. J Am Coll Cardiol 2011; 58:897.
  63. Gordon AC, Mason AJ, Thirunavukkarasu N, et al. Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock: The VANISH Randomized Clinical Trial. JAMA 2016; 316:509.
  64. Adabag AS, Ishani A, Bloomfield HE, et al. Efficacy of N-acetylcysteine in preventing renal injury after heart surgery: a systematic review of randomized trials. Eur Heart J 2009; 30:1910.
  65. Baker WL, Anglade MW, Baker EL, et al. Use of N-acetylcysteine to reduce post-cardiothoracic surgery complications: a meta-analysis. Eur J Cardiothorac Surg 2009; 35:521.
  66. Ho KM, Morgan DJ. Meta-analysis of N-acetylcysteine to prevent acute renal failure after major surgery. Am J Kidney Dis 2009; 53:33.
  67. Fraga CM, Tomasi CD, Damasio DC, et al. N-acetylcysteine plus deferoxamine for patients with prolonged hypotension does not decrease acute kidney injury incidence: a double blind, randomized, placebo-controlled trial. Crit Care 2016; 20:331.
  68. Song JW, Shim JK, Soh S, et al. Double-blinded, randomized controlled trial of N-acetylcysteine for prevention of acute kidney injury in high risk patients undergoing off-pump coronary artery bypass. Nephrology (Carlton) 2015; 20:96.
  69. van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001; 345:1359.
  70. Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med 2006; 354:449.
  71. Wang LC, Lei S, Wu YC, et al. [Intensive insulin therapy in critically ill patients]. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 2006; 18:748.
  72. Schetz M, Vanhorebeek I, Wouters PJ, et al. Tight blood glucose control is renoprotective in critically ill patients. J Am Soc Nephrol 2008; 19:571.
  73. NICE-SUGAR Study Investigators, Finfer S, Chittock DR, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009; 360:1283.
  74. Thomas G, Rojas MC, Epstein SK, et al. Insulin therapy and acute kidney injury in critically ill patients a systematic review. Nephrol Dial Transplant 2007; 22:2849.
  75. Brunkhorst FM, Engel C, Bloos F, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008; 358:125.
  76. Venugopal V, Laing CM, Ludman A, et al. Effect of remote ischemic preconditioning on acute kidney injury in nondiabetic patients undergoing coronary artery bypass graft surgery: a secondary analysis of 2 small randomized trials. Am J Kidney Dis 2010; 56:1043.
  77. Zimmerman RF, Ezeanuna PU, Kane JC, et al. Ischemic preconditioning at a remote site prevents acute kidney injury in patients following cardiac surgery. Kidney Int 2011; 80:861.
  78. Ali ZA, Callaghan CJ, Lim E, et al. Remote ischemic preconditioning reduces myocardial and renal injury after elective abdominal aortic aneurysm repair: a randomized controlled trial. Circulation 2007; 116:I98.
  79. Deftereos S, Giannopoulos G, Tzalamouras V, et al. Renoprotective effect of remote ischemic post-conditioning by intermittent balloon inflations in patients undergoing percutaneous coronary intervention. J Am Coll Cardiol 2013; 61:1949.
  80. Choi YS, Shim JK, Kim JC, et al. Effect of remote ischemic preconditioning on renal dysfunction after complex valvular heart surgery: a randomized controlled trial. J Thorac Cardiovasc Surg 2011; 142:148.
  81. Hausenloy DJ, Candilio L, Evans R, et al. Remote Ischemic Preconditioning and Outcomes of Cardiac Surgery. N Engl J Med 2015; 373:1408.
  82. Meybohm P, Bein B, Brosteanu O, et al. A Multicenter Trial of Remote Ischemic Preconditioning for Heart Surgery. N Engl J Med 2015; 373:1397.
  83. Yang Y, Lang XB, Zhang P, et al. Remote ischemic preconditioning for prevention of acute kidney injury: a meta-analysis of randomized controlled trials. Am J Kidney Dis 2014; 64:574.
  84. Hu J, Liu S, Jia P, et al. Protection of remote ischemic preconditioning against acute kidney injury: a systematic review and meta-analysis. Crit Care 2016; 20:111.
  85. Zhou C, Jeon Y, Meybohm P, et al. Renoprotection by remote ischemic conditioning during elective coronary revascularization: A systematic review and meta-analysis of randomized controlled trials. Int J Cardiol 2016; 222:295.
  86. Pan JS, Sheikh-Hamad D. Remote ischemic preconditioning for kidney protection. JAMA 2015; 313:2124.
  87. Menting TP, Wever KE, Ozdemir-van Brunschot DM, et al. Ischaemic preconditioning for the reduction of renal ischaemia reperfusion injury. Cochrane Database Syst Rev 2017; 3:CD010777.
  88. Haase M, Haase-Fielitz A, Bellomo R, et al. Sodium bicarbonate to prevent increases in serum creatinine after cardiac surgery: a pilot double-blind, randomized controlled trial. Crit Care Med 2009; 37:39.
  89. McGuinness SP, Parke RL, Bellomo R, et al. Sodium bicarbonate infusion to reduce cardiac surgery-associated acute kidney injury: a phase II multicenter double-blind randomized controlled trial. Crit Care Med 2013; 41:1599.
  90. Haase M, Haase-Fielitz A, Plass M, et al. Prophylactic perioperative sodium bicarbonate to prevent acute kidney injury following open heart surgery: a multicenter double-blinded randomized controlled trial. PLoS Med 2013; 10:e1001426.
  91. Molnar AO, Coca SG, Devereaux PJ, et al. Statin use associates with a lower incidence of acute kidney injury after major elective surgery. J Am Soc Nephrol 2011; 22:939.
  92. Brunelli SM, Waikar SS, Bateman BT, et al. Preoperative statin use and postoperative acute kidney injury. Am J Med 2012; 125:1195.
  93. Layton JB, Kshirsagar AV, Simpson RJ Jr, et al. Effect of statin use on acute kidney injury risk following coronary artery bypass grafting. Am J Cardiol 2013; 111:823.
  94. Billings FT 4th, Hendricks PA, Schildcrout JS, et al. High-Dose Perioperative Atorvastatin and Acute Kidney Injury Following Cardiac Surgery: A Randomized Clinical Trial. JAMA 2016; 315:877.
  95. Prowle JR, Calzavacca P, Licari E, et al. Pilot double-blind, randomized controlled trial of short-term atorvastatin for prevention of acute kidney injury after cardiac surgery. Nephrology (Carlton) 2012; 17:215.
  96. Garg AX, Vincent J, Cuerden M, et al. Steroids In caRdiac Surgery (SIRS) trial: acute kidney injury substudy protocol of an international randomised controlled trial. BMJ Open 2014; 4:e004842.
  97. 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.
  98. Mehta RL, Pascual MT, Soroko S, et al. Diuretics, mortality, and nonrecovery of renal function in acute renal failure. JAMA 2002; 288:2547.
  99. Cantarovich F, Rangoonwala B, Lorenz H, et al. High-dose furosemide for established ARF: a prospective, randomized, double-blind, placebo-controlled, multicenter trial. Am J Kidney Dis 2004; 44:402.
  100. Brown CB, Ogg CS, Cameron JS. High dose frusemide in acute renal failure: a controlled trial. Clin Nephrol 1981; 15:90.
  101. van der Voort PH, Boerma EC, Koopmans M, et al. Furosemide does not improve renal recovery after hemofiltration for acute renal failure in critically ill patients: a double blind randomized controlled trial. Crit Care Med 2009; 37:533.
  102. Uchino S, Doig GS, Bellomo R, et al. Diuretics and mortality in acute renal failure. Crit Care Med 2004; 32:1669.
  103. Wu VC, Lai CF, Shiao CC, et al. Effect of diuretic use on 30-day postdialysis mortality in critically ill patients receiving acute dialysis. PLoS One 2012; 7:e30836.
  104. Lameire N, Vanholder R, Van Biesen W. Loop diuretics for patients with acute renal failure: helpful or harmful? JAMA 2002; 288:2599.
  105. Tumlin JA, Finkel KW, Murray PT, et al. Fenoldopam mesylate in early acute tubular necrosis: a randomized, double-blind, placebo-controlled clinical trial. Am J Kidney Dis 2005; 46:26.
  106. Rahman SN, Kim GE, Mathew AS, et al. Effects of atrial natriuretic peptide in clinical acute renal failure. Kidney Int 1994; 45:1731.
  107. Allgren RL, Marbury TC, Rahman SN, et al. Anaritide in acute tubular necrosis. Auriculin Anaritide Acute Renal Failure Study Group. N Engl J Med 1997; 336:828.
  108. Lewis J, Salem MM, Chertow GM, et al. Atrial natriuretic factor in oliguric acute renal failure. Anaritide Acute Renal Failure Study Group. Am J Kidney Dis 2000; 36:767.
  109. Swärd K, Valsson F, Odencrants P, et al. Recombinant human atrial natriuretic peptide in ischemic acute renal failure: a randomized placebo-controlled trial. Crit Care Med 2004; 32:1310.
  110. Acker CG, Singh AR, Flick RP, et al. A trial of thyroxine in acute renal failure. Kidney Int 2000; 57:293.
  111. Beumer C, Wulferink M, Raaben W, et al. Calf intestinal alkaline phosphatase, a novel therapeutic drug for lipopolysaccharide (LPS)-mediated diseases, attenuates LPS toxicity in mice and piglets. J Pharmacol Exp Ther 2003; 307:737.
  112. Bentala H, Verweij WR, Huizinga-Van der Vlag A, et al. Removal of phosphate from lipid A as a strategy to detoxify lipopolysaccharide. Shock 2002; 18:561.
  113. Koyama I, Matsunaga T, Harada T, et al. Alkaline phosphatases reduce toxicity of lipopolysaccharides in vivo and in vitro through dephosphorylation. Clin Biochem 2002; 35:455.
  114. van Veen SQ, van Vliet AK, Wulferink M, et al. Bovine intestinal alkaline phosphatase attenuates the inflammatory response in secondary peritonitis in mice. Infect Immun 2005; 73:4309.
  115. Su F, Brands R, Wang Z, et al. Beneficial effects of alkaline phosphatase in septic shock. Crit Care Med 2006; 34:2182.
  116. Heemskerk S, Masereeuw R, Moesker O, et al. Alkaline phosphatase treatment improves renal function in severe sepsis or septic shock patients. Crit Care Med 2009; 37:417.
  117. Hirschberg R, Kopple J, Lipsett P, et al. Multicenter clinical trial of recombinant human insulin-like growth factor I in patients with acute renal failure. Kidney Int 1999; 55:2423.