Korean Circ J.  2011 Dec;41(12):695-702. 10.4070/kcj.2011.41.12.695.

N-acetylcysteine for Prevention of Contrast-Induced Nephropathy: A Narrative Review

• Jo SH

• KMID: 1776243
• DOI: http://doi.org/10.4070/kcj.2011.41.12.695

Abstract

Contrast-induced nephropathy (CIN) affects in-hospital, short- and long-term morbidity and mortality. It also leads to prolonged hospital stay and increased medical cost. Given the potential clinical severity of CIN, there has been considerable interest in the development of preventative strategies to reduce the risk of contrast-induced renal deterioration in at-risk populations. A number of pharmacologic and mechanical preventive measures have been attempted, but no method other than adequate periprocedural hydration has been conclusively successful. Since its introduction in 2000, N-acetylcysteine (NAC) has been widely investigated, albeit with conflicting findings for its nephroprotection capability in patients receiving contrast media procedures. However, there is still virtually no definitive evidence of effectiveness of NAC. Although the exact mechanism responsible for the protective action of NAC from renal function deterioration remains unclear, the antioxidant and vasodilatory properties of NAC have been suggested as the main mechanisms. This review summarizes the current status of NAC as a potential agent to prevent renal functional deterioration and its limitations.

Keyword

Acetylcysteine; Renal insufficiency; Contrast media; Angiography; Prevention

MeSH Terms

Acetylcysteine
Angiography
Contrast Media
Humans
Length of Stay
Renal Insufficiency
Acetylcysteine
Contrast Media

Figure

• 

  Fig. 1 Linear trends for low rate of contrast-induced nephropathy by dose of NAC and by normal and reduced creatinine clearance rates (>60 mL/min and ≤60 mL/min, respectively). The p values refer to comparisons among the placebo group, the group receiving a standard dose of NAC, and the group receiving a double dose of NAC (calculated with the use of chi-square for trend). No significant interactions were found between groups and creatinine clearance (p=0.25).73) NAC: N-acetylcysteine, CCr: creatinine clearance rate.

Reference

1. Murphy SW, Barrett BJ, Parfrey PS. Contrast nephropathy. J Am Soc Nephrol. 2000. 11:177–182.

2. Nash K, Hafeez A, Hou S. Hospital-acquired renal insufficiency. Am J Kidney Dis. 2002. 39:930–936.

3. McCullough PA, Wolyn R, Rocher LL, Levin RN, O'Neill WW. Acute renal failure after coronary intervention: incidence, risk factors, and relationship to mortality. Am J Med. 1997. 103:368–375.

4. Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis. 1998. 32:5 Suppl 3. S112–S119.

5. Rihal CS, Textor SC, Grill DE, et al. Incidence and prognostic importance of acute renal failure after percutaneous coronary intervention. Circulation. 2002. 105:2259–2264.

6. Manske CL, Sprafka JM, Strony JT, Wang Y. Contrast nephropathy in azotemic diabetic patients undergoing coronary angiography. Am J Med. 1990. 89:615–620.

7. Rudnick MR, Goldfarb S, Wexler L, et al. Nephrotoxicity of ionic and nonionic contrast media in 1196 patients: a randomized trial: the Iohexol Cooperative Study. Kidney Int. 1995. 47:254–261.

8. Jo SH, Youn TJ, Koo BK, et al. Renal toxicity evaluation and comparison between visipaque (iodixanol) and hexabrix (ioxaglate) in patients with renal insufficiency undergoing coronary angiography: the RECOVER Study: a randomized controlled trial. J Am Coll Cardiol. 2006. 48:924–930.

9. McCullough PA, Bertrand ME, Brinker JA, Stacul F. A meta-analysis of the renal safety of isosmolar iodixanol compared with low-osmolar contrast media. J Am Coll Cardiol. 2006. 48:692–699.

10. Merten GJ, Burgess WP, Gray LV, et al. Prevention of contrast-induced nephropathy with sodium bicarbonate: a randomized controlled trial. JAMA. 2004. 291:2328–2334.

11. Mueller C, Buerkle G, Buettner HJ, et al. Prevention of contrast media-associated nephropathy: randomized comparison of 2 hydration regimens in 1620 patients undergoing coronary angioplasty. Arch Intern Med. 2002. 162:329–336.

12. Stevens MA, McCullough PA, Tobin KJ, et al. A prospective randomiz-ed trial of prevention measures in patients at high risk for contrast nephropathy: results of the P.R.I.N.C.E. Study: Prevention of Radiocontrast Induced Nephropathy Clinical Evaluation. J Am Coll Cardiol. 1999. 33:403–411.

13. Solomon R, Werner C, Mann D, D'Elia J, Silva P. Effects of saline, mannitol, and furosemide to prevent acute decreases in renal function induced by radiocontrast agents. N Engl J Med. 1994. 331:1416–1420.

14. Weinstein JM, Heyman S, Brezis M. Potential deleterious effect of furosemide in radiocontrast nephropathy. Nephron. 1992. 62:413–415.

15. Gare M, Haviv YS, Ben-Yehuda A, et al. The renal effect of low-dose dopamine in high-risk patients undergoing coronary angiography. J Am Coll Cardiol. 1999. 34:1682–1688.

16. Stone GW, McCullough PA, Tumlin JA, et al. Fenoldopam mesylate for the prevention of contrast-induced nephropathy: a randomized controlled trial. JAMA. 2003. 290:2284–2291.

17. Russo D, Testa A, Della Volpe L, Sansone G. Randomised prospective study on renal effects of two different contrast media in humans: protective role of a calcium channel blocker. Nephron. 1990. 55:254–257.

18. Huber W, Schipek C, Ilgmann K, et al. Effectiveness of theophylline prophylaxis of renal impairment after coronary angiography in patients with chronic renal insufficiency. Am J Cardiol. 2003. 91:1157–1162.

19. McCullough PA, Wolyn R, Rocher LL, Levin RN, O'Neill WW. Acute renal failure after coronary intervention: incidence, risk factors, and relationship to mortality. Am J Med. 1997. 103:368–375.

20. Tepel M, van der Giet M, Schwarzfeld C, Laufer U, Liermann D, Zidek W. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med. 2000. 343:180–184.

21. Briguori C, Colombo A, Violante A, et al. Standard vs double dose of N-acetylcysteine to prevent contrast agent associated nephrotoxicity. Eur Heart J. 2004. 25:206–211.

22. Cotgreave I, Moldéus P, Schuppe I. The metabolism of N-acetylcysteine by human endothelial cells. Biochem Pharmacol. 1991. 42:13–16.

23. Birck R, Krzossok S, Markowetz F, Schnülle P, van der Woude FJ, Braun C. Acetylcysteine for prevention of contrast nephropathy: meta-analysis. Lancet. 2003. 362:598–603.

24. Kelly AM, Dwamena B, Cronin P, Bernstein SJ, Carlos RC. Meta-analysis: effectiveness of drugs for preventing contrast-induced nephropathy. Ann Intern Med. 2008. 148:284–294.

25. Liu R, Nair D, Ix J, Moore DH, Bent S. N-acetylcysteine for the prevention of contrast-induced nephropathy: a systematic review and meta-analysis. J Gen Intern Med. 2005. 20:193–200.

26. Pannu N, Manns B, Lee H, Tonelli M. Systematic review of the impact of N-acetylcysteine on contrast nephropathy. Kidney Int. 2004. 65:1366–1374.

27. Nallamothu BK, Shojania KG, Saint S, et al. Is acetylcysteine effective in preventing contrast-related nephropathy? a meta-analysis. Am J Med. 2004. 117:938–947.

28. Trivedi H, Daram S, Szabo A, Bartorelli AL, Marenzi G. High-dose N-acetylcysteine for the prevention of contrast-induced nephropathy. Am J Med. 2009. 122:874.e9–874.e15.

29. Gonzales DA, Norsworthy KJ, Kern SJ, et al. A meta-analysis of N-acetylcysteine in contrast-induced nephrotoxicity: unsupervised clustering to resolve heterogeneity. BMC Med. 2007. 5:32.

30. Tepel M, Aspelin P, Lameire N. Contrast-induced nephropathy: a clinical and evidence-based approach. Circulation. 2006. 113:1799–1806.

31. Kshirsagar AV, Poole C, Mottl A, et al. N-acetylcysteine for the prevention of radiocontrast induced nephropathy: a meta-analysis of prospective controlled trials. J Am Soc Nephrol. 2004. 15:761–769.

32. Ozcan EE, Guneri S, Akdeniz B, et al. Sodium bicarbonate, N-acetylcysteine, and saline for prevention of radiocontrast-induced nephropathy: a comparison of 3 regimens for protecting contrast-induced neph-ropathy in patients undergoing coronary procedures: a single-center prospective controlled trial. Am Heart J. 2007. 154:539–544.

33. Barrett BJ, Parfrey PS. Prevention of nephrotoxicity induced by radiocontrast agents. N Engl J Med. 1994. 331:1449–1450.

34. Pannu N, Wiebe N, Tonelli M. Alberta Kidney Disease Network. Prophylaxis strategies for contrast-induced nephropathy. JAMA. 2006. 295:2765–2779.

35. Barrett BJ. Contrast nephrotoxicity. J Am Soc Nephrol. 1994. 5:125–137.

36. Baliga R, Ueda N, Walker PD, Shah SV. Oxidant mechanisms in toxic acute renal failure. Am J Kidney Dis. 1997. 29:465–477.

37. Bakris GL, Lass N, Gaber AO, Jones JD, Burnett JC Jr. Radiocontrast medium-induced declines in renal function: a role for oxygen free radicals. Am J Physiol. 1990. 258(1 Pt 2):F115–F120.

38. Messana JM, Cieslinski DA, Humes HD. Comparison of toxicity of radiocontrast agents to renal tubule cells in vitro. Ren Fail. 1990. 12:75–82.

39. Katholi RE, Woods WT Jr, Taylor GJ, et al. Oxygen free radicals and contrast nephropathy. Am J Kidney Dis. 1998. 32:64–71.

40. Yoshioka T, Fogo A, Beckman JK. Reduced activity of antioxidant enzymes underlies contrast media-induced renal injury in volume depletion. Kidney Int. 1992. 41:1008–1015.

41. DiMari J, Megyesi J, Udvarhelyi N, Price P, Davis R, Safirstein R. N-acetyl cysteine ameliorates ischemic renal failure. Am J Physiol. 1997. 272(3 Pt 2):F292–F298.

42. Salom MG, Ramírez P, Carbonell LF, et al. Protective effect of N-acetyl-L-cysteine on the renal failure induced by inferior vena cava occlusion. Transplantation. 1998. 65:1315–1321.

43. Arstall MA, Yang J, Stafford I, Betts WH, Horowitz JD. N-acetylcysteine in combination with nitroglycerin and streptokinase for the treatment of evolving acute myocardial infarction: safety and biochemical effects. Circulation. 1995. 92:2855–2862.

44. Pollman MJ, Hall JL, Gibbons GH. Determinants of vascular smooth muscle cell apoptosis after balloon angioplasty injury: influence of redox state and cell phenotype. Circ Res. 1999. 84:113–121.

45. Romano G, Briguori C, Quintavalle C, et al. Contrast agents and renal cell apoptosis. Eur Heart J. 2008. 29:2569–2576.

46. Lee HC, Sheu SH, Liu IH, et al. Impact of short-duration administration of N-acetylcysteine, probucol and ascorbic acid on contrast-induced cytotoxicity. J Nephrol. 2011. 04. 20. [Epub]. http://dx.doi.org/10.5301/JN.2011.7741.

47. Jo SH, Koo BK, Park JS, et al. N-acetylcysteine versus AScorbic acid for preventing contrast-Induced nephropathy in patients with renal insufficiency undergoing coronary angiography NASPI study-a prospective randomized controlled trial. Am Heart J. 2009. 157:576–583.

48. Briguori C, Airoldi F, D'Andrea D, et al. Renal Insufficiency Following Contrast Media Administration Trial (REMEDIAL): a randomized comparison of 3 preventive strategies. Circulation. 2007. 115:1211–1217.

49. Solomon R. Contrast-medium-induced acute renal failure. Kidney Int. 1998. 53:230–242.

50. Heyman SN, Reichman J, Brezis M. Pathophysiology of radiocontrast nephropathy: a role for medullary hypoxia. Invest Radiol. 1999. 34:685–691.

51. Yoshioka T, Fogo A, Beckman JK. Reduced activity of antioxidant enzymes underlies contrast media-induced renal injury in volume depletion. Kidney Int. 1992. 41:1008–1015.

52. Zhang H, Spapen H, Nguyen DN, Rogiers P, Bakker J, Vincent JL. Effects of N-acetyl-L-cysteine on regional blood flow during endotoxic shock. Eur Surg Res. 1995. 27:292–300.

53. Salom MG, Ramírez P, Carbonell LF, et al. Protective effect of N-acetyl-L-cysteine on the renal failure induced by inferior vena cava occlusion. Transplantation. 1998. 65:1315–1321.

54. Mehta A, Sekhon CP, Giri S, Orak JK, Singh AK. Attenuation of ischemia/reperfusion induced MAP kinases by N-acetyl cysteine, sodium nitroprusside and phosphoramidon. Mol Cell Biochem. 2002. 240:19–29.

55. Khachigian LM, Collins T, Fries JW. N-acetyl cysteine blocks mesangial VCAM-1 and NF-kappa B expression in vivo. Am J Pathol. 1997. 151:1225–1229.

56. Brady HR, Singer GG. Acute renal failure. Lancet. 1995. 346:1533–1540.

57. Vale JA, Proudfoot AT. Paracetamol (acetaminophen) poisoning. Lancet. 1995. 346:547–552.

58. Holt S, Goodier D, Marley R, et al. Improvement in renal function in hepatorenal syndrome with N-acetylcysteine. Lancet. 1999. 353:294–295.

59. Izzedine H, Kheder-Elfekih R, Deray G, Thabut D. Endothelin-receptor antagonist/N-acetylcysteine combination in type 1 hepatorenal syndrome. J Hepatol. 2009. 50:1055–1056.

60. Kelly AM, Dwamena B, Cronin P, Bernstein SJ, Carlos RC. Meta-analysis: effectiveness of drugs for preventing contrast-induced nephropathy. Ann Intern Med. 2008. 148:284–294.

61. Sadeghi HM, Stone GW, Grines CL, et al. Impact of renal insufficiency in patients undergoing primary angioplasty for acute myocardial infarction. Circulation. 2003. 108:2769–2775.

62. Marenzi G, Assanelli E, Marana I, et al. N-acetylcysteine and contrast-induced nephropathy in primary angioplasty. N Engl J Med. 2006. 354:2773–2782.

63. Thiele H, Hildebrand L, Schirdewahn C, et al. Impact of high-dose N-acetylcysteine versus placebo on contrast-induced nephropathy and myocardial reperfusion injury in unselected patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: the LIPSIA-N-ACC (Prospective, Single-Blind, Placebo-Controlled, Randomized Leipzig Immediate PercutaneouS Coronary Intervention Acute Myocardial Infarction N-ACC) Trial. J Am Coll Cardiol. 2010. 55:2201–2209.

64. Jaffery Z, Verma A, White CJ, et al. A randomized trial of intravenous N-acetylcysteine to prevent contrast induced nephropathy in acute coronary syndromes. Catheter Cardiovasc Interv. 2011. 05. 03. [Epub]. http://dx.doi.org/10.1002/ccd.23157.

65. Tanaka A, Suzuki Y, Suzuki N, et al. Does N-acetylcysteine reduce the incidence of contrast-induced nephropathy and clinical events in patients undergoing primary angioplasty for acute myocardial infarction? Intern Med. 2011. 50:673–677.

66. Hoffmann U, Fischereder M, Krüger B, Drobnik W, Krämer BK. The value of N-acetylcysteine in the prevention of radiocontrast agent-induced nephropathy seems questionable. J Am Soc Nephrol. 2004. 15:407–410.

67. Poletti PA, Saudan P, Platon A, et al. I.v. N-acetylcysteine and emergency CT: use of serum creatinine and cystatin C as markers of radiocontrast nephrotoxicity. AJR Am J Roentgenol. 2007. 189:687–692.

68. Ristikankare A, Kuitunen T, Kuitunen A, et al. Lack of renoprotective effect of i.v. N-acetylcysteine in patients with chronic renal failure undergoing cardiac surgery. Br J Anaesth. 2006. 97:611–616.

69. Haase M, Haase-Fielitz A, Ratnaike S, et al. N-Acetylcysteine does not artifactually lower plasma creatinine concentration. Nephrol Dial Transplant. 2008. 23:1581–1587.

70. ACT Investigators. Acetylcysteine for prevention of renal outcomes in patients undergoing coronary and peripheral vascular angiography: main results from the randomized Acetylcysteine for Contrast-induced Nephropathy Trial (ACT). Circulation. 2011. 124:1250–1259.

71. McCullough PA, Khambatta S, Jazrawi A. Minimizing the renal toxicity of iodinated contrast. Circulation. 2011. 124:1210–1211.

72. Wijns W, Kolh P, Danchin N, et al. Guidelines on myocardial revascularization. Eur Heart J. 2010. 31:2501–2555.

73. Marenzi G, Assanelli E, Marana I, et al. N-acetylcysteine and contrast-induced nephropathy in primary angioplasty 1. N Engl J Med. 2006. 354:2773–2782.

74. Barrett BJ, Parfrey PS. Clinical practice. Preventing nephropathy induced by contrast medium. N Engl J Med. 2006. 354:379–386.