Prevention of contrast-induced renal dysfunction by N-acetylcysteine

Truth or myth?

M Billinger, O.M Hess and B Meier*

Swiss Cardiovascular Center Bern, Cardiology, University Hospital, 3010 Bern, Switzerland

* Corresponding author: Tel.: +41-31-632-3077; Fax: +41-31-382-1069
E-mail address: bernhard.meier{at}insel.ch

Received 13 October 2003; accepted 16 October 2003

See doi:10.1016/j.ehj.2003.11.016 and doi:10.1016/j.ehj.2003.11.011for the articles to which this editorial refers

There is an increase in the use of radiographic contrast agents in cardiovascular medicine for diagnostic and therapeutic interventions. However, these interventions are becoming more and more popular in elderly and polymorbide patients, thereby increasing the risk of contrast-induced complications such as renal dysfunction and delayed allergic reactions. A particular risk for renal dysfunction has been attributed to pre-existing renal dysfunction, diabetic nephropathy, dehydration, druginteractions and the use of large amounts of contrast, etc. The reduction in renal function by contrast agents may cause substantial morbidity and mortality and can lead to end-stage renal disease.

In an attempt to reduce contrast-associated morbidity and mortality, several interventions and drugs have been advocated such as hydration with saline, the use of isotonic and non-ionic contrast agents as well as administration of nephroprotective drugs such as theophylline, dobutamine and atrial natriuretic peptides. The largest experience exists, however, with the antioxidant N-acetylcysteine (NAC).

The mechanism of renal dysfunction after exposure to contrast media is not clear, but seems to be an interplay of renal haemodynamics, toxic effects on tubular epithelial cells and enhanced oxidative stress. Therefore, the use of antioxidants such as NAC has been recommended to protect the kidney and to prevent renal dysfunction.

In this issue of the European Heart Journal Briguori et al.1report on the prophylactic administration of NAC in patients undergoing coronary angiography with a low dose of a non-ionic, low osmolarity contrast medium. They tested the hypothesis of a protective effect of high dose (2x1200mg) vs standard dose (2x600mg) NAC given orally along with saline hydration to prevent contrast-associated nephrotoxicity. Serum creatinine concentrations were similar in the two groups, but there was an increase in creatinine of at least 0.5mg/dl after angiography in 12 of 109 (11%) patients in the standard dose group and 4 of 114 (3.5%) in the double dose group, respectively (P=0.04). Furthermore, the amount of contrast used (larger or smaller than 140ml) had a significant effect on renal dysfunction, i.e. NAC had no effect on renal function in those with low contrast dose (<140ml), whereas in those with high dose (>140ml) NAC significantly reduced renal dysfunction from 18.9% to 5.4% (P=0.04). The authors concluded that the use of double dose of NAC seems to be more protective in preventing contrast-induced renal dysfunction especially in patients with high doses of contrast medium.

In the second paper of this issue of the European Heart Journal, Goldenberg et al.2examined the effect of NAC in prevention of contrast-induced renal dysfunction. In this study somewhat higher doses of NAC than standard dose were given (3x600mg). Both groups received hydration with saline (1ml/kg/h over 24h). An increase of more than 0.5mg/dl in serum creatinine after angiography was observed in 10% of the NAC and in 8% of the control group, respectively (n=ns). The authors concluded that prophylactic administration of oral NAC to prevent contrast-associated nephrotoxicity in patients with renal insufficiency undergoing coronary angiography is not justified.

These two contradictory studies have to be seen in the light of the complex interplay of pharmacology and contrast toxicity. Apparently, Briguori et al. make the point that beside the adjunctive therapy with saline the amount of contrast (>140) and the dose of the antioxidative NAC play an important role for nephroprotection, whereas Goldenberg et al. state that the effect of NAC in patients with mild to moderate renal insufficiency is of limited value and benefits may be observed only when appropriate hydration is not possible.

Apart from other studies without saline infusion3,4most reports5–8in patients undergoing cardiac catheterization have shown no beneficial effect of NAC as adjunctive therapy to saline infusion. Beneficial effects of NAC as adjunctive therapy to saline have been reported only by two other studies namely Briguori and Shyu.1,9Shyu et al. reported a protective effect of NAC in patients with high serum creatinine levels (mean 2.8mg/dl). Assuming the observation of Briguori and Shyu are correct following recommendations for preventing renal dysfunction in patients undergoing cardiac catheterization can be given:

Hydration with saline in all patients (1ml/kg/h 12h before and 12h after the intervention)
Use of a modern non-ionic, low osmolarity contrast agent
Use of high dose NAC (2x1200mg) in patients with high creatinine levels (>2.5mg/d) and large contrast doses (>140ml)

In conclusion, patients with renal insufficiency undergoing diagnostic and therapeutic angiography are at high risk for developing contrast-induced renal dysfunction. The use of small amounts (<140ml) of non-ionic, low osmolarity contrast media with appropriate hydration 12h before and 12h after the intervention helps to reduce the risk of renal dysfunction. The addition of the antioxidant NAC (2x1200mg) may be useful in patients with high serum creatinine levels (>2.5mg/dl) and the use of high doses of contrast material (>140ml).

References

  1. Briguori C. Standard versus double dose of N-acetylcysteine to prevent contrast agent associated nephrotoxicity. European Heart Journal. 2004;25:206–211.[Abstract/Free Full Text]
  2. Goldenberg I. Oral Acetylcysteine as an adjunct to saline hydration for the prevention of contrast-induced nephropathy following coronary angiography: A randomized controlled trial and review of the current literature. European Heart Journal. 2004;25:212–218.[Abstract/Free Full Text]
  3. Diaz-Sandoval LJ, Kosowsky BD, Losordo DW. Acetylcysteine to prevent angiography-related renal tissue injury (the APART trial). Am J Cardiol. 2002;89(3):356–358.[CrossRef][Medline]
  4. Kay J et al. Acetylcysteine for prevention of acute deterioration of renal function following elective coronary angiography and intervention: a randomized controlled trial. JAMA. 2003;289(5):553–558.[Abstract/Free Full Text]
  5. Boccalandro F et al. Oral acetylcysteine does not protect renal function from moderate to high doses of intravenous radiographic contrast. Catheter Cardiovasc Interv. 2003;58(3):336–341.[CrossRef][Medline]
  6. Durham JD et al. A randomized controlled trial of N-acetylcysteine to prevent contrast nephropathy in cardiac angiography. Kidney Int. 2002;62(6):2202–2207.[CrossRef][Medline]
  7. Briguori C et al. Acetylcysteine and contrast agent-associated nephrotoxicity. J Am Coll Cardiol. 2002;40(2):298–303.[CrossRef][Medline]
  8. Allaqaband S et al. Prospective randomized study of N-acetylcysteine, fenoldopam, and saline for prevention of radiocontrast-induced nephropathy. Catheter Cardiovasc Interv. 2002;57(3):279–283.[CrossRef][Medline]
  9. Shyu KG, Cheng JJ, Kuan P. Acetylcysteine protects against acute renal damage in patients with abnormal renal function undergoing a coronary procedure. J Am Coll Cardiol. 2002;40(8):1383–1388.[CrossRef][Medline]

Related articles in EHJ:

Oral acetylcysteine as an adjunct to saline hydration for the prevention of contrast-induced nephropathy following coronary angiography: A randomized controlled trial and review of the current literature
Ilan Goldenberg, Michael Shechter, Shlomi Matetzky, Michael Jonas, Miriam Adam, Hanna Pres, Dan Elian, Oren Agranat, Ehud Schwammenthal, and Victor Guetta
EHJ 2004 25: 212-218. [Abstract] [Full Text]