nacForCIN

NAC for Prevention of Contrast-Induced Nephropathy

By Artur Pawlowicz, MD and Matthew Ryan, MD, Ph.D.

Introduction

  • Contrast- induced nephropathy (CIN) is a type of acute kidney injury (AKI) caused by IV iodinated radiocontrast during computed tomography (CT) scanning and angiography
  • No consensus, but most define CIN as a 25% relative or 0.5 mL/min increase in serum creatinine
  • Exact mechanism for CIN is unknown; likely multifactorial, involving a combination of vasoconstriction (leading to medullary ischemia), direct cytotoxicity, and production of reactive-oxygen species (ROS)
  • Pathologically, CIN manifests as Acute Tubular Necrosis (ATN)
  • Most recover renal function, but in some damage is permanent
  • Development of CIN is associated with increased morbidity and mortality1 (though causation not proven)

Epidemiology

  • Incidence varies greatly by population – estimated at 3% overall but up to 20-30% in patients with pre-existing renal impairment2
  • Risk Factors for CIN
    • Patient Factors
      • Advanced age (>70 yo)
      • Chronic kidney disease (CKD)
      • Diabetes
      • Hypertension
      • Congestive heart failure (CHF)
      • Peripheral vascular disease (PVD)
      • Nephrotoxic drugs
      • Multiple myeloma
      • Intra-aortic balloon pump use
    • Increased contrast load
      • Risk increases with larger contrast loads and repeat contrasted studies (within 48-72 hours)
    • Type of contrast
      • Increased risk with ionic and high- osmolality contrast agents

N-Acetylcysteine

  • Derivative of amino acid cysteine
  • Multiple pharmaceutical uses due to vasodilatory and free radical scavenging properties (both of which have been implicated in CIN), as well as mucolytic properties3
  • Dosage (for CIN prevention):
    • No clear guidelines established
    • Similar doses PO and IV
    • For pre-medication: 600-1,200mg PO bid x 2 days, starting the day before CT / angiography
    • If acute intervention needed: multiple dosages used (mainly IV), from 500mg to several grams
  • Adverse Effects
    • Generally well tolerated
    • Low rates of flushing, hypotension, tachycardia, urticaria, pruritus, and nausea/vomiting reported with both IV and PO forms
    • Anaphylactoid reaction possible with rapid IV infusion, but not PO

Summary of Key Literature

  • Dozens of studies have been performed with mixed results; most are under- powered
  • Tepel et al (2000)4
    • First study to investigate NAC for preventing CIN
    • Enrolled 83 patients with CKD undergoing contrasted CT
    • Received NAC (600mg PO bid x 2 days) or placebo
    • Found decreased CIN rates in NAC group as defined by serum Cr
  • Acetylcysteine for the prevention of Contrast-induced Nephropathy (ACT) trial published (2011)5
    • Largest study to date
    • Enrolled 2308 patients with risk factors for CIN undergoing coronary angioplasty
    • Received NAC (1200mg PO bid x 2 days) or placebo
    • Found no significant difference in rates of CIN, death, or need for dialysis between patients that received NAC vs placebo
  • Traub et al (2013)6
    • Most recent study looking at ED patients
    • Enrolled 399 ED patients with CIN risk factors undergoing contrasted CT
    • Received NAC (3g IV bolus followed by 200mg/hr infusion up to 24h) with fluids or fluids alone
    • Found no significant difference in rates of CIN
  • Multiple meta-analyses of the other small studies have shown inconsistent results. For example:
    • A meta- analysis by Nallamothu (2004) including 30 studies (using both PO and IV NAC) found a non-significant trend towards lower rates of CIN in patients treated with NAC7
    • A meta-analysis by Gonzales et al (2007) including 22 studies (using both PO and IV NAC) found no benefit to NAC administration8
    • A meta-analysis by Kelly et al (2008) including 30 studies (using both PO and IV NAC) found lower rates of CIN with NAC vs hydration alone9
    • A meta-analysis by Sun et al (2013) including 10 studies using IV NAC found a non-significant trend towards benefit, with significant heterogeneity among studies10

Take- Home Points

  • NAC should not be used for the prevention of CIN in patients without risk factors
  • In patients with CIN risk factors, there is currently insufficient evidence to recommend routine NAC use
  • If prophylactic NAC is used for a planned study, the recommended dose is 600-1,200mg bid for 2 days, starting the day prior to the procedure
  • Use of IV NAC should be weighed against the risk of anaphylactoid reaction
  • Proper hydration should be ensured in all patients receiving IV contrast

References / Further Reading

  1. Rudnick M, Feldman H. Contrast-induced nephropathy: what are the true clinical consequences? Clin J Am Soc Nephrol 2008; 3:263.
  2. Rihal CS, Textor SC, Grill DE, et al. Incidence and prognostic importance of acute renal failure after percutaneous coronary intervention. Circulation 2002; 105:2259.
  3. Fishbane S. N-acetylcysteine in the prevention of contrast-induced nephropathy. Clin J Am Soc Nephrol 2008; 3:281.
  4. Tepel M, van der Giet M, Schwarzfeld C, et al. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med 2000; 343:180.
  5. Berwanger O, Cavalcanti AB, Sousa AM, et al. 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.
  6. Traub SJ, Mitchell AM, Jones AE, et al. N-acetylcysteine plus intravenous fluids versus intravenous fluids alone to prevent contrast-induced nephropathy in emergency computed tomography. Ann Emerg Med. 2013 Nov;62(5):511-520.
  7. 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.
  8. 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.
  9. Kelly AM, Dwamena B, Cronin P, et al. Meta-analysis: effectiveness of drugs for preventing contrast-induced nephropathy. Ann Intern Med 2008; 148:284.
  10. Sun Z, Fu Q, Cao L, Jin W, Cheng L, Li Z. Intravenous N-acetylcysteine for prevention of contrast-induced nephropathy: a meta-analysis of randomized, controlled trials. PLoS One. 2013;8(1):e55124.
  11. http://www.ncbi.nlm.nih.gov/pubmed/24365793
  12. http://www.ncbi.nlm.nih.gov/pubmed/23188834
  13. http://www.ncbi.nlm.nih.gov/pubmed/23037460
Edited by Alex Koyfman

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