The Role of N-Acetylcysteine in Contrast Induced Nephropathy

By: Neal Shah, Co-Editor-In-Chief

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Contrast dyes enhance imaging for computer tomography (CT), magnetic resonance (MR), and X-rays.¹  Dyes usually consist of barium, iodine, or gadolinium, depending on the procedure.²  CT and X-ray scans often use iodine for systemic imaging and barium sulfate for GI imaging, whereas MR imaging primarily uses gadolinium.²  Gadolinium and iodine contrast dyes have renal elimination, and could lead to contrast-induced nephropathy (CIN), especially in patients with pre-existing renal impairment.³

The pathophysiology of CIN involves reduced blood flow to the kidneys (that causes ischemia), which leads to toxicity within tubular epithelial cells.³  The resulting reactive oxidative species (ROS) damage nephrons within the kidney and induce necrosis.³  CIN is defined as an abrupt increase in serum creatinine of 0.5 mg/dL or a 25% increase from baseline levels 48 hours after injection of contrast media.^4,5  Current strategies for managing CIN include: removal of nephrotoxic compounds, aggressive hydration, and administration of vasodilatory compounds (e.g. theophylline) or anti-oxidant medications (e.g. N-acetylcysteine [NAC]).^3-5  NAC seemed a promising agent for mitigating CIN due to its low cost, multiple indications, and ease of use, but perspectives have changed.

NAC is a modified amino acid used traditionally to reverse acetaminophen-induced hepatotoxicity and provide mucolytic activity in bronchial diseases.⁶  NAC is a precursor to the free radical scavenger, glutathione (GSH).  Normally, free radicals oxidize GSH, which reduces the damage caused by ROS to our cells.  GSH is depleted upon major oxidative stress, and administration of NAC replenishes this depleted GSH content.⁷  Other uses of NAC include: increased ovulation and fertility in polycystic ovarian syndrome (PCOS) patients,⁸ chemoprevention of certain cancers,⁹ and oxaliplatin-induced neuropathy.¹⁰

The efficacy of NAC in CIN is widely debated.  Data from 2011 and 2012 demonstrate that NAC is not efficacious in minimizing or preventing CIN.  Anderson et. al.’s MEDLINE meta-analysis concluded that papers published from 1990—2010 had no conclusive clinical evidence on NAC’s safety or efficacy in the prevention of CIN.¹¹  They found that while NAC improved serum creatinine levels, there was no improvement in overall renal function.¹¹  A clinical trial in Brazil, published in September 2011, reported that in 2,038 patients with at least one risk factor for CIN, administration of NAC and placebo resulted in similar outcomes of CIN.¹²  The paper concluded that there were no significant risk reductions or enhanced outcomes of any kind with the administration of NAC.¹²  Tanaka et. al reported that the administration of NAC in CIN had no significant differences in morbidity or mortality compared to placebo.¹³  Aligoglu et. al. conducted a study measuring renal function with creatinine and cystatin C levels.¹⁴  Upon administration of oral NAC, there was no significant reduction in creatinine or cystatin C in patients with CIN treated with placebo or NAC.¹⁴  Jaffery et. al. conducted a study in 398 patients, defining CIN as an increase in creatinine concentration ≥ 25% above the baseline level within 72 hours of the administration of intravenous contrast.¹⁵  They reported that high-dose intravenous NAC failed to reduce the incidence of CIN.¹⁵  Aslanger et. al. examined NAC’s prophylactic utility in CIN with a study of 312 patients, but found that intrarenal and intravenous NAC had no significant benefit compared to placebo.¹⁶

The most conclusive evidence against NAC’s efficacy in CIN came from a paper by Gurm et. al. published in January 2012.  A retrospective analysis of NAC use in 10,574 out of 90,578 patients who underwent percutaneous coronary intervention (PCI) demonstrated no statistical significance between NAC treated patients and non-treated patients that developed CIN.¹⁷  The authors concluded that there was no clinical improvement associated with NAC use in CIN.¹⁷

Overall, while NAC remains efficacious in exerting mucolytic effects in bronchial diseases and assisting in decreasing acetaminophen-induced hepatotoxicity, overwhelming clinical evidence has reported against using NAC in CIN.

SOURCES:

1. CT Scan.  Available at: http://www.nlm.nih.gov/medlineplus/ency/article/003330.htm. Accessed June 24, 2012.
2. Contrast Materials.  Available at: http://www.radiologyinfo.org/en/safety/index.cfm?pg=sfty_contrast. Accessed June 24, 2012.
3. Rudnick M, Kesselheim A, Goldfarb S. Contrast-induced nephropathy:  How it develops, how to prevent it.  Cleveland Clinic Journal Of Medicine.  Volume 73.  January 2006.
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5. McCullough PA, Soman SS. Contrast-induced nephropathy.  Crit Care Clin.  2005;21(2):261—80.
6. N-Acetylcysteine.  Available at: http://www.mskcc.org/cancer-care/herb/n-acetylcysteine. Accessed June 24, 2012.
7. Tepel M.  N-Acetylcysteine in the prevention of ototoxicity.  Kidney Int. 2007 Aug;72(3):231-2.
8. Salehpour S, Akbari Sene A, Saharkhiz N, et. al. N-acetylcysteine as an adjuvant to clomiphene citrate for successful induction of ovulation in infertile patients with polycystic ovary syndrome.  J Obstet Gynaecol Res. 2012.
9. Estensen RD, Levy M, Klopp SJ et. al. N-acetylcysteine suppression of the proliferative index in the colon of patients with previous adenomatous colonic polyps.  Cancer Lett. 1999;147(1—2):109—14.
10. Lin PC, Lee MY, Wang WS et. al. N-acetylcysteine has neuroprotective effects against oxaliplatin-based adjuvant chemotherapy in colon cancer patients: preliminary data.  Support Care Cancer. 2006;14(5):484—7.
11. Anderson SM, Park ZH, Patel RV.  Intravenous N-acetylcysteine in the prevention of contrast media-induced nephropathy.  Ann Pharmacother. 2011;45(1):101—7.
12. Berwanger O, Cavalcanti AB, Sousa AG 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(11):1250—9.
13. 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(7):673—7.
14. Alioglu E, Saygi S, Turk U et. al. N-Acetylcysteine in Preventing Contrast-Induced Nephropathy Assessed by Cystatin C. Cardiovasc Ther. 2011.
15. 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. 2012 May 1;79(6):921-6.
16. Aslanger E, Uslu B, Akdeniz C et. al. Intrarenal application of N-acetylcysteine for the prevention of contrast medium-induced nephropathy in primary angioplasty.  Coron Artery Dis. 2012;23(4):265—70.
17. Gurm HS, Smith DE, Berwanger O et. al. Contemporary use and effectiveness of N-acetylcysteine in preventing contrast-induced nephropathy among patients undergoing percutaneous coronary intervention.  JACC Cardiovasc Interv. 2012;5(1):98—104.