Prevention of Contrast-Induced Nephropathy: What is the Best Approach?

MARCH 27, 2018
Contrast-induced nephropathy (CIN) is defined as impairment of renal function occurring within 48 hours of administration of contrast media.1 Objectively, this manifests as a relative increase in serum creatinine of at least 25% above baseline without other precipitating causes. The mechanism is poorly understood in humans, with the majority of information on the pathophysiology coming from animal models.

Currently, it is accepted that CIN is a combination of acute tubular necrosis caused by ischemia and the cytotoxic properties of the contrast itself. In patients with baseline elevations of serum creatinine, such as those with renal disease or diabetes mellitus, 12-26% develop CIN. In patients with normal baseline serum creatinine, the incidence is approximately 3%. Of note, creatinine levels typically peak 3-5 days after administration of contrast, thus the number of patients with CIN may be much larger than estimates predict. Risk factors for developing CIN include pre-existing renal dysfunction, diabetes mellitus, increasing age, heart failure, hypertension, low effective circulatory volume, myocardial infarction, and use of an intraaortic balloon pump.
 
Currently, the only widely accepted prophylaxis is hydration of the patient using normal saline before contrast is administered.2 This presents limitations, however, as not all patients are able to handle large volumes of fluid. Because of this, research has been ongoing to determine what, if anything, can be done to limit the incidence of CIN and to further assess the role of hydration in prevention of CIN.
 
Multiple agents and combinations of agents have been studied for the prevention of CIN. Stone and colleagues evaluated fenoldopam for the prevention of CIN in patients with elevated serum creatinine at baseline.3 They found that the study dose of fenoldopam was ineffective in reducing rates of CIN. Additionally, they determined that no dose or infusion rate of fenoldopam would have been effective.
 
A trial published in the Journal of the American Medical Association assessed an infusion of sodium bicarbonate in preventing CIN.4 Sodium bicarbonate was found to be effective in preventing CIN, but the study enrolled very few patients and few instances of CIN were found on both cohorts. Briguori and colleagues compared normal saline with n-acetylcysteine (NAC) versus sodium bicarbonate with NAC versus normal saline with NAC and ascorbic acid.5 These researchers found sodium bicarbonate with NAC was superior to the other treatments.
 
The RENO trial evaluated hydration, post-contrast administration with normal saline versus treatment with sodium bicarbonate and NAC prior to and post-contrast.6 Both groups got 2 oral doses of NAC after contrast administration. In this trial, rapid infusion of the sodium bicarbonate with NAC was found to be safe and effective in reducing incidence of CIN in patients about to undergo percutaneous coronary intervention compared to saline alone.
 
Researchers have also studied NAC alone for the prevention of CIN.7 Patients in this study were given a standard dose of NAC (600 mg IV bolus followed by 600 mg PO BID for 48 hours after contrast administration), a double dose (1200 mg IV bolus followed by 1200 mg PO BID for 48 hours after contrast administration), or placebo. All the patients were given IV hydration with normal saline (1 mL/kg/hour or 0.5 mL/kg/hr for heart failure patients). A statistically significant difference in serum creatinine elevation was seen with NAC, specifically the double dose cohort (33% control, 15% single dose, 8% double dose; P<0.001). Similar results were seen in the composite endpoint of death, acute renal failure requiring temporary renal-replacement therapy, or the need for mechanical ventilation (P=0.002). The authors advocated for the use of NAC to reduce the severity of CIN, specifically the double dose strategy.

Researchers who studied NAC with normal saline versus normal saline, before and after contrast administration, found administration of NAC with normal saline reduced the change in serum creatinine when compared to normal saline alone.8 It is important to note that this study utilized low osmolality contrast, which is not typically used in the United States. Briguori conducted another study comparing NAC in half-normal saline versus half-normal saline alone.9 Researchers determined the amount of contrast utilized in the study was a better predictor of renal function decline than administration of NAC. The authors advocated pre-medicating patients with NAC only when the amount of contrast utilized in the procedure was less than 140 mL.
 
Most studies evaluating prevention of CIN have utilized hydration with normal saline as that has previously proven to be efficacious in prevention of CIN and is advocated for in the guidelines. The recent AMACING trial, however, brought that practice into question.10 This study evaluated normal saline versus no prophylaxis for prevention of CIN and found the practice of no prophylaxis to be non-inferior to hydration with normal saline in terms of protecting renal function. Although the results were provoking, major limitations included low viscosity, low concentration contrast that was utilized which is not normal practice in the United States leading to a low external validity.    
 
The most recent literature on CIN prevention compared NAC versus placebo and normal saline versus sodium bicarbonate.11 The study was a double blind, placebo and comparator drug controlled randomized clinical trial. There was no statistically significant difference between sodium bicarbonate and normal saline in the primary composite endpoint of death, need for dialysis, or a persistent increase of at least 50% from baseline in the serum creatinine level at 90 days. Additionally, there was no statistically significant differences in the primary endpoint between NAC and placebo. None of the secondary endpoints, including contrast-associated acute kidney injury showed statistically significant differences between cohorts. The authors concluded that periprocedural IV sodium bicarbonate had no benefit over IV normal saline in terms of preventing major adverse kidney events, death or acute kidney injury. The same was concluded with respect to oral NAC compared to placebo.
 
As evidenced by the amount of conflicting data on this topic over the past 2 decades, more studies are necessary to affirm the usage of most agents for prevention of CIN. The most recent literature continues to follow the same pattern leading to more questions being asked about our prevention strategies than providing concreate answers. At this point, hydration with normal saline remains the standard of care for the prevention of CIN with adjunctive therapies being utilized in specific high-risk patient populations although their utility continues to be questioned.
 
This article was collaboratively written with Juliet Franklin, a fourth-year PharmD candidate at Chicago State University College of Pharmacy.

References
  1. Goldenberg I, Matetzky S. Nephropathy induced by contrast media: pathogenesis, risk factors, and preventative strategies. CMAJ. 2005;172(11):1461-71
  2. Lameire N, Kellum JA. Contrast-induced acute kidney injury and renal support for acute kidney injury: a KDIGO summary(Part 2). Crit Care. 2013;17(1):205.
  3. Stone G, McCullough P, Tumlin J, et al. Fenoldopam Mesylate for the Prevention of Contrast Induced Nephropathy: A Randomized Controlled Trial. JAMA. 2003;290(17):2284-91.
  4. Merten G, Burgess W, Gray L, et al. Prevention of Contrast-Induced Nephropathy With Sodium Bicarbonate: A Randomised Controlled Trial. JAMA 2004;291(19):2328-34.
  5. 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;115:1211-17.
  6. Recio-Mayoral A, Chaparro M, Prado B, et al. The Reno-Protective Effect of Hydration With Sodium Bicarbonate Plus N-Acetylcysteine in Patients Undergoing Emergency Percutaneous Coronary Intervention. J Am Coll Cardiol. 2007;49(12):1283–8.
  7. Marzenzi G, Assanelli E, Marana I, et al. N-Acetylcysteine and Contrast Induced Nephropathy in Primary Angioplasty. N Engl J Med. 2006;354:2773-82.
  8. Tepel M, Giet MVD, 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(3):180–4.
  9. Briguori C, Manganelli F, Scarpato P, et al. Acetylcysteine and contrast agent-associated nephrotoxicity. J Am Coll Cardiol 2002;40(2):298–303.
  10. Nijssen EC, Rennenberg RJ, Nelemans PJ, et al. Prophylactic hydration to protect renal function from intravascular iodinated contrast material in patients at high risk of contrast-induced nephropathy (AMACING): a prospective, randomised, phase 3, controlled, open-label, non-inferiority trial. Lancet. 2017; 389: 1312–22.
  11. Weisbord SD, Gallagher M, Jneid H, et al. Outcomes after Angiography with Sodium Bicarbonate and Acetylcysteine. N Engl J Med. 2018;378(7):603–14.


Alexander Kantorovich, PharmD, BCPS
Alexander Kantorovich, PharmD, BCPS
Alexander Kantorovich, PharmD, BCPS, is a Clinical Associate Professor of Pharmacy Practice at Chicago State University College of Pharmacy and Clinical Pharmacy Specialist at Advocate Christ Medical Center in Oak Lawn, Illinois. Dr. Kantorovich earned his Associate of Science degree with an emphasis in chemistry from William Rainey Harper College and received his Doctor of Pharmacy degree from the University of Illinois at Chicago College of Pharmacy. He went on to complete a 2-year pharmacotherapy residency with an emphasis in cardiology and critical care at the Cleveland Clinic and is board certified in pharmacotherapy. His research interests center around cardiovascular pharmacotherapy, anticoagulation, and anticoagulation reversal.
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