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

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

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