Background

The administration of iodinated contrast media is an essential component of a number of diagnostic and therapeutic procedures that involve radiologic imaging. One important potential side-effect of iodinated contrast administration is contrast-induced nephropathy (CIN, see Appendix A for a list of acronyms), defined as an increase in serum creatinine of more than 25 percent or 0.5 mg/dL within 3 days of intravascular administration of contrast media in the absence of an alternative etiology.¹ This definition of CIN, or variations of it, is the one most commonly used in the past by studies examining the risk, prevention, and treatment of CIN. More recent consensus definitions of acute kidney injury, such as RIFLE² and AKIN,³ have not yet been used extensively in the CIN literature. Although some guidelines have employed the term “contrast-induced acute kidney injury” (CI-AKI) instead of CIN, the vast majority of the literature has used the older term, CIN, so we will use the older term in our report.

The precise mechanism of CIN is not entirely understood. The leading theories are that CIN results from hypoxic injury of the renal tubules induced by renal vasoconstriction or by direct cytotoxic effects of the contrast media.^4,5 Some experts have questioned whether acute kidney injury occurring after intravascular administration of contrast media is caused by co-existing risk factors and only coincidentally related to the contrast media, especially if contrast media are administered by the intravenous (IV) route. In a meta-analysis, McDonald et al., 2013 concluded that the incidence of acute kidney injury was similar between patients receiving IV contrast media and patients receiving an imaging procedure without contrast media. Regardless of the precise etiology, however, the development of acute kidney injury after use of intravascular contrast media remains a major concern for clinicians.⁶

Clinicians often worry about the possibility that intra-vascular administration of contrast media in diagnostic or therapeutic procedures could lead to acute or chronic kidney failure. Indeed, CIN is cited as a leading cause of hospital-acquired kidney failure.⁷ Although renal function returns to normal in most patients, acute kidney injury may require short-term renal replacement therapy or may lead to chronic kidney disease and a need for long-term renal replacement therapy. Clinicians are concerned about the risk of CIN because of increasing use of contrast media in radiologic and cardiologic procedures, and the high prevalence of populations vulnerable to CIN (i.e., people having chronic kidney disease, diabetes mellitus, or hypertension, as well as the elderly). Various types of imaging studies or procedures use IV or intra-arterial contrast media, including: IV pyelograms; brain, head and neck, body, or coronary computed tomograms (CT); cerebral, cardiac, or peripheral vascular angiograms; and radiologic therapeutic procedures. Contrast media is injected intravenously for CT and intra-arterially for angiograms and related interventional procedures. More than 62 million CT studies were performed in the United States in 2006 and the use of CT tripled between 1996 and 2010, from 52 studies per 1000 patients to 149 studies per 1000 patients.⁸

The reported incidence of CIN varies, but a reasonable overall estimate is that it occurs in about 2 percent of patients receiving intra-vascular contrast media.⁷ Variation in the populations studied makes it difficult to determine whether the incidence of CIN has increased over time. Most of the estimates are derived from invasive angiographic studies, over the last few decades, using intra-arterial contrast media, which may have a higher risk of CIN than imaging studies using IV contrast media. One problem in determining the precise incidence of CIN is that many patients do not remain hospitalized for enough time after contrast administration to make the diagnosis. In addition, the use of serum creatinine as a marker of renal function has its limitations. It is often difficult to exclude other possible etiologies of elevations in serum creatinine. Furthermore, the incidence may vary according to the osmolality of contrast media used. Although there is consensus that the risk of CIN is highest with high-osmolar contrast media (HOCM), which has an osmolality five to eight times higher than plasma osmolality, HOCM is no longer used in clinical practice. It is unclear whether or not the risk of CIN differs between low-osmolar contrast media (LOCM), which has an osmolality two to three times plasma osmolality, and iso-osmolar contrast media (IOCM), which is isotonic to plasma. It is also often difficult to distinguish the effects of contrast media from the effects of physiologic confounders that could elevate the serum creatinine in patients undergoing radiologic studies. For example, blood flow to the kidneys could be compromised by emboli or vascular compression from catheter manipulation.^9,10 Nevertheless, it is important to carefully examine the evidence on the effectiveness of interventions for preventing CIN while taking into consideration how the effectiveness may depend on factors such as the route of administration or the type of contrast media being used.

Numerous strategies to prevent CIN have been used, including: oral fluids; volume expansion with sodium chloride, sodium bicarbonate, or a combination of both; administration of N-acetylcysteine, statins, angiotensin converting enzyme inhibitors, or angiotensin II receptor blockers; withdrawal of nonsteroidal anti-inflammatory drugs; and hemofiltration or hemodialysis. Withdrawal of metformin does not prevent CIN; it is discontinued before use of contrast because acute kidney injury may lead to metformin-associated lactic acidosis. Recent meta-analyses on the prevention of CIN have yielded contradictory results. A meta-analysis by Sun et al., 2013 concluded that the evidence on use of IV N-acetylcysteine to prevent CIN was too inconsistent to determine the efficacy.¹¹ Another meta-analysis, performed by Loomba et al., 2014,¹² concluded that N-acetylcysteine may help to prevent CIN in patients undergoing coronary angiography, but does not have any impact on clinical outcomes such as need for dialysis or mortality. A meta-analysis by Xie et al., 2014¹³ concluded that statins given before angiography are effective in preventing CIN, but the optimum dose and duration for statin use are unknown. A recent review of randomized controlled trials (RCTs) of sodium bicarbonate administration for prevention of CIN revealed the conflicting nature of the evidence, with some studies showing benefit and others showing no benefit.¹⁴

Despite the number of previous reviews, uncertainty persists about several issues, including:

1. The efficacy of oral fluids versus IV fluids in preventing CIN;^15,16
2. The optimal timing (pre- versus post-contrast media administration or both), duration, and type of IV fluids used to prevent CIN¹⁷;
3. The efficacy of low versus high-dose N-acetylcysteine;
4. The efficacy of a combination of interventions, such as N-acetylcysteine plus sodium bicarbonate;
5. The efficacy of statins, taking into consideration dose and duration of the medication;
6. The efficacy of vasoactive drugs;
7. The efficacy of hemodialysis and hemofiltration relative to the invasive nature and cost of these interventions;
8. Whether any intervention is needed for IV contrast media procedures when there is uncertainty about whether IV contrast media is associated with CIN; and
9. Effect of the volume of contrast media administered, and the possibility of preventing CIN by keeping the volume of contrast media below a threshold.

Guidelines around contrast media administration have been published by a number of organizations. The 2007 American College of Radiology practice guideline focused on the correct administration of contrast media and the patients who are most likely to benefit from using LOCM instead of HOCM, rather than the evidence for or against different preventive measures. Guidelines on the prevention of CIN were published in 2007 by the Canadian Association of Radiologists,¹⁹ and they were published following what they described as an “in-depth literature search with critical review”; however, no further details were included about the methods. Guidelines were also issued in 2006 by the CIN Consensus Working Panel, an international multidisciplinary group; these guidelines were based on an evidence review through 2005.²⁰ One section of the 2012 Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Acute Kidney Injury specifically addressed contrast-induced acute kidney injury. The method of synthesis varied among these guidelines and many were based on literature review and consensus opinions of clinical experts.²¹

In light of the increasing use of contrast media in radiologic and cardiologic procedures, the high prevalence of populations vulnerable to CIN (e.g., people having chronic kidney disease, diabetes mellitus, or hypertension as well as the elderly), and discrepant results from prior analyses, we sought to perform a comprehensive systematic review of this topic for the benefit of clinicians who wish to prevent CIN in patients undergoing imaging studies.

Scope of the Review

We reviewed studies that assess the effectiveness of one or more measures for preventing CIN in patients receiving either IOCM or LOCM, the two types of contrast media still in regular use in the United States (Figure 1 and Table 1). We included studies that reported on specific short-term or long-term outcomes (Table 2). When studies allowed, separate results for CIN prevention were reported for intra-arterial compared to IV contrast.

Figure 1

Analytic framework comparing the benefits and harms of different methods used to prevent contrast-induced nephropathy in patients receiving low-osmolar or iso-osmolar contrast media. AKI=acute kidney injury; CIN=contrast induces nephropathy; CKD=chronic (more...)

Table 1

PICOTS (populations, interventions, comparisons, outcomes, timing, and setting) criteria for defining the scope of the review.

Table 2

Major interventions for preventing contrast-induced nephropathy and main comparisons of interest (number of studies/total number of study participants).

Key Question

In patients undergoing imaging studies requiring intravenous (IV) or intra-arterial contrast media, what is the comparative effectiveness of interventions to prevent contrast-induced nephropathy for the outcomes of incidence of contrast-induced nephropathy, chronic kidney disease, end stage renal disease, mortality, and other adverse events?

1. How does the comparative effectiveness of prevention measures vary by patient characteristics (known risk factors such as age, comorbidity, glomerular filtration rate, or creatinine level)?
2. How does the comparative effectiveness of prevention measures vary according to the type of contrast media used (i.e., low-osmolar contrast media vs. iso-osmolar contrast media)?
3. How does the comparative effectiveness of prevention measures vary by characteristics of the interventions (e.g., dose, duration, and timing)?

Organization of This Report

The following results section reports on a number of comparisons. We report in detail on comparisons for which substantial evidence exists, starting with the comparisons that have received the most attention in the literature (N-acetylcysteine plus IV saline versus IV saline, IV sodium bicarbonate versus IV saline, N-acetylcysteine plus IV saline versus IV sodium bicarbonate, statins plus IV saline versus IV saline, adenosine antagonists plus IV saline versus IV saline, renal replacement therapy versus IV saline, and ascorbic acid plus IV saline versus IV saline). At the end of the results section, we refer to information about other “miscellaneous comparisons” for which the studies were too few or too small to draw conclusions. Details on those comparisons appear in Appendixes H and I.