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 etiology¹ This definition of CIN, or variations of it, is the one most commonly used in past studies examining the risk, prevention, and treatment of CIN. More recent consensus definitions of acute kidney injury, such as RIFLE² and AKIN³, 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 Alternatively, some experts have argued that acute kidney injury occurring after intravascular administration of contrast media is caused instead by co-existing risk factors or medical conditions and is only coincidentally related to the contrast media, especially if contrast media are administered intravenously. In a meta-analysis, McDonald et al. (2013) concluded that the incidence of acute kidney injury was similar between patients receiving intravenous contrast media compared to patients receiving an imaging procedure without contrast media.⁶ 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

Osmolality of the contrast media is thought to be a key factor determining its tolerability.⁷ Since iodinated contrast media was first used in 1929,⁸ developments in the chemistry of contrast media have steadily decreased the number of osmotically active moieties per iodine atom. In the 1990s, high-osmolar contrast media (HOCM, 5-8 times plasma osmolality) was largely replaced by low-osmolar contrast media (LOCM, 2-3 times plasma osmolality) because the latter was associated with fewer severe adverse reactions and less patient discomfort.

The next logical step was the development of contrast media that is isotonic to plasma. Iodixanol has been the only iso-osmolar contrast media (IOCM) available for intravascular injection. One other IOCM, iotrolan, was available in Europe and Japan but was temporarily taken off the market in 1996 after an unexpected number of delayed reactions were reported.⁹ It eventually was discontinued for intravascular use.

Our preliminary search of both primary studies and systematic reviews revealed conflicting reports about whether IOCM is associated with a reduction in CIN risk compared with LOCM. The guidelines by Kidney Disease Improving Global Outcomes (KDIGO) mentioned the use of IOCM and LOCM, but did not make recommendations regarding the circumstances where one type should be administered instead of the other.¹⁰ We therefore sought to gain an understanding of these conflicting results by undertaking a systematic review of the peer-reviewed literature comparing IOCM and/or LOCM. Although the question has been raised whether acute kidney injury that develops after iodinated contrast exposure is causally or coincidentally related (i.e., contrast associated and not induced), it is not necessary to answer this question in order to assess the comparative effect of IOCM and LOCM on observed acute kidney injury following administration.

In reviewing this literature, we also sought to determine whether differences in CIN risk between contrast types are affected by the route of administration (intra-arterial versus intravenous), since there is some evidence that intra-arterial administration is associated with more risk than intravenous administration.^6,11,12 Theories for a potential difference in risk between intra-arterial and intravenous contrast administration include differences in the volume of contrast given, differences in hemodynamic stability of patients undergoing intra-arterial versus intravenous imaging, or confounding factors such as an increased risk of atheroemboli occurring with intra-arterial procedures.

Scope of the Review

We compared the effectiveness of two types of contrast media, IOCM and LOCM, for the prevention of CIN (Figure 1). We reviewed all randomized controlled trials (RCTs) that reported on short-term outcomes (less than 7 days) or long-term outcomes (at least 30 days) after receiving LOCM or IOCM. We compared the effects of the interventions on the incidence of CIN, and other potential harms and benefits.

Figure 1

Analytic framework: comparing benefits and harms of different contrast media. AKI = acute kidney injury; CIN = contrast induced nephropathy; CKD = chronic kidney disease; ESRD = end stage renal disease; IOCM = iso-osmolar contrast media; KQ = Key Question; (more...)

Key Question

Key Question: What are the comparative benefits and harms of different contrast media in patients receiving imaging studies requiring intravenous or intra-arterial administration?

1. How do benefits or harms of contrast media differ by patient characteristics (known risk factors such as age, comorbidity, glomerular filtration rate (GFR), or creatinine clearance)? How do benefits or harms differ by the dose of contrast medium (i.e., by volume of dose and number of doses)?
2. How do benefits or harms of contrast media differ according to the type of preventive strategy used?