Changing Paradigms in Contrast Nephropathy

The advent of radiologic imaging revolutionized our diagnostic capabilities by allowing us to noninvasively view internal body structures. Its resolution was further augmented by the development of radiographic contrast media. Consequently, contrast-enhanced radiologic imaging has become indispensable in disease diagnosis, making intravascular contrast one of the most common medical substances used. Each year, over 8 million L intravascular contrast media are used in over 80 million procedures worldwide.¹ Because of their extensive usage, the presence of any adverse reactions, either anaphylactoid or nonanaphylactoid, could result in wide-ranging consequences. Fortunately, most types of adverse reactions are either relatively mild or infrequent, except for renal dysfunction. Contrast nephropathy is described as an increase in serum creatinine beginning 1–3 days after an intravascular contrast dose that is not attributable to any other cause. It was not described until the early 1950s, decades after the introduction of intravascular contrast.² However, reports of its nephrotoxicity quickly increased, particularly with the pronounced increase in its use. Indeed, it is now considered one of the top iatrogenic causes of AKI.^3,4 However, despite this notion, we actually do not have an accurate estimate of its incidence; reports vary from 1% to 2% in the general population to up to 50% after coronary angiography in high-risk groups.⁴ There are numerous potential reasons for these inconsistencies, including differences in diagnostic criteria, patient characteristics, dose and type of contrast, studies performed (e.g., intravenous versus intra-arterial), etc.^5–7 The importance of having precise estimates of its incidence stems from studies suggesting that, although most patients have cases that are mild and reversible, it is associated with increased short- and long-term morbidity (e.g., CKD and ESRD) and mortality.^8,9

Determination of the real rate of contrast nephropathy would require randomizing patients to receive either a contrast-enhanced or noncontrast imaging study. However, such studies are not feasible. Thus, most of our original estimates of the incidence of contrast nephropathy come from observational studies lacking controls, raising the possibility that contrast was blamed for other forms of AKI and thus, overestimating the incidence of contrast nephropathy. This possibility was first advanced by the work by Cramer et al.,¹⁰ which measured serum creatinine levels 3 days before and after exposure to either a contrast-enhanced or a noncontrast-enhanced computed tomography (CT) scan and found that the rates of AKI were not different between the groups. A subsequent study by Heller et al.¹¹ also failed to find a clear association between the use of contrast media and the development of AKI. Despite these studies having better controls than the majority of the prevailing literature at the time and having provocative findings suggesting that contrast nephropathy was substantially less common than believed, these studies were largely overlooked up until this last decade, during which time there has been an increasing interest in accurately estimating the risk of contrast nephropathy.^12–14

In this issue of the Journal of the American Society of Nephrology, Wilhelm-Leen et al.¹⁵ report the incidence of AKI in hospitalized patients using the 2009 Nationwide Inpatient Sample database, which represents nearly 8 million hospitalizations. AKI rates were estimated in patients who received radiocontrast compared with matched patients who did not. Analysis of their overall cohort revealed no significant increases in AKI postcontrast. They concluded that contrast nephropathy is not as common as previously believed, and this may result in underutilization of indicated contrast studies. These results are consistent with the increasing number of studies published predominantly in the radiology literature.^12–14 For instance, studies by McDonald et al.^13,14 retrospectively analyzed propensity score–matched patients who underwent contrast-enhanced and/or nonenhanced scans in a single center. They found that, although the incidence of AKI increased with each stepwise increase in CKD stage, this was independent of whether they received intravenous contrast, even in patients with the highest severity of CKD. Thus, the well controlled study by Wilhelm-Leen et al.¹⁵ together with the ones by McDonald et al.^13,14 and others have challenged our dogma regarding the actual incidence of contrast nephropathy, which seems to be much lower than previously assumed. They have thus raised some important questions with regard to the role of contrast in AKI and whether we should modify our approach to patients who may need to receive contrast.

The first question that one might ask is if contrast causes AKI at all. We would submit that causation is difficult to prove or disprove in these studies, even when using the viewpoint of Hill.¹⁶ In fact, it is even difficult to ascertain the diagnosis of contrast nephropathy in these types of clinical studies, because they rely on administrative data, chart reviews, etc., where key clinical information (time courses, severity of associated factors, etc.) is often not available/retrievable, accurately documented, or controlled. Rather, support for causation comes from other lines of evidence. Experimentally, radiocontrast media are direct cytotoxic agents that can induce necrosis and apoptosis of renal tubular cells and disrupt nitric oxide–mediated vasodilation, impairing renal perfusion, particularly in the renal medulla.¹⁷ Interestingly, despite these direct cellular effects, it only causes AKI in animals that have been presensitized with nonsteroidal anti-inflammatory drugs, nitric oxide inhibition, dehydration, etc. Some authors have maintained that this presensitization requirement suggests that radiocontrast is not significantly nephrotoxic in vivo and that the experimental model is, therefore, not clinically relevant. However, the fact that contrast only causes clinically apparent nephrotoxicity in susceptible subjects makes it quite similar to human contrast nephropathy, which rarely occurs in the absence of a concomitant risk factor. Thus, the experimental data are strong, albeit not perfect. However, establishing cause and effect of contrast in clinical AKI is more difficult. It requires making the diagnosis on the basis of not only the appropriate time course of AKI after contrast but also, the absence of other obvious causes of AKI. Although we often use these criteria to make the diagnosis clinically, we cannot completely rule out the presence of other causative factors. Overall, however, we believe that the preclinical and cardiac studies provide reasonable evidence that contrast can cause AKI.

This leads to the second question: if contrast can cause AKI, why are these studies finding AKI rates to be no different between matched patients, regardless of whether they were exposed to intravenous contrast? The most likely contributing reason is potential selection bias in these retrospective studies. This is because, despite authors’ best attempts at accounting for the most important risk factors, it is impossible to normalize for everything that led the physician to select a noncontrasted CT rather than a contrast-enhanced CT in each individual patient. Indeed, contrast is often withheld in the sickest patients and those with the highest risk of AKI unless absolutely necessary. These factors alone would tend to create a dissimilar populace. Moreover, there are several important factors that are not accounted for, such as dehydration and medications, and it is impossible to account for the severity of each factor (severe diabetic nephropathy versus mild diabetic nephropathy, etc.). Thus, patient selection and preparation by the physicians could influence the overall rates of contrast nephropathy. In this respect, it would be interesting to determine whether the incidence of intravenous immunoglobulin- or aminoglycoside-induced AKI, as determined in large cohorts, is also very low, because we have become more selective and adept in using them.

Despite these inherent constraints in determining causation and the true incidence of contrast nephropathy, the study by Wilhelm-Leen et al.¹⁵ as well as previous ones show that the overall incidence of intravenous contrast nephropathy, at least with the current mode of patient selection and preparation, is significantly lower than previously believed, and this has likely led to withholding of contrast media, despite being indicated, which in turn, potentially led to suboptimal care. In this respect, it is interesting to point out a salient finding in the study by Wilhelm-Leen et al.¹⁵: that administration of contrast during acute coronary syndrome led to a decrease in AKI. It is tempting to speculate that the patients who received contrast benefitted from the definitive therapy (e.g., percutaneous coronary angioplasty), which helped preserve their renal function. However, we recognize that it is just as likely that the sicker patients did not undergo the contrasted procedures.

In light of these studies but bearing in mind the remaining uncertainties, we propose to proceed in the following manner. First, because the risk of contrast nephropathy is negligible in stable patients with normal renal function or mild renal impairment, we would continue to perform contrast-enhanced studies without any hesitation. Second, although the risk of AKI may be slightly higher in patients with moderate renal dysfunction (eGFR<45 ml/min or serum creatinine >2 mg/dl), the overall risk is still very low; thus, contrast-enhanced imaging should not be denied (albeit we would err on the side of administering hydration, because it may decrease the risk even more). Third, in patients with eGFR rates <30 ml/min, we believe that it may be appropriate to moderately liberalize the overall use of contrast. However, as elegantly noted in a previous editorial, “guidelines have a propensity to slide almost imperceptibly from recommendation to expectation and onto requirement; their consequences should thus be carefully considered.”¹⁸ Therefore, we think that it is premature to endorse the indiscriminate use of contrast, because although the incidence of AKI is low, the sheer number of patients who would be exposed to contrast may be substantial. Thus, we should continue to carefully weigh the potential benefits versus the risks of the procedure. Perhaps the greatest service provided to us by Wilhelm-Leen et al.¹⁵ as well as other pioneers in this renewed field is that they are forcing us to redefine the risks of contrast and changing the questions that we need to answer.

Disclosures

None.