The Death of Contrast-Induced Nephropathy Is Premature

The occurrence of acute kidney injury (AKI) resulting from the intravascular administration of contrast media (CM), commonly referred to as contrast-induced nephropathy (CIN), has become firmly entrenched.

CIN has been described with both intra-arterial and intravenous (IV) administration of CM. Most clinical studies of CIN occur in a population receiving CM during coronary angiography, even though most intravascular CM exposures occur via IV administration during contrast-enhanced computed tomography (CECT).

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Within the past decade, an increasing number of studies have called into question the true incidence and even the existence of CIN after IV CM administration. This has led some physicians to opine that CIN after IV CM administration has been overstated, may not even occur, and is not of a sufficient magnitude to be clinically significant (1). Physicians should be concerned about the implications of these opinions, given the associations of AKI with short-term and long-term mortality and the development of chronic kidney disease (CKD) (2, 3). Thus, in order to “first do no harm,” it is important to critically examine the literature reports that have been purported to negate the risk of CIN from IV CM administration.

The initial studies of CIN after CECT were limited by the absence of control groups of patients who underwent unenhanced computed tomography (CT). The inclusion of a control group is necessary to determine whether factors other than CM may be responsible for the observed AKI in a given study. The next generation of studies included a control group and demonstrated similar rates of AKI after CECT and unenhanced CT, with conclusions that the entity of CIN after IV CM either had been overstated or does not exist (1). These studies have several limitations, including small sample sizes (especially of high-risk patients) and evidence of selection bias. Selection bias could steer patients with predisposition to AKI other than CM exposure to receive unenhanced CT imaging, whereas AKI in the CECT group could still be attributable to CM exposure, thus biasing the risk of CIN toward the null in these studies (1). Thus, the similar incidence of AKI could be attributable to factors other than CM that may have influenced inclusion in the control group. In an effort to diminish the impact of selection bias, contemporary studies were performed with the use of propensity score methods. Propensity scores adjust for risk factors that may influence receipt of the exposure variable (CECT in this case) in an attempt to make retrospective observational analyses more similar to prospective randomized trials.

It is instructive to review two large propensity score–adjusted studies on IV CIN. McDonald et al. (4) performed a retrospective propensity score–adjusted analysis of 12,508 patients to evaluate the risk of AKI in a cohort exposed to CECT or unenhanced CT. Patients in both groups were stratified by baseline estimated GFR (eGFR) and were matched 1:1 by propensity score. The incidences of AKI between CECT and unenhanced CT were similar for each eGFR cohort (≥90 mL/min: 1.2%–1.3%; 60–89 mL/min: 2.1% versus 2.0%; 30–59 mL/min: 5.8% versus 6.2%; and <30 mL/min: 14% versus 14%, respectively), with no statistically significant increased odds of AKI. Davenport et al. (5) also performed a propensity score–adjusted cohort analysis of 17,652 patients who underwent CECT or unenhanced CT with risk stratification by eGFR. The incidence of AKI was similar between higher eGFR cohorts in CECT versus those in unenhanced CT (eGFR >60 mL/min: 5.4% versus 5.5%; 45–59 mL/min: 10.5% and 10.8%, respectively). In patients with eGFR 30 to 44 mL/min, the incidence of AKI was slightly higher among those with CECT exposure than in those with unenhanced CECT (16.7% versus 14.2%, odds ratio 1.40; 95% confidence interval 0.997–1.970). In patients with eGFR <30 mL/min, however, there was an increased incidence of AKI among those with CECT exposure compared with unenhanced CT (36.4% versus 19.4%, respectively). These studies show similar incidence rates of AKI between CM exposed and unexposed patients with normal or mildly impaired renal function. However, in the Davenport study, the odds of AKI were increased in patients with severe and possibly moderate renal impairment who were exposed to CM. The disparate results between these two studies are likely due to differences in baseline cohort characteristics, differences in propensity score models, and the relatively small number of the highest-risk patients.

These and other propensity score–adjusted studies examining IV CIN have significant limitations. Although propensity score adjustment may reduce selection bias, it is not equivalent to the balance of risk factors achieved in prospective randomized controlled trials. The retrospective basis of propensity score adjustment leaves open the possibility that there are confounders not included in the propensity score models that were considered by clinicians in deciding which patients received CECT or unenhanced CT.

Currently available propensity studies demonstrating equivalence of AKI between groups exposed and not exposed to CM are also limited by the numbers of patients studied who are truly at increased risk. Despite the robust number of patients studied, the majority have normal or mildly impaired renal function. In the studies by McDonald et al. (4) and Davenport et al. (5), the proportion of patients with eGFR >60 mL/min were 45% and 79%, respectively. It should not be surprising to any nephrologist that the AKI rates for these two groups were similar, given that it is well established that CM is rarely nephrotoxic in patients with normal or mildly impaired renal function. Conversely, the number of patients in these studies with more severe pre-existing CKD, and thus at higher risk of CIN, was comparatively small, with only 11% of individuals in the study by McDonald et al. (4), and 0.6% of those in the study by Davenport et al. (5), having an eGFR <30 mL/min. Other limitations include failure to adjust for other confounding covariates, including prophylactic strategies, concomitant use of nephrotoxic medications, and volume of CM administered; the inclusion of patients with AKI before CT was performed; and misclassification of comorbidities by International Classification of Diseases 9th edition codes. Furthermore, these studies were composed primarily of inpatients, who are inherently more at risk for AKI from multiple causes; were not adjusted for the clinical indications for the CTs; and did not include assessments for long-term mortality or development of CKD.

In addition to the limitations of the current observational literature, there are other important reasons why physicians should not adopt a cavalier position on the nephrotoxicity of IV CM. Multiple experimental studies have demonstrated CM nephrotoxicity (6). The limitations of these experimental studies notwithstanding, the collective evidence of these studies raises a serious concern about CM nephrotoxicity in humans. Furthermore, AKI in general and from CM specifically has been associated with an increased risk of CKD and long-term mortality, and these associations are supported by experimental studies proving plausible biologic mechanisms for these adverse outcomes (2, 3).

So how should physicians interpret the risk of AKI from IV CM administration in light of recent studies? It is clear that there is a negligible risk for AKI from IV CM in patients with normal (eGFR ≥60 mL/min) or mildly impaired (eGFR 45–59 mL/min) renal function. It is also clear that patients with eGFR <30 mL/min are at greatest risk for CIN and should continue to be classified as such, despite mixed findings of propensity-matched studies. This leaves open the question of how to risk classify patients with eGFR between 30 and 45 mL/min. Although propensity-adjusted studies suggest this group is not at increased risk, there remain lingering concerns over the methods behind these observational studies. We suggest that risk classification for CM nephrotoxicity should not be based solely on eGFR, especially for patients with eGFR of 30 to 45 mL/min. Physicians evaluating the nephrotoxic risk of CM should take into consideration each patient’s unique risk factors for AKI and the benefit gained from a CECT. Resolution of the question of the potential risk of IV CM nephrotoxicity in patients historically considered to be at moderate to high risk will require additional clinical research. Prospective randomized trials will not be possible for ethical reasons. However, observational studies should be conducted in a variety of clinical settings, primarily in patients with eGFR <45 mL/min, with adequate power using methods that adjust for patient differences.

April 2018 (Vol. 10, Number 4)

References

1. Luk L, Steinman J, Newhouse JH. Intravenous contrast-induced nephropathy–the rise and fall of a threatening idea. Adv Chronic Kidney Dis 2017; 24:169–175.

2. Coca SG, et al. The prognostic importance of a small acute decrement in kidney function in hospitalized patients: A systematic review and meta-analysis. Am J Kidney Dis 2007; 50:712–720.

3. Coca SG, et al. Long-term risk of mortality and other adverse outcomes after acute kidney injury: A systematic review and meta-analysis. Am J Kidney Dis 2009; 53:961–973.

4. McDonald JS, et al. Risk of intravenous contrast material-mediated acute kidney injury: A prospective score-matched study stratified by baseline-estimated glomerular filtration rate. Radiology 2014; 271:65–73.

5. Davenport MS, et al. Contrast material-induced nephrotoxicity and intravenous low-osmolality iodinated contrast material: Risk stratification by using estimated glomerular filtration rate. Radiology 2013; 268:719–728.

6. Andreucci M, et al. Update on the renal toxicity of iodinated contrast drugs used in clinical medicine. Drug Healthc Patient Saf 2017; 9:25–37.