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- ↵⁎Reprint requests and correspondence:
Dr. Roxana Mehran, Columbia University Medical Center and The Cardiovascular Research Foundation, 161 Fort Washington Avenue, 5th Floor, New York, New York 10032
Acute kidney injury (AKI) after exposure to intravenous or intra-arterial iodinated contrast material (contrast-induced [CI]-AKI) increases morbidity and length of hospital stay. Our group and others reported on the association of this complication with early and late clinical outcomes. Interesting aspects in these subjects include 3 types of studies: 1) those investigating the pathophysiology of this phenomenon; 2) those investigating its predictive factors and its clinical sequelae; and 3) those investigating preventive measures. Many centers have contributed individual, albeit mostly small-size, studies to this end. Nonetheless, we have learned some very useful lessons over the years.
Although the precise pathophysiologic mechanism for CI-AKI is still unknown, we recognized early the importance of the adverse effects of high contrast media osmolality and low intravascular volume status. Additional risk factors have been identified by a plethora of small studies. Through the development of a simple score that takes several of the most prominent predictors into consideration, we have attempted to improve the estimation of CI-AKI risk (1).
Despite original reports that focused on the importance of CI-AKI requiring dialysis as the major prognostic factor, it became progressively evident that even an incremental decrease in creatinine clearance without dialysis would also be prognostically important. An increase by 25% over baseline has been widely used, although more sensitive definitions have also been proposed.
The value of preventive measures has been more controversial. Pre-procedure hydration to reach euvolemia has been the first clear winner that also happens to be very inexpensive and therefore quite cost-effective. Its only cost is a silent one. The pre-procedure length of stay for an ambulatory invasive procedure can be prolonged; this may cause inconvenient delays and scheduling conflicts if not attended to properly from an administrative point of view. Other than hydration, most tested measures have been highly controversial. Low osmolality contrast media seems better than high osmolality, but in an era in which most contrast media are in the low range, one needs to wonder whether “the lower the better” is a clinically meaningful statement.
N-acetylcysteine and sodium bicarbonate have emerged through impressive initial studies but have been subsequently subjected to criticism. In this issue of the Journal, Thiele et al. (2) report on the lack of efficacy of high-dose intravenous N-acetylcysteine for the prevention of CI-AKI in patients with ST-segment elevation myocardial infarction. The investigators also observed that N-acetylcysteine reduced oxidative stress; however, reperfusion injury, measured as myocardial salvage index by magnetic resonance imaging, was similar between the N-acetylcysteine and placebo groups. Although these data do not support the routine administration of high-dose intravenous N-acetylcysteine, there are several noteworthy limitations that need to be recognized. First, the sample size of 258 patients was modest for the detection of CI-AKI. The absolute reduction in the CI-AKI with N-acetylcysteine was 6%, a difference that was not statistically significant. The lack of observed benefit may represent a type II error, that is, concluding that a benefit does not exist when one really does. Second, the mean creatinine clearance was approximately 85 ml/min, suggesting that many patients were at low risk of CI-AKI. Third, some events classified as CI-AKI may have had alternative or multiple causes. Hypotension, even transient, may precipitate AKI that is unrelated to contrast exposure. Although the random allocation to treatment should have attenuated any misclassification, concern remains, given the modest sample size of the trial. Last, although similar rates of clinical events at 6 months suggest the lack of a treatment effect, these comparisons remain grossly underpowered. No trial to date has been adequately powered for the detection of meaningful clinical end points.
Meta-analyses have attempted to address these difficult issues without the ability to add any more definitive information due to the fact that they carry all the limitations of the small studies on which they are based. However, meta-analyses have been helpful for understanding sources of heterogeneity between studies (3). For example, the treatment effect for preventive therapies seems to be greatest in smaller trials. Furthermore, there is evidence of publication bias where positive trials are more likely to be published. Therefore, a definitive conclusion cannot be reached based on the multitude of conflicting data, much of which is from small trials.
The latter has been a critical issue of clinical investigation in CI-AKI. The absence of robust sponsorship in this area of interest has promoted the conduct of largely underfunded (and hence typically underpowered) clinical studies that have left major questions unanswered. These include the following: 1) Does AKI have a causal relationship with subsequent mortality? 2) Is this risk modifiable by any of the preventive measures? 3) If AKI is a marker of association with subsequent mortality, would any preventive measures be beneficial in such patients?
These crucial questions become even more important when one realizes that they are operational in the context of severe comorbid conditions such as coronary heart disease, diabetes mellitus, renal insufficiency, and congestive heart failure. These patients need a dedicated investigation with an adequately powered clinical trial to address the issues of effective prevention and outcome of CI-AKI after iodinated contrast exposure.
Dr. Mehran has received modest lecture honoraria from Bracco (through NACCME) and Guerbet, and research support (to Columbia University Medical Center) from Bracco. Dr. Dangas has received modest lecture honoraria from Bracco (through NACCME) and Guerbet.
↵⁎ Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
- American College of Cardiology Foundation
- Mehran R.,
- Aymong E.D.,
- Nikolsky E.,
- et al.
- Thiele H.,
- Hildebrand L.,
- Schirdewahn C.,
- et al.
- Brar S.S.,
- Hiremath S.,
- Dangas G.,
- Mehran R.,
- Brar S.K.,
- Leon M.B.