Contrast-Induced Nephropathy: Confounding Causation
Author: Richard Sinert, DO (Professor of Emergency Medicine / Vice Chair of Research, SUNY Downstate Medical Center) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UT Southwestern Medical Center / Parkland Memorial Hospital) and Brit Long, MD (@long_brit)
I would like to applaud the study “Risk of Acute Kidney Injury After Intravenous Contrast Media Administration” by Hinson et al in the February 2017 issue of Annals of Emergency Medicine. Before discussing the details of this study, I would like to give a historical perspective on how the study of CIN has evolved.
Since the first observation by Bartels et al of the association between between contrast administration and Acute Kidney Injury (AKI), multiple studies gave further added weight to the association between intravenous contrast and AKI[3-7].
Although CIN is defined by a relatively small change in serum creatinine (SCr) (25% from baseline or an absolute increase of 0.5 mg/dl 48-72 hours post infusion), the consequences for CIN patients at least on the surface seemed dire. Among cardiac catheterization patients, CIN increased the mortality rates from 6% to 16% in one study and from 0.6% to 31% in another. Higher composite mortality rates and need for renal replacement (relative risk = 36) were also observed in patients who met the definition for CIN following CT-PA, after intravenous contrast in pulmonary embolism patients who developed CIN.
At this point an iatrogenic injury (CIN) was linked to an easily measured disease marker (timed changes in SCr) that seemed to be associated with adverse outcomes. Not surprisingly, the medical community with the best of intentions studied the risks, and a wide-range,, of potential measures to prevent CIN.
Yet all these studies documenting CIN incidence, risks, outcomes, and prophylactic strategies suffer a bias common to many observational studies— confounding bias,. Confounding bias occurs when an exposure is inappropriately causally linked to an outcome, when a separate exposure (confounding variable) other than the one of interest better explains the observed outcome. Since the definition of CIN requires a second timed measurement of SCr, these studies must select for a relatively ill group of hospitalized patients undergoing repeated laboratory testing; selection bias must be considered. Decrements in kidney function signaled by a rise of SCr could have occurred from the incident disease before or after contrast administration. In addition, intercurrent hemodynamic instability (eg., sepsis, hemorrhage, diuresis) and a multitude of nephrotoxins (eg., NSAID’s, ACE-Inhibitors, antibiotics) are common complications during hospitalization, which may also explain an increased SCr and associated higher mortality rates. Newhouse et al found that among 32,161 hospitalized patients not exposed to contrast, 19% of patients had a 25% increase in SCr, which would have fulfilled diagnostic criteria for CIN had they been exposed to IV contrast.
Lipsitch et al stated that non-causal associations between outcomes and exposures are the result of either mismeasurement (recall bias), confounding bias, or selection bias. To prevent confounding, Lipsitch et al suggests designing a negative control experiment where the observation is repeated under conditions that are not expected to produce the outcome of interest. If the outcome is encountered without the exposure, then a confounding bias may exist. This form of negative control experiment in which the incidence of AKI is compared across patients exposed and unexposed to contrast has been studied by multiple investigators, , ,  , all failed to find a statistically significant difference in AKI rate (using CIN definition) between those exposed to contrast and controls.
These studies[18-21] that compared the incidence of CIN between contrast- exposed and unexposed groups also posed methodological issues related to the differences in the baseline risks of AKI between the two study groups. It is not surprising that the patients hospitalized after requiring a contrast-enhanced CT may be inherently different that those not requiring a similar study. To account for this potential selection bias, multiple studies have compared the incidence of AKI between contrast exposed and unexposed patients utilized propensity-scoring matching. Propensity-score matching is a methodology that balances the baseline outcome risks between the study groups. Even utilizing propensity-score matching for AKI, multiple studies, , , ,  again failed to find a statistically higher incidence of AKI in the contrast- exposed compared to unexposed group of hospitalized patients. In addition, the increases in risks of higher mortality rate in the CIN patients were not found when propensity-scoring matching accounted for the baseline risk of mortality of the contrast-exposed and non-contrast exposed patients.
The most recent CIN study by Hinson et al in this recent issue of Annals of Emergency Medicine represents the latest in the line of investigations into the causal relationship between contrast and AKI. Hinson et al conducted a retrospective study over a 5-year period comparing the incidence of AKI among three groups, including contrast-enhanced CT (n=7,201), non-contrast enhanced CT (n=5,499), and those in whom CT was not performed (n=5,234). These three groups were propensity-scoring matched for AKI risks. AKI was defined both using the common CIN definition and definitions of AKI as reported in the Acute Kidney Injury Network/Kidney Disease Improving Global Outcomes (KDIGO) guidelines. Applying the traditional definition of CIN, AKI was found in 10.6%, 10.2%, and 10.9% in contrast-enhanced CT, non-contrast CT, and non-CT groups, respectively. Utilizing the KDIGO AKI definitions, AKI occurred in 6.7%, 8.9%, and 8.1% in contrast-enhanced CT, non-contrast CT, and non-CT groups, respectively.
Compared to previous propensity-scoring matched studies mentioned above, Hinson et al went a step further by conducting a multiple logistic regression analysis, including in their model known predictors of AKI and contrast administration. From the multiple logistic regression model, contrast administration produced a non-significant odds-ratio for AKI as defined by both the CIN (0.96 [95% CI, 0.85-1.08]) and KDIGO criteria (1.00 [95% CI, 0.87-1.1.6]). Moreover, the authors found no differences among the three study groups for the development of chronic kidney disease, need for dialysis, or renal transplantation in the following 6 months post-contrast exposure.
Although patients with elevated SCr (> 4.0 mg/dl) were excluded from their primary analysis, multiple logistic regression analysis of patients with elevated baseline SCr found no independent risk of AKI for contrast administration.
In conclusion, comparing the methodological rigor of more recent CIN studies to those in the past, it seems clear that earlier studies purporting a causal relationship between AKI and contrast administration were only identifying an association but not a true clinical entity. Older CIN studies were biased by confounding variables (e.g., hemodynamic instability, nephrotoxins), with well-established links to AKI providing a sufficient cause for AKI without implicating contrast as an additional AKI risk.
The history of the study of CIN is just another example of evidence-based medicine successfully applied to the debunking of a common belief in a clinical syndrome. As ED physicians are faced with the challenge of rapidly diagnosing life-threatening conditions (i.e. aortic dissection/aneurysmal rupture, pulmonary embolism, occlusion or aneurysmal rupture of cerebral vessels, traumatic vascular injury), we should not delay emergent contrast-enhanced CT scans waiting for SCr.
References / Further Reading
 Hinson JS, Ehmann MR, Fine DM, et al. Risk of Acute Kidney Injury After Intravenous Contrast Media Administration. Ann Emerg Med 2017.
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 Mitchell AM, Jones AE, Tumlin JA, Kline JA. Prospective study of the incidence of contrast-induced nephropathy among patients evaluated for pulmonary embolism by contrast-enhanced computed tomography. Acad Emerg Med 2012;19:618-25.
 Mehran R, Aymong ED, Nikolsky E, et al. A simple risk score for prediction of contrast-induced nephropathy after percutaneous coronary intervention: development and initial validation. J Am Coll Cardiol 2004;44:1393-9.
 Lin KY, Zheng WP, Bei WJ, et al. A novel risk score model for prediction of contrast-induced nephropathy after emergent percutaneous coronary intervention. International journal of cardiology 2017;230:402-12.
 Li H, Wang C, Liu C, Li R, Zou M, Cheng G. Efficacy of Short-Term Statin Treatment for the Prevention of Contrast-Induced Acute Kidney Injury in Patients Undergoing Coronary Angiography/Percutaneous Coronary Intervention: A Meta-Analysis of 21 Randomized Controlled Trials. American journal of cardiovascular drugs: drugs, devices, and other interventions 2016;16:201-19.
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 Newhouse JH, Kho D, Rao QA, Starren J. Frequency of serum creatinine changes in the absence of iodinated contrast material: implications for studies of contrast nephrotoxicity. AJR Am J Roentgenol 2008;191:376-82.
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 Cramer BC, Parfrey PS, Hutchinson TA, et al. Renal function following infusion of radiologic contrast material. A prospective controlled study. Arch Intern Med 1985;145:87-9
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 Hsieh MS, Chiu CS, How CK, et al. Contrast Medium Exposure During Computed Tomography and Risk of Development of End-Stage Renal Disease in Patients With Chronic Kidney Disease: A Nationwide Population-Based, Propensity Score-Matched, Longitudinal Follow-Up Study. Medicine 2016;95:e3388.
 Tremblay LN, Tien H, Hamilton P, et al. Risk and benefit of intravenous contrast in trauma patients with an elevated serum creatinine. J Trauma 2005;59:1162-6; discussion 6-7.
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 Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl. 2012;2:1-138.