In this issue of Academic Emergency Medicine, Sinert et al.1 highlight three central controversies surrounding contrast-induced nephropathy (CIN): 1) does the current definition of CIN identify patients who have acute kidney injury (AKI) as a result of iodinated contrast-media exposure; 2) does a rise in creatinine following iodinated contrast exposure, that meets the definition of CIN, identify patients at increased risk of subsequent severe renal failure and death; and 3) does iodinated contrast cause clinically significant AKI1 CIN results from the convergence of biochemical and pathophysiologic processes that initiate an insidious course with many parallels to other insidious diseases such as benign essential hypertension and diabetes mellitus. The initial stage is indolent and asymptomatic. The resulting outcomes may take years to manifest, occurring across a wide spectrum of severity, ranging from mild chronic renal insufficiency to abject end stage renal failure. Moreover, CIN may elude its due blame for renal injury, which may be misplaced on chronic injury from other diseases. Accordingly, CIN remains difficult to fully characterize, diagnose, and manage.
Defining Contrast-induced Nephropathy
An enormous preclinical literature has described multiple mechanisms initiated by intravenous (IV) contrast that can injure the kidney, including arteriolar vasospasm, platelet aggregation and increased coagulation in small vessels, and free radical mediated injury to the renal tubular epithelium.2,3 However, in the clinical setting, current definitions of CIN all incorporate serum creatinine as the main dependent variable and are therefore hobbled by the inadequacies of creatinine as a biomarker of AKI. The nonlinear relationship between the rise in serum creatinine concentration and kidney function (as estimated glomerular filtration rate4) generally leads to clinical underestimation of the degree of kidney injury associated with small increases in serum creatinine (Figure 1). For this reason, the standard definition of CIN includes both a relative threshold (increase in creatinine of ≥25%) and an absolute threshold (increase in creatinine of ≥0.5 mg/dL). While some experts apply only the absolute threshold to populations with preexisting renal insufficiency, the article by Sinert et al. includes only patients with baseline serum creatinine values in the normal range. Among several proposed definitions of CIN, only two have been studied with respect to short-term (weeks to months) and long-term (months to years) outcomes, specifically severe renal failure and death. Harjai et al.5 compared both the relative and the absolute portions of the standard definition, separately and combined, as well as two alternatives longitudinally for mortality at 1 year, finding that the combined standard definition had the highest prognostic accuracy. Solomon et al.6 have also proposed a definition of an absolute increase in creatinine of ≥0.3 mg/dL, which demonstrated improved sensitivity when compared to the standard definition, although equal specificity for death at 3 years. However, Solomon et al. did not include patients without preexisting renal insufficiency, defined by an elevated baseline serum creatinine.6 In the emergency care setting, where many patients do not have an abnormal baseline serum creatinine, the utility of this definition may be limited in the emergency care setting, where many patients have an abnormal baseline serum creatinine.
The timing of creatinine rise after AKI further impairs its relevance in emergency care. The peak increase in serum creatinine observed with CIN following IV contrast exposure typically occurs 3 to 5 days after exposure, with recovery to the same or a different baseline >7 days after contrast exposure. Thus, limiting the follow-up period to 2 days may underestimate cases of CIN by 10% to 60%.2,3 Further complicating the identification of CIN, prophylactic treatments such as n-acetylcysteine and sodium bicarbonate may spuriously delay a measurable rise in creatinine. The rate of severe outcomes following the development of CIN remains the same, regardless of whether creatinine increases early or late after exposure to contrast material.2,3,7–9 In short, the development of alternative markers of AKI is needed to improve both the ability and accuracy of identification of patients at risk of severe outcomes following the development of CIN, leading to the second controversy discussed in the article.
Is CIN a Nephropathy or a Laboratory Creatininopathy?
Most CIN data come not from ambulatory patients undergoing contrast-enhanced computed tomography scanning, but instead from patients undergoing cardiac catheterization. These studies consistently demonstrate an increase in severe outcomes, both short- and long-term, specifically severe renal failure and death, among patients who have a rise in serum creatinine following the IV administration of iodinated contrast meeting the standard definition of CIN, compared to patients who did not develop CIN.2,6 Patients who develop severe outcomes such as renal failure and death following contrast administration usually have concurrent risk factors such as hypertension, diabetes, and vascular disease with superimposed acute stressors such as hemorrhage, dehydration, sepsis, and hypotension.2 Many patients who develop severe renal failure do so after several exposures to contrast within a few days. No study has controlled for these confounders to allow a quantitative estimate of the true nephrotoxicity of 100 to 150 mL of nonionic, low-osmolar iodinated contrast in an emergency department (ED) population. The relative importance of synchronous risk factors and our ability to manipulate these factors to change outcomes introduces the third controversy raised in the article.
Is CIN a Marker of Death or a Cause?
What is the cause-and-effect relationship between the administration of contemporary IV iodinated contrast media and the subsequent development of renal failure and death? Similar to other retrospective studies of inpatients, Sinert et al. found a similar rate of nephropathy among inpatients exposed to iodinated contrast agents compared to patients who were not.1,10–12 Since patients are not routinely screened for CIN following contrast exposure, and these studies do not include extended follow-up, this and other retrospective studies may underestimate the prevalence of CIN and subsequent consequences. Other studies have demonstrated a significant underlying rate of nephropathy among hospitalized patients in general, which is associated with increased subsequent morbidity and mortality.13–15 In this article, Sinert et al. compare their findings to those of a prospective ED-based study of patients by Mitchell et al.,16 undergoing contrast-enhanced computerized tomography, speculating that other inpatient causes of nephropathy likely contributed to the observed high rate of nephropathy in the study.1,16 However, 51% of patients enrolled in the study by Mitchell were discharged from the ED, and the incidence of CIN (10%) was the same in both hospitalized and discharged patients.16,17
The work by Sinert et al. highlights the wide and deep gap in knowledge that separates current practice from an evidence-based approach.1 Current literature remains devoid of a large, prospective placebo-controlled study designed to test the degree of kidney injury caused by iodinated intravenous contrast in the emergency care setting. More work is needed to risk stratify patients for the development of clinically important contrast-induced AKI with respect to the context and potential knowledge to be gained from contrast-enhanced images to evaluate threats to life.
In summary, Sinert et al. identify several important controversies surrounding the use of contrast-enhanced imaging studies, particularly in our practice, highlighting the necessity of research aimed at answering these important questions. The facts remain that ample literature strongly implicates iodinated contrast as a direct nephrotoxin and shows that CIN is temporally associated with an increased risk of severe renal failure and death. At the present time, the weight of the evidence points toward contrast as a real cause of kidney injury.