Does IV contrast cause renal failure?

Does IV Contrast Cause Renal Failure?
Latest evidence / how do we proceed

By Richard Sinert DO
(Professor of Emergency Medicine, Vice-Chairman of Research, State University of New York Downstate Medical Center)

Edited by Alex Koyfman MD (@EMHighAK) and Stephen Alerhand MD (@SAlerhand)

Contrast-Induced Acute Kidney Injury (CI-AKI) is a syndrome defined by an absolute (0.5 mg/dl) or relative increase (25%) in Serum Creatinine (SCr) 48-72 hours after intravenous or intra-arterial iodinated contrast administration. At first look Emergency Medicine Physicians should be very concerned about CI-AKI, a completely iatrogenic cause of renal failure implicated as one of the most common causes of hospital-acquired Acute Kidney Injury (AKI)^[i], accounting for 11%^[ii] – 12%^[iii] of cases. Acute Renal Replacement Therapy (RRT) will be required for 3%[iv] – 15%[v] of CI-AKI patients. Hospitalized patients complicated by CI-AKI compared to patients with similar pre-morbid characteristics experience longer hospital stays5^,[vi],[vii] and suffer significantly higher in-hospital[viii],[ix],[x] and long-term mortality rates[xi]. Those patients who survive CI-AKI are predisposed to continued loss of kidney function.^[xii],[xiii]

Yet, the relationship between contrast with renal failure is based solely on observations of patients only after contrast exposure. We must be reminded that observational studies can only show associations not causation between the purported risk and outcome. Studies of CI-AKI use a prospective cohort study design, where all the study patients are exposed to contrast and followed over time to define the incidence of CI-AKI. Since no patients unexposed to contrast are followed up; all other potential etiologies of renal failure are overwhelmed by contrast exposure. This methodology which all patients have the exposure of interest are especially prone to confounding bias, where a hidden variable(s), explains the causal link between risks and outcomes better than the observed temporal association. The question remains whether the observational prospective cohort studies underlying the definition of CI-AKI are convincing enough to support contrast as an independent risk for renal failure. I would like to examine the evidence behind the causal chain linking contrast-enhanced CT Scans with AKI, progression to Chronic Kidney Disease (CKD), need for RRT, and death.

Causal relationships can only truly be proven with prospective studies where randomized groups are exposed and unexposed and followed over time to accurately measure incidence of the outcome of interest. However, randomized prospective studies of CI-AKI would not be feasible from ethical or sample size requirements. We are only left to measure the strength of the observed association between contrast exposure and renal failure. Lipsitch et al[xiv] suggests a counterfactual test to limit confounding bias inherent in observational studies. A counterfactual test requires a negative control experiment where the observation is repeated under conditions not expected to produce the outcome of interest. If the outcome is encountered without the exposure, then a confounding bias may exist, significantly weakening the association between the risk and its believed outcome.

A counterfactual methodology for testing the causal link between contrast and AKI compares the incidence of AKI between those patients exposed and unexposed to intravenous contrast. Such a counterfactual methodology of studying CI-AKI has been reported in systematic reviews of CI-AKI by Rao et al[xv] in 2006 and McDonald et al[xvi] in 2013. These two systematic reviews, found no statistically significant difference in the incidence of AKI in contrast exposed compared to unexposed patients. The majority of the studies reviewed in these two systematic reviews mixed inpatients with ED patients with and without CKD. Sinert et al[xvii] studied ED patients with normal baseline renal function (SCr < 1.5 mg/dl) comparing 773 contrast-exposed to 2,956 unexposed. Using the conventional definition of CI-AKI, unexposed compared to contrast-exposed patients had a significantly (P=0.003) higher incidence of AKI 8.96% vs. 5.69%, respectively. From this data it would appear that intravenous contrast was not a risk for AKI, but protected against hospital-acquired AKI. The patients in the contrast exposed and unexposed groups that developed AKI by the CI-AKI criteria had similar outcomes with respect for RRT requirements and mortality rates.

The findings of these studies suggest a significant risk of a confounding bias in the current definition of CI-AKI. Since by definition CI-AKI only occurs in patients with a pre-existing reason for contrast, the possibility that other etiologies besides contrast exposure are in part or wholly responsible for AKI. Confounding the risk of contrast causing AKI includes not only the primary disease that prompted the CT, but also pre-existing or intercurrent processes such as progression of CKD, hypovolemia, hypotension, sepsis, or other nephrotoxic exposures (e.g. NSAIDs, antibiotics, toxins, etc.).

The PROSPERO[xviii] study is a planned systematic review of CI-AKI after CT Scans will utilize a similar counterfactual methodology, including more recent studies by Davenport et al[xix] and McDonald et al [xx] that used propensity-matching analysis to reduce confounding bias of observational studies[xxi]. Both the Davenport et al19 and McDonald et al20 studies of patients with normal kidney function (SCr < 1.5 mg/dl) also failed to find a higher rate of CI-AKI in contrast-exposed compared to unexposed patients receiving CT-Scans. In the ED, contrast exposure does not appear to have a direct causal link either to the increases in SCr, the need for RRT, or death. We hope that the POSPERO18 study will finally dispel the association between contrast exposure with either AKI, CKD, need for RRT, or death.

The implications of questioning the definition of CI-AKI to define a specific disease are: that it is safe to administer intravenous contrast to patients with normal renal function without the fear of AKI. Informed consent policies for discussing the risks of AKI after contrast are no longer justified. Further additional studies are clearly indicated in the group with an elevated SCr or an estimated GFR less than 60 ml/min/1.73m².

Future studies of CI-AKI in patients with baseline renal insufficiency should include suitable negative controls of unexposed patients with the addition of propensity matching for the conventional risks for AKI. These studies must have appropriate power to detect clinically significant outcomes such as rates of RRT and mortality.

References:

[i] Shusterman N, Strom BL, Murray TG, Morrison G, West SL, Maislin G. Risk factors and outcome of hospital-acquired acute renal failure. Clinical epidemiologic study. Am J Med 1987;83:65-71.
[ii] Nash K, Hafeez A, Hou S. Hospital-acquired renal insufficiency. Am J Kidney Dis 2002;39:930-6.
[iii] Hou SH, Bushinsky DA, Wish JB, Cohen JJ, Harrington JT. Hospital-acquired renal insufficiency: a prospective study. Am J Med 1983;74:243-8.
[iv] Nikolsky E, Mehran R, Turcot D, et al. Impact of chronic kidney disease on prognosis of patients with diabetes mellitus treated with percutaneous coronary intervention. Am J Cardiol 2004;94:300-5.
[v] Marenzi G, Lauri G, Assanelli E, et al. Contrast-induced nephropathy in patients undergoing primary angioplasty for acute myocardial infarction. J Am Coll Cardiol 2004;44:1780-5.
[vi] Wickenbrock I, Perings C, Maagh P, et al. Contrast medium induced nephropathy in patients undergoing percutaneous coronary intervention for acute coronary syndrome: differences in STEMI and NSTEMI. Clin Res Cardiol 2009;98:765-72.
[vii] Shema L, Ore L, Geron R, Kristal B. Contrast-induced nephropathy among Israeli hospitalized patients: incidence, risk factors, length of stay and mortality. Isr Med Assoc J 2009;11:460-4
[viii] Levy EM, Viscoli CM, Horwitz RI. The effect of acute renal failure on mortality. A cohort analysis. JAMA 1996;275:1489-94.
[ix] Senoo T, Motohiro M, Kamihata H, et al. Contrast-induced nephropathy in patients undergoing emergency percutaneous coronary intervention for acute coronary syndrome. Am J Cardiol 2010;105:624-8.
[x] Medalion B, Cohen H, Assali A, et al. The effect of cardiac angiography timing, contrast media dose, and preoperative renal function on acute renal failure after coronary artery bypass grafting. J Thorac Cardiovasc Surg 2010;139:1539-44.
[xi] Rihal CS, Textor SC, Grill DE, et al. Incidence and prognostic importance of acute renal failure after percutaneous coronary intervention. Circulation 2002;105:2259-64.
[xii] Amdur RL, Chawla LS, Amodeo S, Kimmel PL, Palant CE. Outcomes following diagnosis of acute renal failure in U.S. veterans: focus on acute tubular necrosis. Kidney Int 2009;76:1089-97.
[xiii] Goldenberg I, Chonchol M, Guetta V. Reversible acute kidney injury following contrast exposure and the risk of long-term mortality. Am J Nephrol 2009;29:136-44.
[xiv] Lipsitch M, Tchetgen E, Cohen T. Negative controls: a tool for detecting confounding and bias in observational studies. Epidemiology 2010;21:383-8.
[xv] Rao QA, Newhouse JH. Risk of nephropathy after intravenous administration of contrast material: a critical literature analysis. Radiology 2006;239:392-7.
[xvi] McDonald JS, McDonald RJ, Comin J, et al. Frequency of acute kidney injury following intravenous contrast medium administration: a systematic review and meta-analysis. Radiology 2013;267:119-28.
[xvii] Sinert R, Brandler E, Subramanian RA, Miller AC. Does the current definition of contrast-induced acute kidney injury reflect a true clinical entity? Academic emergency medicine : official journal of the Society for Academic Emergency Medicine 2012;19:1261-7
[xviii] Kayibanda JF, Hiremath S, Knoll GA, et al. Does intravenous contrast-enhanced computed tomography cause acute kidney injury? Protocol of a systematic review of the evidence. Systematic reviews 2014;3:94.
[xix] Davenport MS, Khalatbari S, Dillman JR, Cohan RH, Caoili EM, Ellis JH. Contrast material-induced nephrotoxicity and intravenous low-osmolality iodinated contrast material. Radiology 2013;267:94-105.
[xx] McDonald RJ, McDonald JS, Bida JP, et al. Intravenous contrast material-induced nephropathy: causal or coincident phenomenon? Radiology 2013;267:106-18.
[xxi] Luo Z, Gardiner JC, Bradley CJ. Applying propensity score methods in medical research: pitfalls and prospects. Medical care research and review : MCRR 2010;67:528-54.