Tag Archives: contrast-induced acute kidney injury

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, UTSW / 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[1] 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[2] 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[3] from 6% to 16% in one study[7] and from 0.6% to 31% in another[6].  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[4].

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[5],[6] and a wide-range[7],[8],[9] 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[10],[11].   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[12] 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[13] 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[13] 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[14], [15], [16], [17] , 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[18].  Even utilizing propensity-score matching for AKI, multiple studies[19], [20], [21], [22], [23] 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[1] 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[1] 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[24].   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[1] 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

[1] Hinson JS, Ehmann MR, Fine DM, et al. Risk of Acute Kidney Injury After Intravenous Contrast Media Administration. Ann Emerg Med 2017.

[2] Bartels ED, Brun GC, Gammeltoft A, Gjorup PA. Acute anuria following intravenous pyelography in a patient with myelomatosis. Acta Med Scand 1954;150:297-302.

[3] Pickering JW, Blunt IR, Than MP. Acute Kidney Injury and mortality prognosis in Acute Coronary Syndrome patients: A meta-analysis. Nephrology (Carlton, Vic) 2016.

[4] 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.

[5] 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.

[6] 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.

[7] 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.

[8] Wang N, Qian P, Kumar S, Yan TD, Phan K. The effect of N-acetylcysteine on the incidence of contrast-induced kidney injury: A systematic review and trial sequential analysis. International journal of cardiology 2016;209:319-27.

[9] Subramaniam RM, Suarez-Cuervo C, Wilson RF, et al. Effectiveness of Prevention Strategies for Contrast-Induced Nephropathy: A Systematic Review and Meta-analysis. Ann Intern Med 2016;164:406-16.

[10] Grimes DA, Schulz KF. Bias and causal associations in observational research. Lancet 2002;359:248-52.

[11] McNamee R. Confounding and confounders. Occup Environ Med 2003;60:227-34; quiz 164, 234.

[12] 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.

[13] Lipsitch M, Tchetgen Tchetgen E, Cohen T. Negative controls: a tool for detecting confounding and bias in observational studies. Epidemiology 2010;21:383-8.

[14] 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

[15] Heller CA, Knapp J, Halliday J, O’Connell D, Heller RF. Failure to demonstrate contrast nephrotoxicity. Med J Aust 1991;155:329-32.

[16] Bruce RJ, Djamali A, Shinki K, Michel SJ, Fine JP, Pozniak MA. Background fluctuation of kidney function versus contrast-induced nephrotoxicity. AJR Am J Roentgenol 2009;192:711-8.

[17] Sinert R, Brandler E, Subramanian RA, Miller AC. Does the current definition of contrast-induced acute kidney injury reflect a true clinical entity? Acad Emerg Med 2012;19:1261-7.

[18] Haukoos JS, Lewis RJ. The Propensity Score. JAMA 2015;314:1637-8.

[19] 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.

[20] McDonald RJ, McDonald JS, Carter RE, et al. Intravenous contrast material exposure is not an independent risk factor for dialysis or mortality. Radiology 2014;273:714-25.

[21] 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.

[22] 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.

[23] Cely CM, Schein RM, Quartin AA. Risk of contrast induced nephropathy in the critically ill: a prospective, case matched study. Critical care (London, England) 2012;16:R67.

[24] 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.

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.