Intravenous iodinated contrast media are routinely used to improve the diagnostic accuracy of computed tomography (CT). The use of CT imaging in the emergency department (ED) has increased exponentially. Contrast medium administration is reported to be the third most common cause of iatrogenic acute kidney injury,[2,3] and has been linked to an increased risk of major adverse events, including dialysis initiation, renal failure, stroke, myocardial infarction, and death.[2,4,5] In the ED, intravenous administration of contrast media for enhancement of CT imaging is often necessary in diagnosing acute critical conditions. Recent studies performed in the ED have reported an incidence of contrast-induced nephropathy (CIN) as high as 14%, and linked CIN to a 2-fold increased risk of major adverse events within 1 year.[6,7] Although these reports are concerning, the causal relationship between the administration of intravenous contrast media and the development of acute kidney injury has recently been challenged.[8,9]
The Contrast Media Safety Committee recommends that the term “postcontrast acute kidney injury” (PC-AKI) should replace the older term “CIN,” and suggests using the terms recommended by the American College of Radiology Committee on Drugs and Contrast Media when acute kidney injury occurs following contrast medium administration. The Contrast Media Safety Committee stated that PC-AKI is the best term to apply to renal function deterioration after intravascular contrast medium administration because, unlike some of the older terms, it does not imply that the contrast medium is the cause. PC-AKI is loosely defined as an increase in creatinine level or decrease in glomerular filtration rate after contrast medium administration. The most common description is an increase in creatinine level by 25% after contrast medium administration or an absolute increase of 0.3 to 0.5 mg/dL within 3 days.
Congestive heart failure (CHF), especially in advanced stages of New York Heart Association class 3–4, contributes to the development of PC-AKI primarily by decreasing renal perfusion. It is related to systolic dysfunction and low stroke volume. In fact, some researchers specifically identified an ejection fraction (EF) of < 30% to 40% as an independent predictor of CIN. However, the association between diastolic dysfunction and PC-AKI remains largely unknown until now.
The gold standard for estimating the diastolic function of the heart is to measure the left ventricular end-diastolic pressure with catheterization. However, it is invasive and not routinely practiced in the current clinical settings. On the other hand, E/E′ (early left ventricular filling velocity to early diastolic mitral annular velocity ratio) can be assessed noninvasively with echocardiography and is known to be less influenced by heart rate, atrial activity, or EF.
A previous study demonstrated that, among the echocardiographic variables, E/E′ was an independent predictor of CIN after coronary angiography. This, in turn, suggests that diastolic dysfunction may be a useful parameter in the risk stratification of patients with CIN.
However, it has been suggested that intra-arterial contrast medium administration during catheter-based angiography, with or without percutaneous coronary intervention, is associated with a higher incidence of PC-AKI than intravenous contrast medium administration.[15,16] Catheter-based procedures may be complicated by hemodynamic instability, and by embolization of cholesterol or thrombi in the renal arteries caused by catheter manipulations. Any of these may lead to post-interventional AKI, which is often misinterpreted as CIN.[18,19]
In this present study, we tested the hypothesis that, compared with patients who did not develop acute kidney injury, those who developed PC-AKI after contrast-enhanced CT (CECT) showed considerable diastolic dysfunction.
2 Materials and methods
2.1 Data source
This retrospective study was conducted by collecting the data of patients who visited an emergency medical center of a university-affiliated hospital in Korea (Ajou University Hospital) between January 2008 and December 2014. During the study period, our mean annual ED census was 76,657 total visits (range 44,997–91,994), with a mean annual admission rate of 25.03% (range 22.28–29.22%). We used a clinical research database containing basic information on patient demographic characteristics, diagnoses, and laboratory test results taken from the electronic health records.
This study was approved by the local institutional review board, and the need for informed consent was waived (approval no. AJIRB-MED-MDB-18-231). Patient information was anonymized and de-identified before the analysis.
2.2 Enrolled patients and study setting
In this single-hospital, retrospective case-control study, the data of patients who underwent CECT in the ED were extracted. Among the patients who underwent CECT, those who
- 1) underwent laboratory evaluations that included serum creatinine level measurements before CECT and within 72 hours after CECT, and
- 2) had undergone echocardiography within 1 month of the CECT were included.
- 1) were 18 years old or younger,
- 2) had no hospital admission after undergoing CECT,
- 3) had any history of hemodialysis or end-stage renal disease, or
- 4) had incomplete or abnormal data for determining the development of PC-AKI were excluded.
The enrolled patients were divided into 2 groups according to the occurrence of PC-AKI. To determine the occurrence of PC-AKI, when multiple serum creatinine values were available within 72 hours, the highest serum creatinine level within 72 hours after the patient underwent CECT was extracted and compared with the baseline serum creatinine level before CECT (Roche Cobas Integra 800; Roche Diagnostics GmbH, Mannheim, Germany). Similar to other researchers, we defined PC-AKI as an elevation in the serum creatinine level of ≥ 0.5 mg/dL or ≥ 25% within 72 hours after CECT.[20–22]
2.3 Data collection
Standardized extraction of demographic, clinical, and laboratory data from the medical records was performed by an emergency physician and a nephrologist. Any discrepancy between the datasets extracted by the 2 physicians was resolved by a third physician. The physicians were blinded to the patients’ serum laboratory test results. The patients’ sex, age, body mass index, and medical history were obtained from the electronic health records. We extracted the laboratory results at the time of each patient's visit to the ER, to establish the patient's baseline status before undergoing CECT. Laboratory tests including the determination of serum levels of blood urea nitrogen, creatinine, and electrolytes were performed when the patient visited the ED. The comorbidities included hypertension, diabetes mellitus (DM), chronic kidney disease (CKD), heart failure, multiple myeloma (MM), and liver cirrhosis (all identified using the International Classification of Diseases, 9th Revision, Clinical Modification codes).
2.4 Echocardiographic parameters
Echocardiography was performed with either a Vivid 7 (GE Vingmed, Horten, Norway) or an iE33 (Phillips Medical Systems, Andover, Mass) according to the recommendations of the American Society of Echocardiography (ASE). To test intraobserver and interobserver variability, the E/E’ of 20 consecutive patients were measured. Left ventricular end-diastolic dimension (LVEDD) and left ventricular end-systolic dimension (LVESD) were measured in 2-dimensional M mode. Left ventricular systolic function was defined by the EF. The EF was calculated using the modified Simpson's method (i.e., by subtracting LVESD from LVEDD). Left ventricular mass was estimated using the Devereux-modified American Society of Echocardiography cube formula, and the left ventricular mass index (LVMI) was calculated by dividing the left ventricular mass by the body surface area.
Pulsed wave Doppler was used to check velocities in the 4-chamber apical view. Volume sampling was positioned at the tip of the mitral valve to measure early left ventricular filling velocity (E) and left atrial contraction velocity (A). Tissue Doppler was then conducted with volume sampling repositioning at the septal annulus of the mitral valve to measure the early (E′) and late (A) diastolic mitral annular velocities. E/E′ and E/A were calculated to represent diastolic function. The deceleration time, defined as the time between the E wave and the upper deceleration slope extrapolated to the zero line, was also determined. The variability was determined as the difference between the two sets of observations divided by the mean of the observations and expressed as a percentage. The interobserver and intraobserver variability was 5.4 ± 4.4% and 4.4 ± 3.8% for the measurement of septal E/E’.
2.5 Statistical analysis
Continuous variables are reported as either the median with the interquartile range using the Mann-Whitney U test or as the mean and standard deviation using the 2-tailed t test, for comparisons depending on a normal distribution of data. Categorical variables are presented as frequencies and percentages, using the Chi-square test for comparison. A P value of <.05 was considered statistically significant. After univariate linear regression to determine the development of PC-AKI after CECT, the echocardiographic parameters with a P value of ≤.05 were included in the multivariate regression model. A univariate analysis was performed to identify factors associated with the occurrence of PC-AKI in patients who underwent CECT. Logistic regression analysis was performed to identify the E/E′ value that could be considered positively correlated with the occurrence of PC-AKI in patients who underwent CECT. Two-sided P values of <.05 were considered statistically significant. Further, we constructed receiver operating characteristic curves to evaluate our multivariate model for predicting the development of PC-AKI. All statistical analyses were performed using the R program software for Mac, version 3.2.2 (R Development Core Team, Vienna, Austria).
3.1 Baseline characteristics of patients with and those without PC-AKI
We included 327 patients, aged 18 years and older, who had a CECT scan and underwent an echocardiography performed within 1 month of the CT scan at our institute over 20 years.
The baseline characteristics of the study subjects are detailed in Table 1. The mean age was 63.84 ± 14.66 years, and 48.54% were men. The mean values of estimated glomerular filtration rate (eGFR) and E/E′ was 51.55 ± 7.66 mL·min−1·1.73 m−2 and 11.56 ± 5.33, respectively. A total of 32 patients (9.79%) developed PC-AKI. The prevalence of DM, CKD, and MM was significantly higher in the PC-AKI group than in the non-PC-AKI group. The laboratory findings showed that patients with PC-AKI demonstrated significantly lower serum bicarbonate levels than those without PC-AKI. However, there were no differences in eGFR between the PC-AKI group and the non-PC-AKI group. The echocardiographic findings revealed that E/E′ and LVMI were significantly increased in patients with PC-AKI (Table 1).
When patients were classified into 3 groups based on E/E′ values of 8 and 15, PC-AKI occurred in 9 (16.98%) patients in the highest tertile, compared with 20 (10.42%) in the middle tertile and 3 (3.66%) in the lowest tertile (P = .03). In addition, patients in the highest tertile were older and had lower eGFR levels (Table 2). Among the echocardiographic parameters, LVMI, LVEDD, and LVESD were significantly increased in patients in the highest tertile (Table 2).
3.2 Risk factors for the development of PC-AKI
The logistic regression analysis showed that a higher E/E′ value (odds ratio [OR] 5.39, 95% confidence interval [CI] 1.51–25.23, P = .015) was a significant risk factor for PC-AKI (Table 3). After adjustment for DM, CKD, MM, and serum bicarbonate (T.CO2), E/E′ remained as an independent risk factor (OR 1.09, 95% CI 1.02–1.16, P = .009, as a continuous variable). The validity of the multivariate model was verified by the Hosmer and Lemeshow test (P = .712 > .05).
3.3 Receiver operating characteristic analysis of E/E′ for the development of PC-AKI
To estimate the predictive accuracy of the echocardiographic parameter E/E′ for the development of PC-AKI, receiver operating characteristic analysis was performed. The area under the curve for E/E′ was 0.75 (95% CI 0.68–0.82, P < .001) (Fig. 1).
This is the first study to show the relationship between PC-AKI and diastolic dysfunction after CECT in the ED. This study showed that patients with PC-AKI exhibited higher E/E′ and LVMI on echocardiography. Increased E/E′, which is a well-known marker of increased left ventricular end-diastolic pressure, can be assessed noninvasively with echocardiography in real clinical settings.
In addition, the highest tertile of E/E′ was associated with a significantly increased risk of PC-AKI, beyond the well-known risk factors such as DM, MM, and CKD. This indicates that diastolic dysfunction may be a useful parameter for predicting the development of PC-AKI after a CECT scan.
The commonly reported risk factors for PC-AKI include renal insufficiency, DM, advanced age, heart failure, periprocedural volume depletion or hypotension, and high volume of contrast media.[23,24] In our study, DM, CKD, MM, and low T.CO2 were risk factors of PC-AKI development.
Although CHF is a well-proven risk factor for CIN, only low EF has previously been studied among various components of heart failure such as diastolic dysfunction, ventricular hypertrophy, and volume overload.[11,12,25] This has likely been because a decreased effective circulatory volume is considered the primary event in the development of CIN in patients with CHF.[26,27]
Moreover, most studies demonstrated that EF only affects the CIN rates in patients with severe CHF of New York Heart Association class 3–4 or with an EF of <30% to 40%. Given that CIN occurs in higher rates in patients with lower severity of CHF, the hemodynamic compromise status in milder stages of heart failure may not be properly represented by EF.
Pump failure and decreased renal perfusion may aggravate the impairment of renal function by mainly activating the renin–angiotensinogen–aldosterone system. The pathophysiological mechanisms in systolic heart failure including renal ischemia and increased oxidative stress play an important role in the development of PC-AKI. Initially, left ventricular hypertrophy occurs to compensate for the stiffness of the left ventricle, by increasing stroke volume. However, pathologic proliferation, fibrotic deposition, and calcification of the ventricle become evident, and left ventricular compliance eventually decreases. The same vicious cycle in hemodynamics is considered to be the chief mechanism behind a higher E/E′ causing PC-AKI. Further, there is accumulating evidence demonstrating the relationship between diastolic dysfunction and increased inflammation, neurohumoral activation, and impaired renal hemodynamics despite the presence of preserved left ventricular EF.[30–33]
This study has several limitations. First, it was a single-center study. Further large-scale, randomized controlled multicenter trials are needed to confirm and assess the clinical applicability of our findings. Second, there may be a selection bias because patients who visited the ED and underwent both CECT and echocardiography may be high-risk patients. Therefore, our results may overestimate the incidence of PC-AKI in the general ED. However, it is indisputable that diastolic dysfunction is an independent risk factor for the development of PC-AKI because our study confirmed that the PC-AKI risk increased according to E/E′ among our patients. Third, we could not provide information about contrast volume, type of contrast media, and other nephrotoxic drugs used before and after CECT scan. Fourth, studies were observational in nature, the influence of residual confounders could not be completely excluded.
In conclusion, we demonstrated that, among the echocardiographic parameters, E/E′ can be a useful predictor for the development of PC-AKI after a CECT scan. It should be noted that the occurrence of PC-AKI after CECT is higher in the presence of diastolic dysfunction. Nephroprotective point-of-care clinical decision support has the potential to improve outcomes in ED patients with diastolic dysfunction.
We would like to thank all members and personnel of the Department of Emergency Medicine of Ajou University School of Medicine.
Conceptualization: Min-Jeong Lee, Hyuk-Hoon Kim.
Data curation: Hyuk-Hoon Kim.
Formal analysis: Hyuk-Hoon Kim.
Investigation: Min-Jeong Lee.
Writing – original draft: Min-Jeong Lee.
Writing – review & editing: Min-Jeong Lee.
Hyuk-Hoon Kim orcid: 0000-0003-1957-3020.
. Kocher KE, Meurer WJ, Fazel R, et al. National trends in use of computed tomography in the emergency department
. Ann Emerg Med 2011;58: 452-462 e453.
. Nash K, Hafeez A, Hou S. Hospital-acquired renal insufficiency. Am J Kidney Dis 2002;39:930–6.
. Hou SH, Bushinsky DA, Wish JB, et al. Hospital-acquired renal insufficiency: a prospective study. Am J Med 1983;74:243–8.
. Coca SG, Peixoto AJ, Garg AX, et al. The prognostic importance of a small acute decrement in kidney function in hospitalized patients: a systematic review and meta-analysis. Am J Kidney Dis 2007;50:712–20.
. Solomon RJ, Mehran R, Natarajan MK, et al. Contrast-induced nephropathy and long-term adverse events: cause and effect? Clin J Am Soc Nephrol 2009;4:1162–9.
. Mitchell AM, Kline JA, Jones AE, et al. Major adverse events one year after acute kidney injury after contrast-enhanced computed tomography. Ann Emerg Med 2015;66: 267-274 e264.
. Mitchell AM, Jones AE, Tumlin JA, et al. Incidence of contrast-induced nephropathy after contrast-enhanced computed tomography in the outpatient setting. Clin J Am Soc Nephrol 2010;5:4–9.
. Aycock RD, Westafer LM, Boxen JL, et al. Acute kidney injury after computed tomography: a meta-analysis. Ann Emerg Med 2018;71: 44-53 e44.
. McDonald RJ, McDonald JS, Bida JP, et al. Intravenous contrast material-induced nephropathy: causal or coincident phenomenon? Radiology 2013;267:106–18.
. Kodzwa R. Updates to the ACR manual on contrast media. Radiol Technol 2017;89:186–9.
. Rosenstock JL, Gilles E, Geller AB, et al. Impact of heart failure on the incidence of contrast-induced nephropathy in patients with chronic kidney disease. Int Urol Nephrol 2010;42:1049–54.
. 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.
. Nagueh SF, Smiseth OA, Appleton CP, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of echocardiography and the european association of cardiovascular imaging. J Am Soc Echocardiogr 2016;29:277–314.
. Koo HM, Doh FM, Ko KI, et al. Diastolic dysfunction
is associated with an increased risk of contrast-induced nephropathy: a retrospective cohort study. BMC Nephrol 2013;14:146.
. Solomon R. Contrast-induced acute kidney injury: is there a risk after intravenous contrast? Clin J Am Soc Nephrol 2008;3:1242–3.
. Dong M, Jiao Z, Liu T, et al. Effect of administration route on the renal safety of contrast agents: a meta-analysis of randomized controlled trials. J Nephrol 2012;25:290–301.
. Wichmann JL, Katzberg RW, Litwin SE, et al. Contrast-induced nephropathy. Circulation 2015;132:1931–6.
. Bruce RJ, Djamali A, Shinki K, et al. Background fluctuation of kidney function versus contrast-induced nephrotoxicity. AJR Am J Roentgenol 2009;192:711–8.
. Newhouse JH, Kho D, Rao QA, et al. 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.
. van der Molen AJ, Reimer P, Dekkers IA, et al. Post-contrast acute kidney injury - Part 1: Definition, clinical features, incidence, role of contrast medium and risk factors: Recommendations for updated ESUR Contrast Medium Safety Committee guidelines. Eur Radiol 2018;28:2845–55.
. Weisbord SD, Mor MK, Resnick AL, et al. Incidence and outcomes of contrast-induced AKI following computed tomography. Clin J Am Soc Nephrol 2008;3:1274–81.
. Morcos SK, Thomsen HS, Webb JA. Contrast-media-induced nephrotoxicity: a consensus report. Contrast Media Safety Committee, European Society of Urogenital Radiology (ESUR). Eur Radiol 1999;9:1602–13.
. 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.
. Pannu N, Wiebe N, Tonelli M. Alberta Kidney Disease N. Prophylaxis strategies for contrast-induced nephropathy. JAMA 2006;295:2765–79.
. Dangas G, Iakovou I, Nikolsky E, et al. Contrast-induced nephropathy after percutaneous coronary interventions in relation to chronic kidney disease and hemodynamic variables. Am J Cardiol 2005;95:13–9.
. Heyman SN, Rosenberger C, Rosen S. Regional alterations in renal haemodynamics and oxygenation: a role in contrast medium-induced nephropathy. Nephrol Dial Transplant 2005;20: (Suppl 1): i6–11.
. Gami AS, Garovic VD. Contrast nephropathy after coronary angiography. Mayo Clin Proc 2004;79:211–9.
. Kagan A, Sheikh-Hamad D. Contrast-induced kidney injury: focus on modifiable risk factors and prophylactic strategies. Clin Cardiol 2010;33:62–6.
. Afshinnia F, Spitalewitz S, Chou SY, et al. Left ventricular geometry and renal function in hypertensive patients with diastolic heart failure. Am J Kidney Dis 2007;49:227–36.
. Sciarretta S, Paneni F, Palano F, et al. Role of the renin-angiotensin-aldosterone system and inflammatory processes in the development and progression of diastolic dysfunction
. Clin Sci (Lond) 2009;116:467–77.
. Mohammed SF, Ohtani T, Korinek J, et al. Mineralocorticoid accelerates transition to heart failure with preserved ejection fraction via “nongenomic effects”. Circulation 2010;122:370–8.
. Kalogeropoulos A, Georgiopoulou V, Psaty BM, et al. Inflammatory markers and incident heart failure risk in older adults: the Health ABC (Health, Aging, and Body Composition) study. J Am Coll Cardiol 2010;55:2129–37.
. Kosmala W, Derzhko R, Przewlocka-Kosmala M, et al. Plasma levels of TNF-alpha, IL-6, and IL-10 and their relationship with left ventricular diastolic function in patients with stable angina pectoris and preserved left ventricular systolic performance. Coron Artery Dis 2008;19:375–82.