Risk of acute kidney injury in patients who undergo coronary angiography and cardiac surgery in close succession

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1 European Heart Journal (2012) 33, doi: /eurheartj/ehr493 CLINICAL RESEARCH Interventional cardiology Risk of acute kidney injury in patients who undergo coronary angiography and cardiac surgery in close succession Byungsoo Ko 1,2, Santiago Garcia 1,2, Salima Mithani 1,2, Venkat Tholakanahalli 1,2, and Selcuk Adabag 1,2 * 1 Division of Cardiology and Department of Internal Medicine, Veterans Administration Medical Center, Cardiology 111C, One Veterans Drive, Minneapolis, MN 55417, USA; and 2 Department of Medicine, University of Minnesota, 420 Delaware St. SE, Minneapolis, MN 55455, USA Received 18 August 2011; revised 8 December 2011; accepted 15 December 2011; online publish-ahead-of-print 11 January 2012 Aims Cardiac surgery and coronary angiography are both associated with risk of acute kidney injury (AKI). We hypothesized that the risk of post-operative AKI increases when coronary angiogram and cardiac surgery are performed in close succession, without sufficient time for recovery from the adverse effects of intravenous contrast.... Methods We included 2133 consecutive patients who underwent cardiac surgery at the Minneapolis Veterans Administration and results Medical Center from 2004 to Acute kidney injury was defined by the AKI network and the Risk, Injury, Failure, Loss, End-stage (RIFLE) criteria. Patients were years old. Mean pre-operative creatinine and estimated glomerular filtration rate were mg/dl and ml/min/1.73 m 2, respectively. Cardiac surgery was performed 14 days (range 0 235) after coronary angiography. Acute kidney injury occurred in 680 (32%) patients per AKI network, 390 (18%) patients per RIFLE risk, and 111 (5%) patients per RIFLE injury criteria. Age, body mass index, diabetes mellitus, New York Heart Association class III/IV, cardiopulmonary bypass time, and impaired pre-operative renal function were independent predictors of AKI. However, time between coronary angiogram and cardiac surgery was not a predictor (P ¼ 0.41). AKI occurred in 35% of 433 patients operated within 3 days of coronary angiogram vs. 31% of 1700 patients operated after 3 days (P ¼ 0.17). Results were the same in patients with impaired pre-operative renal function and those with contrast-induced nephropathy.... Conclusion Risk of AKI after cardiac surgery is not influenced by the time between coronary angiogram and cardiac surgery. These results do not support the notion of delaying cardiac surgery for the sole purpose of renal recovery after coronary angiogram Keywords Acute kidney injury Surgery complications Coronary angiogram Cardiac surgery Outcome Introduction Acute kidney injury (AKI) occurs in up to 30% of patients after cardiac surgery 1,2 and has been associated with morbidity, mortality, and longer hospitalization. 3 7 Age, pre-existing kidney disease, cardiopulmonary bypass time, intra-aortic balloon pump use, and valve surgery increase the risk of AKI after cardiac surgery On the other hand, contrast-induced nephropathy after coronary angiography occurs in up to 10% of patients with normal renal function and up to 25% of patients with pre-existing renal impairment. 12 Recently, there has been an interest in the temporal relationship between coronary angiography and cardiac surgery suggesting that a double hit on the renal function in close succession increases the risk of AKI after cardiac surgery However, these reports were limited by utilization of non-conventional definitions of post-operative AKI and relatively small sample size. The purpose of the present investigation was to assess the influence of the time between coronary angiography and cardiac surgery on the incidence of post-operative AKI in a large cohort of patients using the AKI network 17 and Risk, Injury, Failure, Loss, End-stage (RIFLE) * Corresponding author. Tel: , Fax: , adaba001@umn.edu Published by Oxford University Press 2012.

2 2066 B. Ko et al. definitions of AKI. 18 We hypothesized that the risk of AKI increases when coronary angiogram and cardiac surgery are performed in close succession, without sufficient time to allow kidney function to recover from the adverse effects of intravenous contrast. Methods Study population This study was approved by the human studies and the research and development committees of the Minneapolis Veterans Affairs Medical Center. Individual consent was waived. A total of 2268 patients underwent coronary artery bypass graft (CABG) surgery or valve surgery (with or without concomitant CABG) at the Minneapolis Veterans Affairs Medical Center between January 2004 and September Of these, 28 patients who were on haemodialysis preoperatively and 107 patients who had incomplete data were excluded. A total of 2133 patients were included in the final analysis. Data collection Pre-operative clinical variables, procedural details, and laboratory test results, including creatinine, were obtained from electronic medical records and cardiovascular surgery database at our medical centre. This ongoing database is part of a national database of prospectively collected data of patients undergoing cardiac surgery within the Veterans Affairs Healthcare System. 8,19 Estimated glomerular filtration rate (egfr) was calculated using the Modification of Diet in Renal Disease formula, that is, egfr ¼ 186 creatinine age (1.21 if black) (0.742 if female). 20 Outcome variables The primary outcome variable was development of AKI after cardiac surgery as defined by the AKI network (absolute increase of 0.3 mg/dl or a relative increase of 50% in serum creatinine from baseline value within 48 h after surgery, or requiring post-operative haemodialysis). 17 Secondary outcome variables were the RIFLE risk (maximum serum creatinine level by the 7th post-operative day/preoperative serum creatinine level 1.5 or pre-operative egfr/egfr on the 7th post-operative day. 1.25) and RIFLE injury (maximum serum creatinine level by the 7th post-operative day/pre-operative serum creatinine level 2.0 or pre-operative egfr/egfr on the 7th post-operative day. 1.5) criteria for AKI. 18 Data analysis Variables are presented as mean + one standard deviation or as percentages. Continuous variables were compared with t-test when normally distributed and non-parametric Mann Whitney U test when skewed. Categorical variables were compared with chi-square test. Predictors of AKI were identified with logistic regression analysis. The variables with P, 0.1 in univariable analysis and variables that are known to be associated with AKI were included in the multivariable model. Number of days between coronary angiogram and cardiac surgery was analysed as a continuous variable in univariable and multivariable logistic models. Secondary analyses were performed using 1, 3, 5, and 7 days as cut-off. Pre-determined subgroup analyses were performed in patients with pre-operative egfr, 60 ml/min/1.73 m 2,in those who received high-dose intravenous contrast (i.e. greater than median value of 100 ml), and in patients who developed contrast-induced nephropathy. This analytic strategy has been published before. 19,21 Analyses were performed using SPSS statistical software, version 19. All analyses were two-sided. P, 0.05 was considered statistically significant. Results Patient characteristics The baseline characteristics of the 2133 study patients who underwent cardiac surgery are given in Table 1. Patients were years old and 99% were male. The majority (69%) of the patients underwent CABG only. Mean pre-angiogram creatinine and egfr were mg/dl and ml/min/1.73 m 2. Mean preoperative creatinine and egfr were mg/dl and ml/min/1.73 m 2, respectively (Table 1). Predictors of acute kidney injury A total of 680 (32%) patients had AKI per the AKI network definition and 390 (18%) and 111 (5%) met the RIFLE risk and injury criteria, respectively. Patients who developed AKI after surgery were older, more likely to have diabetes, cerebrovascular disease, and worse pre-angiogram and pre-operative renal function than those who did not develop AKI (Table 1). Acute kidney injury patients also had more symptoms, were more likely to undergo surgery other than CABG, and had longer cardiopulmonary bvpass time than those who did not develop AKI (Table 1). Consequently, patients who developed AKI had a higher operative (30-day) mortality than those who did not (4.1% vs. 1.0%; P, ). In multivariable analysis, age, body mass index, diabetes mellitus, New York Heart Association (NYHA) class III/IV, cardiopulmonary bypass time, and impaired pre-operative renal function (egfr, 60 ml/min/1.73 m 2 ) were independent predictors of AKI after cardiac surgery (Table 2). Incidence of AKI with each type of surgical procedure is listed in Table 3. Frequency of AKI was higher in patients who underwent valve surgery with or without CABG. Highest risk occurred in those who underwent double-valve surgery (Table 3). Time from coronary angiogram and acute kidney injury Cardiac surgery was performed after a median 14 days (range 0 235) following coronary angiography. There was no difference in the length of time between coronary angiogram and cardiac surgery in patients who developed AKI vs. those who did not [median (interquartile range) 13 days (5 31) vs. 14 days (4 31); P ¼ 0.12]. There was no difference in the incidence of AKI as a function of days from coronary angiogram (Figure 1). In multivariable regression analysis after adjusting for confounding factors, the number of days between coronary angiogram and cardiac surgery, taken as a continuous variable, was not a predictor of post-operative AKI (odds ratio: 0.99; 95% confidence interval: ; P ¼ 0.41). Subgroup analysis Subgroup analyses were performed in patients with pre-operative egfr, 60 ml/min/1.73 m 2 and in patients who had contrast-induced nephropathy. Time between coronary angiogram and cardiac surgery was not an independent predictor of AKI in

3 Kidney injury after cardiac surgery 2067 Table 1 Baseline characteristics of the study patients per the acute kidney injury network criteria Variables All patients, n AKI, n No AKI, n P-value... Age (years) , Male (%) Black race (%) BMI (kg/m 2 ) Ever smoked (%) Diabetes mellitus (%) , Prior MI (%) Prior heart surgery (%) NYHA III/IV (%) , Chronic obstructive lung disease (%) Peripheral arterial disease (%) Cerebrovascular disease (%) , Pre-angiogram creatinine (mg/dl) , Pre-operative creatinine (mg/dl) , Pre-angiogram egfr (ml/min) , Pre-operative egfr (ml/min) , Pre-angiogram egfr, 60 ml (%) , Pre-operative egfr, 60 ml (%) , Haemoglobin (g/dl) , CABG only (%) , Elective surgery (%) Estimated mortality (%) , Pre-operative IABP (%) Pre-operative diuretics (%) ,0.01 Ischaemic time (min) , CPB time (min) , Intravenous contrast (ml) AKI, acute kidney injury; BMI, body mass index; MI, myocardial infarction; egfr, estimated glomerular filtration rate; CABG, coronary artery bypass graft; IABP, intra-aortic balloon pump; NYHA, New York Heart Association; CPB, cardiopulmonary bypass. Table 2 Multivariable predictors of acute kidney injury after cardiac surgery Variables Odds ratio (95% P-value CI)... Age ( ), BMI ( ), Diabetes mellitus ( ) NYHA III/IV ( ) CPB time (min) ( ), Pre-operative egfr, 60 ml/min/1.73 m ( ) 0.04 BMI, Body mass index; CPB, cardiopulmonary bypass; egfr, estimated glomerular filtration rate; NYHA, New York Heart Association. either of these high-risk subgroups (OR: 0.99; 95% CI: ; P ¼ 0.32 for egfr, 60 ml/min/1.73 m 2 and OR: 1.0; 95% CI: ; P ¼ 0.19 for contrast-induced nephropathy). Also, there was no interaction with the amount of intravenous contrast used during coronary angiogram. Time between coronary angiogram and cardiac surgery was not associated with AKI in patients who received above median (.100 ml) vs. below median (,100 ml) amount of contrast. Discussion In this retrospective cohort study of more than 2000 patients who underwent cardiac surgery after coronary angiogram, we found that the number of days between coronary angiogram and cardiac surgery was not a predictor of post-operative AKI, suggesting that the two procedures can be safely performed in close succession. These results remained the same in high-risk subgroups such as the patients with pre-operative renal insufficiency or those who had contrast-induced nephropathy. The independent predictors of AKI after cardiac surgery in this cohort were advanced age, high body mass index, diabetes mellitus, NYHA

4 2068 B. Ko et al. Table 3 Incidence of acute kidney injury in relation to the type of cardiac surgical procedure a Procedure Number of patients, CPB time (min), AKIN, RIFLE risk, RIFLE injury, n median (IQR) n n n CABG (42) 29% 17% 4% AVR (40) 33% 20% 7% CABG-AVR (49) 48% 25% 8% Other surgery (86) 37% 19% 7% AKIN, Acute Kidney Injury Network; AVR, aortic valve replacement; CABG, coronary artery bypass graft; IQR, interquartile range; RIFLE, Risk, Injury, Failure, Loss, End-stage kidney disease. a Row percentages are displayed. Figure 1 Incidence of acute kidney injury after cardiac surgery in relation to the deciles of the number of days since coronary angiography. class III/IV, prolonged cardiopulmonary bypass time, and impaired pre-operative renal function (egfr, 60 ml/min/1.73 m 2 ). There have been a few relatively small studies on the association between the risk of post-operative AKI and the timing of contrast exposure before the cardiac surgery, but the results are mixed. Del Duca et al. 14 analysed 649 patients undergoing cardiac surgery and found that cardiac catheterization performed within 5 days before the operation was independently associated with post-operative AKI. However, as the authors acknowledged, a significantly greater number of patients requiring urgent operation underwent cardiac surgery within 5 days of cardiac catheterization. 14 Since the patients who require emergent surgery are usually sicker, this might have confounded their results. Medalion et al. 15 studied 395 patients who underwent CABG after contrast exposure and identified that patients operated within 24 h of coronary catheterization had increased risk of post-operative AKI. However, again more patients in the group who underwent CABG within 24 h of contrast exposure had unstable angina and urgent operations than those who were operated later. In a retrospective study of 423 patients, Ranucci et al. 16 showed that surgery on the same day of cardiac catheterization was independently associated with the increased risk of AKI and suggested delaying cardiac surgery beyond 24 h of exposure to contrast agents. Although patients requiring emergent operation were excluded in this study, the baseline characteristics of patients who were operated within vs. after 24 h of contrast exposure were not compared. Hennessy et al. 13 reported that the patients who developed post-operative AKI were more likely to have had catheterization within 24 h of surgery. On the other hand, Brown et al. 22 and Greason et al. 23 suggested that in selected patients undergoing aortic valve replacement, coronary catheterization could be performed on the same day of the surgery. The present study advances the existing data from prior investigations on two fronts. First, in this investigation, we have used the widely accepted AKI network definition and the RIFLE criteria of AKI as the outcomes vs. the less sensitive criteria used in prior investigations Second, our study cohort included consecutive patients of various risks undergoing a variety of cardiac surgical

5 Kidney injury after cardiac surgery 2069 procedures, in contrast to studies that only included low-risk patients and specific surgical procedures, excluding patients with moderate kidney disease (Stage 3), and those who underwent angiography without left ventriculography. 22,23 Thus, in this regard, our data more closely reflect the real-world experience. In the past literature, AKI has been typically defined on the basis of the Society of Thoracic Surgeons National Cardiac Surgery Database criteria, that is, post-operative serum creatinine.2.0 mg/dl or.2 times the most recent pre-operative creatinine level or requirement for dialysis post-operatively. 13 There is, however, growing evidence that even small increments in serum creatinine are associated with adverse outcomes, 5,6,24,25 which prompted us to use the more sensitive and widely accepted definition by the AKI network criteria. 15 The RIFLE definition of AKI 16 was also used in our study for sensitivity analysis. Utilization of widely accepted AKI criteria, such as those used in this study, will allow comparison of the results of future studies. Several studies have examined the risk factors associated with the development of AKI after cardiac surgery. 2 These include advanced age, pre-operative kidney dysfunction, prolonged cardiopulmonary bypass time, undergoing valvular heart surgery, congestive heart failure, diabetes mellitus, peripheral vascular disease, pre-operative use of intra-aortic balloon pump, and chronic obstructive pulmonary disease. 2,3,26 29 Our results confirm these data. The strengths of this investigation are the large sample size, utilization of AKI network and RIFLE definitions as outcomes, and inclusion of various cardiac surgical procedures. Furthermore, the study cohort included patients with a wide range of risk for AKI, including those with baseline kidney failure and those who underwent urgent/emergent operation thus making the findings of this investigation more applicable to the general population. Our study also has several limitations that are worth noting. First, the diagnosis of AKI was based on changes of serum creatinine, which is a poor marker of kidney dysfunction early after surgery. 30,31 It is, however, the most commonly applied measure of renal function to date. Several biomarkers of AKI, including cystatin C, urine interleukin-18, and urine neutrophil gelatinase-associated lipocalin, have been identified over the past few years, but still need validation in larger studies. 32 Second, factors which could potentially be associated with AKI, such as perioperative haemodynamic status, bleeding, transfusion and pressor use and medication use were not included in our database. Furthermore, the reason for shorter or longer times from angiography, which were not specified in our database, might correlate with the acuity of the patient and could have influenced the development of AKI. Third, even though our study cohort is the largest reported to date, we cannot exclude the possibility that the lack of statistical significance is due to the lack of statistical power (type II error). Finally, almost all patients in our cohort were male. Caution is required when extrapolating these results to female patients. In conclusion, in this large cohort of cardiac surgery patients, the risk of AKI after cardiac surgery was not influenced by the time between coronary angiogram and cardiac surgery, even in the highrisk patients. Based on these results, delaying cardiac surgery for the sole purpose of renal recovery after coronary angiography is probably not warranted. Acknowledgements Authors acknowledge the contributions of Deborah J. 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