Survival in patients with acute kidney injury requiring dialysis after coronary artery bypass grafting

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1 European Journal of Cardio-Thoracic Surgery 45 (2014) doi: /ejcts/ezt247 Advance Access publication 8 May 2013 ORIGINAL ARTICLE Survival in patients with acute kidney injury requiring dialysis after coronary artery bypass grafting Torbjörn Ivert a,b, *, Martin J. Holzmann c,d and Ulrik Sartipy a,b a b c d Department of Cardiothoracic Surgery and Anaesthesiology, Karolinska University Hospital, Stockholm, Sweden Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden Department of Emergency Medicine, Karolinska University Hospital, Stockholm, Sweden Department of Internal Medicine, Karolinska Institutet, Stockholm, Sweden * Corresponding author. Department of Cardiothoracic Surgery and Anesthesiology, Karolinska University Hospital, S Stockholm, Sweden. Tel: ; fax: ; torbjorn.ivert@karolinska.se (T. Ivert). Received 30 January 2013; received in revised form 30 March 2013; accepted 8 April 2013 Abstract OBJECTIVES: The aim was a nationwide analysis of need for dialysis and survival in all patients who had coronary artery bypass grafting (CABG) in Sweden during 2002 up to METHODS: Primary isolated CABG was performed in patients without preoperative need for dialysis. Survival was analysed in patients suffering postoperative acute kidney injury requiring dialysis. RESULTS: Postoperative dialysis was needed in 162 patients (0.6%). Old age, female gender, reduced glomerular filtration rate (GFR), diabetes mellitus, peripheral vascular disease, chronic obstructive pulmonary disease, prior myocardial infarction, prior stroke and reduced left ventricular function were associated with need for dialysis. Only 0.3% of the patients with GFR >60 ml/min/1.73 m 2 needed postoperative dialysis compared with 9.5% if GFR was <30 ml/min/1.73 m 2. Sixteen of 54 patients (27%) with GFR <30 l/min/1.73 m 2 and a 50% increase in postoperative serum creatinine needed dialysis. There were 42 deaths (26%) within 30 days in patients who needed dialysis and 1% if dialysis was not required. Early mortality was markedly higher in patients who required dialysis than in those without dialysis after multivariable adjustment for age, sex, diabetes mellitus, left ventricular function and GFR (odds ratio 19, 95% confidence interval 13 29). The corresponding risk of late death was 2-fold higher in patients who survived for 90 days and had required dialysis compared with those who did not (hazard ratio 2.4, 95% confidence interval ). Five-year survival was 43 and 89%, respectively. The risk of death increased with age. Five-year survival after dialysis was 66% in patients younger than 65 years, but 32% in those aged over 70 years. Fifty-one per cent (14 of 27) of patients 80 years of age or older who required dialysis died early compared with 3% (68 of 2426) of those who did not (P < 0.001). Nine survivors who needed dialysis developed end-stage renal disease. CONCLUSIONS: Need for dialysis after non-emergency was an uncommon serious complication associated with high early mortality and an increased risk of late death. Old age and impaired preoperative renal function were strong predictors of need for dialysis after CABG. Postoperative dialysis after CABG was a marker of poor outcome but could, in some patients, be life-saving. Keywords: Coronary artery bypass grafting Dialysis Survival INTRODUCTION Renal failure requiring dialysis following open heart surgery is a well-recognized risk factor for mortality and the development of serious complications that prolong stay in the intensive care unit and increase health care costs [1 10]. A postoperative increase in serum creatinine of 25% or more from the preoperative baseline has been associated with a 15-fold increase in hospital mortality after cardiac surgery and poor long-term survival [3]. Filsoufi and colleagues reported a hospital mortality of 37% after cardiac surgery requiring postoperative dialysis compared with 3% in a control group, together with significantly decreased long-term survival in the dialysis group [5]. The aim of the present study was a nationwide analysis of need for postoperative dialysis and survival in patients who had nonemergency coronary artery bypass grafting (CABG) in Sweden and did not have dialysis before the operation. MATERIALS AND METHODS Between , a total of consecutive adult patients underwent CABG in Sweden. Discharge information of these operations was obtained from the Swedish Heart Surgery Register. Data from the Register of Information and Knowledge about Swedish Heart Intensive Care Admissions (RIKS-HIA), the National Patient Register, the Swedish Renal Registry and the Cause of Death Register were linked using each patient s unique personal identification number. The final database did not contain any patient identifiers. After exclusion of patients treated with dialysis The Author Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

2 T. Ivert et al. / European Journal of Cardio-Thoracic Surgery 313 before the operation, those having had previous (n = 766) or concomitant cardiac procedures (n = 5470), those operated upon as emergencies (n = 1716) and patients in whom the preoperative serum creatinine level was not measured (n = 1254), the study group comprised patients who had undergone nonemergency primary isolated CABG. Emergency procedures were excluded because angiography had been performed recently before the operation and may have influenced renal function. Reported demographic and clinical variables from medical records were age, sex, diagnosis of diabetes mellitus, hypertension, hyperlipidaemia and serum creatinine concentration before the operation. A patient was defined as having diabetes mellitus if treated with insulin or oral hypoglycaemic agents or on dietary regimen only, hypertensive if taking anti-hypertensive medication and having hyperlipidaemia if taking lipid-lowering drugs. Peripheral vascular disease was defined as a history of exertional claudication, carotid artery stenosis >50% or previous or planned vascular surgery. Patients classified as having chronic obstructive pulmonary disease had a history of daily use of steroids or bronchodilators. Left ventricular function was assessed by ventriculography or echocardiography and categorized with ejection fraction <30, and >50% as severely reduced, reduced or normal, respectively. The European System for Cardiac Operative Risk Evaluation (EuroSCORE) was used to identify patients at high risk [11]. Coronary artery bypass grafting was performed without cardiopulmonary bypass on about 5% of occasions, mainly to revascularize the anterior heart or if the ascending aorta was too diseased to be manipulated. The study complied with the Declaration of Helsinki and was approved by the Regional Ethics Committee in Stockholm. Informed consent was obtained from the patients to include their data in the national registers. Renal function It was mandatory to report serum creatinine (scr) to the register from January It was measured at the time of hospital admission, in most cases on the day before surgery, but in some elective cases up to 4 weeks beforehand. The highest serum creatinine level recorded during the entire postoperative course was submitted. Postoperative serum creatinine was missing in 3599 patients (12.8%). Coronary angiography was usually performed several weeks before measurement of the serum creatinine level. Estimated preoperative glomerular filtration rate (GFR), expressed in millilitres per minute per 1.73 m 2 body surface area, was calculated using the modified Modification of Diet in Renal Disease (MDRD) study equation, as follows: GFR MDRD = 186 (serum creatinine in µmol/l/88.4) age In women, the value was multiplied by [12, 13]. Chronic kidney disease (CKD) was defined as a GFR <60 ml/min/1.73 m 2. The Acute Kidney Injury Network (AKIN) definition was used to classify patients into different stages of acute kidney injury, as follows: stage 1, >0.3 mg/dl increase of postoperative serum creatinine or % increase in postoperative scr; stage 2, % increase; and stage 3, >200% increase in postoperative scr [14]. A decision to start postoperative dialysis in the intensive care unit was based on local institutional practices. The thresholds were increasing serum creatinine, urea and potassium levels and difficulties in the management of fluid balance. During the study period, continuous haemofiltration was available and used in all the intensive care units treating patients after open heart surgery. Patients suffering end-stage renal disease after CABG were reported to the Swedish Renal Registry. Data and statistical methods Follow-up regarding death from any cause was complete and obtained from the Cause of Death Register. The Kaplan Meier method was used to calculate cumulative survival curves, and the log-rank test was used to compare differences between the curves. Patients still alive up to February 2011 were censored in the survival analyses. Baseline characteristics were described as means and standard deviations for continuous variables and as frequencies with percentages for categorical variables. Percentages were calculated after exclusion of patients for whom data were missing. Patient characteristics in the two groups were compared using Yatescorrected χ 2 test for categorical variables, Student s t-test for continuous variables or the Mann Whitney U-test in the case of skewed distributions. Unconditional logistic regression with and without multivariable adjustment was used to assess the association between need for postoperative dialysis and early mortality (death within 30 days of surgery). Multivariable analyses considering baseline characteristics and manual forward and backward step-wise selection were used to obtain a final parsimonious model including the following variables: age, sex, diabetes mellitus, preoperative left ventricular function and preoperative estimated GFR. Odds ratios and 95% confidence intervals (CIs) were calculated. Cox proportional hazards regression with and without multivariable adjustment was used to analyse survival. By an procedure analogous to the one described above, a multivariable model including age, sex, diabetes mellitus, preoperative left ventricular function, preoperative estimated GFR, rehospitalization for myocardial infarction and rehospitalization for heart failure was used to calculate hazard ratios and 95% confidence intervals. Multiple imputation was used to impute missing values in the study data set. One hundred data sets were imputed, and estimates from these data sets were combined using standard methods. We assumed that missing values were missing at random. The objective of imputation was to maintain statistical power and to limit selection bias that may occur when observations with missing covariates are deleted. A complete case analysis was performed, including only observations without missing values for model covariates. Stata version 12.1 (StataCorp LP, College Station, TX, USA) was used for all analyses. RESULTS The number of CABGs performed each year from 2002 to 2008 decreased from 4746 to 3366, whereas the use of postoperative dialysis among the patients was unchanged (Fig. 1). Postoperative dialysis was needed in 162 of the patients (0.6%). Patients who required dialysis after the operation were older, more often female, had lower GFR and more often had a history of diabetes, peripheral vascular disease, chronic obstructive pulmonary disease, prior myocardial infarction, prior stroke or reduced left ventricular function (Table 1). These differences in characteristics are reflected in the significantly higher EuroSCORE among patients who needed dialysis. Need for dialysis was 1% (17 of ADULT CARDIAC

3 314 T. Ivert et al. / European Journal of Cardio-Thoracic Surgery 1763) in patients 80 years of age or over and 0.4% (62 of ) among those years old (P = 0.002). Few patients who had good renal function before the operation and an increase of scr <50% needed dialysis (Table 2). Only 0.3% of the patients with GFR >60 ml/min/1.73 m 2 needed postoperative dialysis compared with almost 10% if GFR was <30 ml/ min/1.73 m 2 before the operation. Acute kidney injury stage 1 occurred in 2617 of patients (10.6%) in whom postoperative scr was available, stage 2 in 369 (1.5%) and stage 3 in 101 patients (0.4%). Preoperative CKD defined as GFR <60 ml/min/1.73 m 2 was Figure 1: Number of coronary artery bypass graft (CABG) procedures performed per year and percentage of patients having postoperative dialysis. seen in 5592 of the patients (19.8%), of whom 91 needed dialysis (1.6%). Sixteen of 54 patients (27%) with GFR <30 ml/min/1.73 m 2 and a 50% increase in scr needed dialysis. Over time, the proportion of patients undergoing CABG diagnosed with preoperative CKD declined from 25% (1183 of 4746) in 2002 to 13% in 2008 (444 of 3366; P < 0.001). Patients were followed for a median of 5.5 years. During a total follow-up period of years, there were 3995 deaths among patients without postoperative dialysis (14%) and 96 among the 162 with postoperative dialysis (59%). Survival at 1 month, 1 and 5 years was 99.0, 97.4 and 89.0% in patients without postoperative dialysis compared with 74.1, 59.2 and 42.7% in patients treated with postoperative dialysis, respectively (Fig. 2). Survival rate improved markedly among dialysis patients who survived the initial 3 months postoperatively. There were 42 early deaths (25.9%) in patients who needed postoperative dialysis compared with 288 (1.0%) among patients without dialysis (Table 3). After multivariable adjustment, the risk of early death was 19-fold higher in those who needed postoperative dialysis than in patients who did not require dialysis. The risk of late death among the 106 patients with postoperative dialysis who survived longer than 90 days was about twice that of patients who did not have dialysis after multivariable adjustment (Table 4). Patients who survived for 3 months were younger and had better left ventricular function and lower EuroSCORE than patients who died within 90 days (Table 5). Nine of the 106 survivors at 90 days (8%) developed end-stage renal disease and needed permanent dialysis. They were younger (average age 58 years), had worse preoperative renal function (mean GFR of 25 ml/min/1.73 m 2 ) and more frequently had diabetes (67%) and peripheral vascular Table 1: Characteristics of patients having coronary artery bypass grafting from 2002 to 2008 and requirements for postoperative dialysis Characteristic All patients Postoperative dialysis P-value No Yes Number of patients (%) (99.4) 162 (0.6) Age (years) a 67 (9.2) 67 (9.2) 70 (9.8) <0.001 Female sex (%) 6022 (21) 5976 (21) 46 (28) 0.04 GFR (ml/min/1.73 m 2 ) a 77 (21) 77 (21) 56 (25) <0.001 Diabetes mellitus (%) 5133 (24) 5078 (23) 55 (44) <0.001 Hypertension (%) 7201 (57) 7152 (57) 49 (72) 0.20 Hyperlipidaemia (%) 7298 (58) 7261 (58) 37 (55) 0.43 Peripheral vascular disease (%) 2472 (9.0) 2444 (9.0) 28 (18) <0.001 Current smoking (%) 2296 (19) 2287 (19) 9 (14) 0.29 COPD (%) 1842 (6.5) 1823 (6.5) 19 (12) 0.01 Prior myocardial infarction (%) (46) (46) 97 (60) <0.001 Prior stroke (%) 1465 (5.2) 1449 (5.2) 16 (9.9) 0.01 Left ventricular function Ejection fraction >50% (%) (69) (69) 67 (42) <0.001 Ejection fraction 30 50% (%) 7318 (27) 7247 (27) 71 (44) Ejection fraction <30% (%) 1066 (3.9) 1044 (3.9) 22 (14) EuroSCORE b 4(0 19) 4 (0 19) 6 (0 13) <0.001 Internal thoracic artery use (%) (95) (95) 148 (91) 0.09 No. of anastomoses b 3(1 9) 3 (1 9) 3 (1 6) 0.60 CABG without CPB (%) 1470 (5.2) 1463 (5.2) 7 (4.3) 0.74 a Mean with SD. b Median with range. CABG: coronary artery bypass grafting; COPD: chronic obstructive pulmonary disease; CPB: cardiopulmonary bypass; GFR: estimated glomerular filtration rate.

4 T. Ivert et al. / European Journal of Cardio-Thoracic Surgery 315 Table 2: Need for postoperative dialysis in patients in relation to estimated glomerular filtration rate (GFR) before coronary artery bypass grafting and percentage increase of postoperative serum creatinine (scr) Table 3: Risk of death within 30 days after coronary artery bypass grafting from 2002 to 2008 in relation to the need for postoperative dialysis among patients Characteristic No. of patients (%) Postoperative dialysis n % GFR (ml/min/1.73 m 2 ) (80.2) (14.6) (4.2) < (1.0) Increase in scr (%) < (87.5) a (AKIN stage 1) 2617 (10.6) (AKIN stage 2) 369 (1.5) (AKIN stage 3) 101 (0.4) Missing a Alternatively, >0.3 mg/dl increase of postoperative serum creatinine. AKIN: Acute Kidney Injury Network classification. Figure 2: Survival after CABG in relation to the use of postoperative dialysis. The number of patients at risk is indicated at 1, 5 and 10 years. disease (44%) compared with patients who had transient renal dysfunction. Of those requiring dialysis, survival at 5 years was 66% in patients younger than 65 years compared with 32% in patients older than 70 years (Fig. 3). Fifty-one per cent (14 of 27) of patients 80 years of age or older who required dialysis died early compared with 3% (68 of 2426) of those without dialysis (P < 0.001). DISCUSSION We examined the data of patients who had non-emergency primary isolated CABG; no complex cardiac or emergency procedures were included. None of the patients had an angiographic Characteristic Postoperative dialysis No Yes Number of patients Number of early deaths (%) 288 (1.0) 42 (26) Odds ratio (95% confidence interval) Crude (23 49) Adjusted for age and sex (20 44) Adjusted for EuroSCORE (13 29) Multivariable adjusted a (13 29) a Adjusted for age, sex, diabetes mellitus, preoperative left ventricular function and preoperative estimated glomerular filtration rate. Table 4: Risk of all-cause late death in relation to the use of postoperative dialysis in patients who survived 90 days after coronary artery bypass grafting from 2002 to 2008 Characteristic Postoperative dialysis No Yes Number of patients Number of deaths (%) 3570 (13) 40 (38) Hazard ratio (95% confidence interval) Crude ( ) Adjusted for age and sex ( ) Adjusted for EuroSCORE ( ) Multivariable adjusted a ( ) a Adjusted for age, sex, diabetes mellitus, preoperative left ventricular function, preoperative estimated glomerular filtration rate, rehospitalization for myocardial infarction and rehospitalization for heart failure. examination immediately prior to surgery. The use of contrast media may cause impairment of renal function, but was not a cause of kidney injury in this cohort [15]. Patients with dialysisdependent renal failure before the operation were excluded, because they represent a population with a severalfold increase in early and late mortality and higher complication rates than nondialysis patients [4, 6, 16 19]. Complete and valid information concerning deaths was obtained by linking unique personal identification numbers to a national register. Chronic kidney disease with GFR <60 ml/min/1.73 m 2 was present in 20% of our electively operated patients compared with 26% of patients in the Society of Thoracic Surgeons National Adult Cardiac (STS) database and 25% of patients who had cardiac surgery at Veterans Affairs hospitals [6, 20]. Even a small increase in scr can reflect renal injury and may influence prognosis with increased morbidity and mortality [2, 8, 9, 20, 21]. Significant increases in postoperative scr have been reported in up to one-third of patients after CABG [2, 5, 6, 20]. Postoperative ADULT CARDIAC

5 316 T. Ivert et al. / European Journal of Cardio-Thoracic Surgery Table 5: Characteristics of patients who needed postoperative dialysis: deaths within 90 days and those who survived for 90 days or longer after coronary artery bypass grafting from 2002 to 2008 Characteristic Postoperative dialysis P-value Deaths 90 days Survivors >90 days Number of patients (%) 56 (34) 106 (66) Age (years) a 73 (7) 67 (10) <0.001 Female sex (%) 18 (32) 28 (26) 0.59 GFR (ml/min/1.73 m 2 ) a 58 (24) 55 (24) 0.74 Diabetes mellitus (%) 16 (47) 39 (48) 0.38 Hypertension (%) 14 (64) 35 (76) 0.38 Hyperlipidaemia (%) 12 (50) 25 (55) 0.91 Peripheral vascular 10 (18) 18 (17) 0.94 disease (%) Current smoking (%) 3 (14) 6 (14) 0.78 COPD (%) 10 (18) 9 (8) 0.13 Prior MI (%) 36 (64) 61 (52) 0.51 Prior stroke (%) 4 (7) 12 (11) 0.57 Left ventricular function Ejection fraction >50% 21 (38) 46 (44) 0.58 (%) Ejection fraction (34) 52 (49) % (%) Ejection fraction <30% 15 (27) 7 (7) (%) EuroSCORE b 8(0 13) 5 (0 12) <0.001 Internal thoracic artery 50 (89) 98 (92) 0.70 use (%) No. of anastomoses b 3(2 6) 3 (1 6) 0.63 CABG without CPB (%) 3 (5) 4 (4) 0.46 a Mean with SD. b Median with range. CABG: coronary artery bypass grafting; COPD: chronic obstructive pulmonary disease; CPB: cardiopulmonary bypass; GFR: estimated glomerular filtration rate; MI: myocardial infarction. Figure 3: Survival of patients who required postoperative dialysis in relation to age at surgery. renal failure strongly correlates with longer hospital stay, increased morbidity and higher mortality [2, 6, 7, 18 20]. Obesity is also associated with an increased risk of postoperative renal insufficiency in patients undergoing isolated CABG [10]. Generally, renal failure after CABG is more common in women and in patients with diabetes, peripheral artery disease, cerebrovascular disease and chronic lung disease [2]. Renal failure in cardiac surgical patients not only results in increased in-hospital mortality, but also adversely affects long-term survival [3, 4]. During this 8-year study, we observed that fewer patients with preoperative CKD presented for CABG, reflecting better awareness of the risk associated with an elevated scr and improved preoperative management and understanding of the pathophysiology of renal dysfunction [21, 22]. Repeated episodes of fluid restriction should be avoided in particularly elderly patients awaiting surgery. Renal replacement therapy is an advanced expensive life-saving technique and is a limited resource in many intensive care units. According to the national Swedeheart Register, in 2010 postoperative dialysis was used on between 0.6 and 4.1% of occasions depending on the centre, patient case mix, indications and resources ( There were certainly some patients in whom other serious complications (such as brain injury or other severe organ dysfunction) developed, resulting in a prognosis so dismal that dialysis was considered inappropriate even in light of declining renal function. In some respects, the patients who had postoperative dialysis therefore represent a selected group assumed to stand a good chance of recovery after renal replacement therapy. None of the 162 patients who required dialysis would have survived without it. None had needed dialysis before the operation, and their renal dysfunction was expected to be transitory, but nine patients needed permanent dialysis. The characteristics of patients who required postoperative dialysis differed from those who did not. They were older and had significantly more comorbidities. The strong impact of old age on risk for postoperative dialysis indicates that atherosclerosis contributes to renal vulnerability. Factors reported to be independent predictors of the need for postoperative dialysis included age, preoperative renal dysfunction, type of surgery, haemodynamic instability, diabetes, aortic surgery, congestive heart failure, recent myocardial infarction, peripheral vascular disease, previous cardiac surgery and duration of cardiopulmonary bypass [1, 5]. There is a direct correlation between preoperative renal dysfunction and increase in scr following CABG and requirement for dialysis. Postoperative dialysis was required in 0.6% of our patients, lying at the low end of the range of rates reported in the literature, which is % depending on patient risk factors [1, 4 7, 23 25]. In the STS database, 0.2% of patients with normal renal function needed dialysis compared with 11% of those having a GFR <30 ml/min/1.73 m 2 [6]. Our finding that 10% needed postoperative dialysis if GFR was <30 ml/min/1.73 m 2 is consistent with the STS database [6]. In broad agreement with our findings, Wijeysundera and colleagues have reported that low GFR, diabetes mellitus and reduced left ventricular function increased the risk of postoperative dialysis. They found that 0.4% of low-risk patients needed renal replacement therapy, compared with 10% of patients with high risk scores [23]. The 5-year survival of 43% among our patients requiring postoperative dialysis was superior to the 5-year survival of 29% in a reported cohort needing postoperative dialysis that included combined procedures and unstable patients [5]. Like Filsoufi and co-workers, we found that the risk of death was highest during the first postoperative months. An elevated risk for long-term mortality has been reported to be independent of whether renal function had recovered at discharge from hospital [3].

6 T. Ivert et al. / European Journal of Cardio-Thoracic Surgery 317 Limitations of the study This retrospective analysis of national data has limitations because of missing information of different management of renal failure in between institutions. Valid information about body weight and length of intensive care unit stay was only available from a few institutions and could not be analysed. Detailed haemodynamic and fluid balance parameters, repeat renal function tests or other biomarker measurements were not available. Only the peak serum creatinine level after the operation was reported to the national register. There was no information about the use of blood products, medication in the intensive care unit and the time when dialysis was initiated, as well as its duration. We conclude that need for dialysis after non-emergency was uncommon and that an impaired preoperative renal function and old age were strong predictors of need for dialysis. 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