Acute Kidney Injury Following Coronary Artery Bypass ...circheartfailure.ahajournals.org/content/circhf/early/2012/12/10/... · Acute Kidney Injury Following Coronary Artery Bypass

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Acute Kidney Injury Following Coronary Artery Bypass Surgery and

Long-term Risk of Heart Failure

Olsson et al: Kidney Injury, CABG and Heart Failure

Daniel Olsson BS; Ulrik Sartipy MD, PhD;

Frieder Braunschweig, MD, PhD; Martin J. Holzmann MD, PhD

From the Departments of Emergency Medicine (D.O., M.J.H.); Cardiothoracic Surgery and

Anesthesiology (U.S.); and Cardiology (F.B.), all at Karolinska University Hospital, and

Departments of Medicine (D.O., F.B., M.J.H) and Molecular Medicine and Surgery (U.S.) at

the Karolinska Institutet, all in Stockholm, Sweden.

Correspondence to Martin Holzmann, Department of Emergency Medicine Karolinska University Hospital 17176 Stockholm Sweden E-mail: [email protected] Telephone: +46 851770000 Fax: +46 851771111

DOI: 10.1161/CIRCHEARTFAILURE.112.971705

Journal Subject Codes: 7, 8, 10, 36, 110

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Abstract

Background—Acute kidney injury (AKI) after coronary artery bypass grafting (CABG) is

common and increases the risk of postoperative complications and mortality. There is little

information on the association between AKI after CABG and long-term risk of incident heart

failure.

Methods and Results—All patients (n = 24 018) undergoing primary, isolated CABG in

Sweden between 2000 and 2008 with complete information on pre- and postoperative serum

creatinine values and no prior hospitalization for heart failure were included. The

postoperative increase in serum creatinine was used to define different stages of AKI: stage 1,

0.3 to 0.5 mg/dL; stage 2, 0.5 to 1 mg/dL; stage 3, >1 mg/dL. Hazard ratios (HR) with 95%

confidence intervals (CI) were calculated for first hospitalization for heart failure for each

stage of AKI using Cox proportional hazards regression. Twelve percent of the study

population developed AKI. During a mean follow-up of 4.1 years there were 1325 (5.5%)

cases of incident heart failure. Hazard ratios with 95% CI for heart failure in AKI stage 1, 2

and 3 were 1.60 (1.34 to 1.92), 1.87 (1.54 to 2.27), and 1.98 (1.53 to 2.57) respectively, after

multivariable adjustment for age, sex, diabetes mellitus, estimated glomerular filtration rate,

left ventricular ejection fraction, and myocardial infarction before surgery or during follow-

up.

Conclusions—Acute kidney injury is associated with increased long-term risk of heart failure

after CABG. Patients with AKI after CABG should be followed closely in order to detect

early changes in cardiac function.

Key Words: acute kidney injury, heart failure, coronary artery bypass grafting

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Coronary artery bypass grafting (CABG) is the most common cardiac surgical procedure, and

an effective method of relieving angina and improving the prognosis for selected patients with

ischemic heart disease.1 Despite a gradual decline over the past decade, more than 1000

patients per million population still undergo CABG in the United States each year.2 Acute

kidney injury (AKI) is a frequent complication after CABG with an incidence between 8 and

15%3,4 and has been associated with an increased risk of postoperative complications as well

as increased short- and long-term mortality.4–7 A minor elevation of postoperative serum

creatinine by 0.5 mg/dL has been found to be associated with an almost threefold increase in

30-day mortality.6

Heart failure (HF) is a highly prevalent syndrome with a poor prognosis, resulting in

substantial morbidity and reduced quality of life despite recent advances in treatment.8 Also,

HF is the most common cause of hospital admission in the United States and Europe9,10 and

HF hospitalization per se is linked to adverse outcome and high treatment costs.11 Heart

failure is closely interrelated with kidney dysfunction. Both conditions share risk factors such

as hypertension, diabetes mellitus and ischemic heart disease and may promote the

progression of the other. The co-existence of kidney and heart disease is known as the

“cardiorenal syndrome”.12 Five different subtypes of cardiorenal syndrome have been

described based on the different modes of pathological interaction between the kidney and

heart where acute or chronic dysfunction in one organ results in acute or chronic dysfunction

in the other.12

While the general relationship between chronic kidney disease (CKD) and chronic HF has

received considerable attention in the literature13 studies investigating the impact of AKI on

the development of HF are scarce, and in the context of cardiac surgery has never been

examined. This study aimed to describe the risk of first hospitalization for HF in relation to

AKI in a large nationwide cohort of patients who underwent a first isolated CABG.

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interrelated with kidney dysfunction. Both conditions share risk

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Methods

Study population

All patients who underwent CABG between January 1, 2000 and December 31, 2008 in

Sweden were eligible for the study. The patients were identified from the Swedish Web-

system for Enhancement and Development of Evidence-based care in Heart disease Evaluated

According to Recommended Therapies (SWEDEHEART) register, where all patients

undergoing cardiac surgery in Sweden have been registered since 1992.14 The register

contains information on patients’ previous medical history and a number of pre-, peri- and

postoperative variables. The agreement between information contained in medical records and

the register has been estimated to 93-95%.14 Patients were excluded from the study if they

had: undergone previous cardiac surgery; underwent other than isolated CABG during the

operation; had missing pre- and/or postoperative creatinine values; died within 30 days of

surgery; had a history of previous hospitalization for heart failure; were diagnosed with

myocardial infarction (MI) within 14 days before surgery; underwent CABG within 24 hours

from decision; had an eGFR <15 mL/min/1.73 m2; or they were diagnosed with heart failure

within 30 days of surgery. The numbers of patients excluded are presented in Figure 1. The

study complied with the Declaration of Helsinki and was approved by the Regional Ethics

Committee in Stockholm, Sweden.

Definitions

Pre- and postoperative serum creatinine (SCr) values were used to define AKI. The

preoperative SCr value was normally taken within 24 hours before surgery. The postoperative

SCr value recorded was the highest value observed during the entire postoperative period.

Acute kidney injury was classified into three stages according to absolute increases in

postoperative SCr values: stage 1, 0.3 to < 0.5 mg/dL (26 to < 44 μmol/L); stage 2, 0.5 to < 1

mg/dL (44 to < 88 μmol/L); and stage 3, 1 mg/dL ( 88 μmol/L). The reference group was

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missing pre- and/or postoperative creatinine values; died within 0

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ction (MI) within 14 days before surgery; underwent CABG w h

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defined as an increase of < 0.3 mg/dL (< 26 μmol/L) or a decrease in postoperative SCr. The

classification has been used in a recently published study5 and is based on AKIN criteria15 and

traditional definitions.5

Glomerular filtration rates were estimated using the simplified Modification of Diet in

Renal Disease (MDRD) study equation.16 Diagnosis of hypertension, hyperlipidemia, chronic

obstructive pulmonary disease and diabetes mellitus were made on the basis of patients´

ongoing pharmacological treatment for these illnesses. Peripheral vascular disease was

defined as previous surgery to the abdominal aorta, iliac artery or carotid artery or the

presence of claudication. Left ventricular function was assessed by echocardiography prior to

surgery and categorized as normal (ejection fraction > 50%), reduced (ejection fraction 30 to

50%) or severely reduced (ejection fraction < 30%).

Outcome

The primary study outcome was first hospitalization for HF defined as a primary discharge

diagnosis of HF in the Swedish National Inpatient Register, where patients hospitalized in

Sweden have been registered since 1964. This register covers the whole country since 1987.17

This register was also used to ascertain information about illnesses prior to surgery. The

validity of the diagnosis “heart failure” in this register has been shown to be 95% if it is the

principal cause of hospitalization.17,18 A secondary outcome was a composite of first

hospitalization for HF or death from any cause. The date of death was obtained from the

Swedish Cause-of-Death register, where all deaths of persons residing in Sweden are

registered.

Data from SWEDEHEART, the Inpatient Register and the Cause-of-Death Register were

linked by the National Board of Health and Welfare, using the unique personal identification

number that is assigned to each permanent resident of Sweden. Follow-up began 30 days

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postoperatively and ended at first hospitalization for HF, death or December 31, 2008,

whichever came first.

Statistical analysis

Patient characteristics were described using frequencies and percentages for categorical

variables, and means and standard deviations for continuous variables. The Kaplan-Meier

method was used to calculate the cumulative incidence of first hospitalization for HF and for

the composite endpoint of death or first hospitalization for HF. Failure curves were

constructed for each level of AKI. Cox proportional hazards regression models were used to

study the association between AKI and first hospitalization for HF. Patients who died before

December 31, 2008 were censored at the date of death. All patients who were alive, without

being hospitalized for HF, were censored on December 31, 2008. The relative risk of

hospitalization for HF was estimated for each stage of AKI compared to no AKI, and reported

with 95% confidence intervals with and without multivariable adjustment. We constructed

several multivariable models, considered all baseline characteristics, and primary interaction

terms, and reached a final parsimonious model by a manual forward and backward stepwise

selection procedure. Variables influencing the hazard ratio 0.1 were included in the

multivariable analysis. Age, sex, diabetes mellitus, left ventricular ejection fraction, estimated

glomerular filtration rate, myocardial infarction before surgery or during follow-up were

included in the final model. Adding preoperative stroke, hyperlipidemia, hypertension,

chronic obstructive pulmonary disease, use of cardiopulmonary bypass, use of the internal

thoracic artery, number of obstructed coronary arteries or history of peripheral vascular

disease, did not improve the final model.

We also investigated primary interactions. Left ventricular ejection fraction was used as a

three-level categorical variable (normal, reduced and severely reduced). Age and eGFR were

used as continuous variables. All other variables were used as dichotomous variables in the

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able models, considered all baseline characteristics, and prima y

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analysis. Some data were missing in the study dataset and multiple imputation by chained

equations was used to impute missing values. All multivariable analyses were performed on

the imputed dataset. We assumed that the missing values were missing at random. The

frequency of missing values in the variables included in the final multivariable analysis, with

24 018 patients were none for age, sex, eGFR, and myocardial infarction before surgery or

during follow-up; 8% for left ventricular ejection fraction; and 29% for diabetes mellitus. One

hundred datasets were imputed and estimates from these datasets were combined using

standard methods. The proportionality assumption of the primary analysis was tested by

formal and graphical test and no indication of a violation was found. We also performed a

complete-case analysis where only observations without missing values for model covariates

were included (n = 16 002). Sex- and eGFR-specific analyses were performed to estimate the

risk for incident HF in these subgroups. STATA version 12.1 (StataCorp LP, College Station,

TX, USA) was used for data analysis.

Results

The study population consisted of 24 018 patients with a mean age of 66.8 ±9.2 years and

21% were women. Patients’ characteristics are presented in Table 1. The overall incidence of

AKI was 12% and did not vary significantly between 2000 to 2004 compared with 2004 to

2008. Patients with AKI were more likely to be: older; have hypertension, peripheral vascular

disease, diabetes mellitus, and a reduced GFR; have had a prior myocardial infarction, a

previous stroke or severely reduced left ventricular ejection fraction, compared with patients

without AKI. The median duration of hospital stay in the department of cardio-thoracic

surgery was 6, 7, 7 and 9 days for patients with no kidney injury, AKI stage 1, 2, and 3

respectively.

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Heart failure hospitalization

During 99 005 person-years of follow-up (mean 4.1 ±2.4 years), 1325 (5.5%) patients were

hospitalized for new-onset HF. In patients with AKI, 12% were hospitalized for HF during

follow-up compared to 5% in patients without AKI. The cumulative incidence of first

hospitalization for HF is shown in Figure 2.

The hazard ratio for HF increased with the severity of AKI in both unadjusted and

multivariably adjusted analyses (Table 2). In crude analysis, hazard ratios with 95% CI for the

association between AKI stages 1, 2 and 3 and risk of HF were 2.22 (1.96 to 2.65), 3.10 (2.57

to 3.74) and 3.95 (3.08 to 5.08) compared with patients who did not develop AKI.

In the primary analysis, all stages of AKI remained significantly associated with an

increased risk of HF even after adjustment for age, sex, diabetes mellitus, left ventricular

ejection fraction, estimated glomerular filtration rate, and myocardial infarction before or

after surgery (Table 2). Similar results were found when the primary analysis was performed

using the Acute Kidney Injury Network (AKIN) classification of AKI (Table 1, supplemental

material).15

The cumulative incidence of the composite endpoint of death or hospitalization for HF is

shown in Figure 3. The overall mortality in the study population during follow-up was 15%.

The mortality in patients with no kidney injury, AKI stages 1, 2 and 3 was 14%, 21%, 28%,

and 38%, respectively, during follow-up. Hazard ratios with 95% CI after adjustment for

confounders for the association between AKI and HF or death were 1.31 (1.17 to 1.46), 1.60

(1.42 to 1.80) and 2.13 (1.82 to 2.49) for AKI stages 1, 2 and 3 respectively, compared with

the reference group.

To account for the possible impact of missing data, we performed a complete-case

analysis, including only those patients with complete information on all confounders (n=16

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002). The hazard ratios for HF hospitalization were similar to the primary analysis; 1.57 (1.27

to 1.95), 1.72 (1.35 to 2.18) and 1.83 (1.33 to 2.51) respectively for stages 1, 2 and 3 of AKI.

The primary endpoint was also analyzed with respect to gender. Female patients were

slightly older and more likely to be treated for diabetes mellitus, hypertension and,

hyperlipidemia, but less likely to have received an internal thoracic artery bypass graft during

surgery. The hazard ratio for men and women increased with the severity of AKI in crude,

age-adjusted, and multivariable analysis. Adjusted hazard ratios for men were 1.51 (1.22 to

1.85), 1.79 (1.44 to 2.24) and 1.80 (1.32 to 2.45) for AKI stages 1, 2 and 3, respectively. The

corresponding values in women were 2.06 (1.44-2.94), 2.14 (1.44-3.19), and 2.85 (1.75-4.63).

The number of events for no kidney injury and AKI stages 1, 2 and 3 for men was 777, 105,

92 and 46 respectively, and 220, 36, 30 and 19 for women respectively.

Presence or absence of chronic kidney disease

The eGFR-stratified analysis was performed dividing patients into those with eGFR < 60 and

those with eGFR 60 mL/min/1.73m2. The results are presented in Table 3. Due to few

events in AKI stages 2 and 3 we merged these groups in the analysis. Both patients with and

without pre-existing chronic kidney disease had an increased risk of HF during follow-up if

they developed AKI postoperatively. Notably, the point estimates suggested that there might

be a stronger association between AKI and risk of HF among patients without pre-existing

chronic kidney disease.

Discussion

The main finding was that AKI after CABG was associated with an increased long-term risk

of new-onset HF. Importantly, AKI remained an independent predictor of hospitalization for

HF even after adjustment for confounders commonly involved in the etiology of HF. Notably,

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even a relatively modest increase in postoperative SCr of 0.3 to 0.5 mg/dL was associated

with a significant increase in the risk of new-onset HF.

Chronic kidney disease has been widely recognized as an independent risk factor for

cardiovascular morbidity and mortality in patients with an established diagnosis of chronic

HF.19–21 Accumulating evidence also suggests that patients with impaired kidney function are

at increased risk of developing HF.22,23 The present study expands the understanding of

cardio-renal interaction by demonstrating that an acute injury to kidney function in the setting

of cardiac surgery independently adds to patients’ long-term risk of HF.

In this study incident HF was defined as hospitalization for HF in patients with no prior

hospitalization for HF. Hospitalization is recognized as a clinically significant and objective

outcome in HF studies since it reflects disease severity, and is associated with a poor

prognosis and causes significant health expenditure.24 Furthermore, the outcome of

hospitalization does not depend on whether the underlying mechanism of HF is primarily

systolic or diastolic dysfunction. Our data were obtained from nationwide databases in a

country where all acute hospital care is provided within the public health care system,

suggesting that relatively uniform thresholds for hospitalization were applied and that all

patients in need of acute hospital care were captured. However, it is likely that we

underestimated the true rate of incident HF since some patients may have developed signs and

symptoms of HF without being hospitalized. Furthermore, we cannot specify the proportion

of death’s representing fatal HF events. Still, despite these limitations, AKI was significantly

associated with first HF hospitalization.

This study evaluated the association between AKI and HF in the context of coronary artery

bypass surgery. This is a clinically important given the large number of patients undergoing

CABG, the high incidence of AKI as a perioperative complication and also that ischemic

heart disease is the leading etiology for HF. It is well known that renal dysfunction is linked

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to an increase in cardiovascular events and mortality after cardiac surgery13,25,26 and that

patients with chronic renal dysfunction have an increased risk of HF.13 Our study adds to this

knowledge by emphasizing the independent contribution of acute renal injury to the long-term

risk of developing HF. This finding is consistent with a recent report in patients undergoing

coronary angiography, showing that AKI is a significant risk factor for long-term mortality

and cardiovascular events including hospitalization for HF.27 Thus, our data highlight the role

of AKI as an important marker of increased risk of cardiovascular events in general and HF in

particular and suggest that patients with AKI should be subject to particularly close follow-up.

Furthermore, the results direct attention toward a clinical need of developing strategies to

prevent AKI. While trials using N-acetylcysteine as a protective measure did not change

outcome,28 a randomized study in patients with left ventricular dysfunction undergoing

cardiac surgery has shown potential renoprotective effects with neseritide.29

Our findings suggest a harmful effect of AKI on the heart, which is consistent with

cardiorenal syndrome type 3. This syndrome describes the connection between acute

impairment of renal function and injury to or dysfunction of the heart.12 Several mechanisms

have been proposed to mediate the harmful effects of AKI on the heart, including the release

of inflammatory mediators, and hemodynamic and electrolyte disturbances.30 One of the most

common cardiac complications after AKI is acute decompensated HF.30 This complication

could explain why the greatest increase in the cumulative incidence of HF in our study

occurred within the first year. Patients who develop HF after AKI might have early signs of

decreased left ventricular systolic and diastolic dysfunction. This concurs with the findings of

an earlier animal study in which left ventricular dilatation was detected within 48 hours of

induced renal ischemia.31 To our knowledge, no studies have been published that have

examined the acute effect of AKI on left ventricular function measured by echocardiography

in humans.

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12

Although our results are consistent with cardiorenal syndrome type 3, several other

explanations are possible. Acute kidney injury after CABG may cause persistent loss of GFR.

A recently published review and meta-analysis suggests an increased risk of developing

chronic kidney disease after AKI.32 The cause of worsening renal function is unclear, but one

animal study has shown long-term development of renal fibrosis after induced ischemia to the

kidney.33 Therefore, AKI may precipitate or accelerate the course of chronic kidney disease32,

which is associated with cardiovascular disease and HF.13,20,24 Since we had no information

about SCr values after discharge we could not control for persisting loss of renal function and

subsequent worsening of kidney function. Other factors could also explain the connection

between AKI after CABG and an increased long-term risk of developing HF. Cardiovascular

disease, reduced kidney function before surgery, hemodynamic alterations or acute heart

failure during surgery are risk factors for both acquiring AKI and the development of HF in

the long-term.3,8,34

Several explanations have been proposed to elucidate the prognostic value of kidney

function in HF, including impairment of hemodynamic status, neurohormonal activation and

inflammatory processes that promote atherosclerosis, general vascular disease and other

factors.19,20,30,35 Although our study cannot provide novel pathophysiological insight, the

independent effect of acute changes in kidney function following cardiac surgery seem to be a

valuable marker of increased risk for developing cardiovascular events in general and HF in

particular.

The risk of HF associated with AKI was increased independently of pre-existing kidney

disease in the analysis stratified for baseline GFR. Interestingly, our results suggest that the

risk related to severe AKI may be greater in patients without chronic kidney disease than in

patients with pre-existing kidney disease.

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13

Women with AKI had a higher relative risk for HF in all stages of AKI than men,

suggesting that the impact of AKI may be more substantial in women. The evidence of

differences in postoperative risks between men and women is not uniform. A recent study

showed that female sex is an independent risk factor for mortality and morbidity after cardiac

surgery36, although another study found that the difference in mortality was largely explained

by preoperative risk factors.37

The main strength of our study was the size of the study population and length of follow-

up. Also, our study population was recruited from a nationwide register and may therefore be

generalizable to other countries with a similar level of healthcare. The registers used for

follow-up were virtually complete and no patients were lost to follow-up. Also, the outcome

studied has been found to have a high validity in the register used.18

However, the present study also has several limitations. Information for some of the

traditional risk factors for cardiovascular disease was missing for a part of the study

population, but in a subset of more than 16 000 patients complete data on all potential

confounders for HF was available, and in this subset a similar association between AKI and

HF was found as in the total study population. Hypertension and smoking, which are common

cardiovascular risk factors, did not change point estimates significantly and were therefore not

used in the final statistical model. Another limitation is that we did not have information if

medication that may mitigate the development of HF was stopped postoperatively in patients

with AKI more frequently than among those without AKI. Also, we did not have information

on some preoperative risk factors for HF as presence of anemia or if patients were treated

with angiotension-converting-enzyme inhibitors, angiotensin-receptor-blockers, betablockers

or aldosterone antagonists before surgery. Another limitation was the lack of information

regarding proteinuria at baseline. Also, we did not have information on changes in life style

during the nine years of inclusion, which may have affected the risk of developing heart

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14

failure. Even though we could adjust for left ventricular systolic dysfunction we did not have

information about diastolic function. Thus, there may have been residual confounding that we

could not control for which may have affected our results.

Conclusions

Acute kidney injury after coronary artery bypass grafting was associated with increased long-

term risk of first hospitalization for HF. This was true for patients with or without pre-existing

chronic kidney disease, and for both sexes. Patients with AKI after CABG should be followed

closely in order to detect early changes in cardiac function. Our results should be interpreted

with caution since we could not control for medication or anemia before or after surgery.

Acknowledgments

The authors are thankful to the steering committee of SWEDEHEART for making their

register available for the purpose of this study.

Disclosures

None.

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JR, van Veldhuisen DJ. Renal function, neurohormonal activation, and survival in patients with chronic heart failure. Circulation. 2000; 102:203-210. 20. Smilde TDJ, Hillege HL, Voors AA, Dunselman PHJ, Van Veldhuisen DJ. Prognostic importance of renal function in patients with early heart failure and mild left ventricular dysfunction. Am. J. Cardiol. 2004; 94:240-243. 21. McAlister FA, Ezekowitz J, Tonelli M, Armstrong PW. Renal insufficiency and heart failure: prognostic and therapeutic implications from a prospective cohort study. Circulation. 2004; 109:1004-1009. 22. Kottgen A, Russell SD, Loehr LR, Crainiceanu CM, Rosamond WD, Chang PP, Chambless LE, Coresh J. Reduced kidney function as a risk factor for incident heart failure: the atherosclerosis risk in communities (ARIC) study. J. Am. Soc. Nephrol. 2007; 18:1307-1315. 23. Cowie MR, Wood DA, Coats AJ, Thompson SG, Poole-Wilson PA, Suresh V, Sutton GC. Incidence and aetiology of heart failure; a population-based study. Eur. Heart J. 1999; 20:421-428. 24. Bui AL, Horwich TB, Fonarow GC. Epidemiology and risk profile of heart failure. Nat Rev Cardiol. 2011; 8:30-41. 25. Holzmann MJ, Ahnve S, Hammar N, Jörgensen L, Klerdal K, Pehrsson K, Ivert T. Creatinine clearance and risk of early mortality in patients undergoing coronary artery bypass grafting. J. Thorac. Cardiovasc. Surg. 2005; 130:746-752. 26. Holzmann MJ, Hammar N, Ahnve S, Nordqvist T, Pehrsson K, Ivert T. Renal insufficiency and long-term mortality and incidence of myocardial infarction in patients undergoing coronary artery bypass grafting. Eur. Heart J. 2007; 28:865-871. 27. James MT, Ghali WA, Knudtson ML, Ravani P, Tonelli M, Faris P, Pannu N, Manns BJ, Klarenbach SW, Hemmelgarn BR. Associations between acute kidney injury and cardiovascular and renal outcomes after coronary angiography. Circulation. 2011; 123:409-416. 28. Burns KEA, Chu MWA, Novick RJ, Fox SA, Gallo K, Martin CM, Stitt LW, Heidenheim AP, Myers ML, Moist L. Perioperative N-acetylcysteine to prevent renal dysfunction in high-risk patients undergoing cabg surgery: a randomized controlled trial. JAMA. 2005; 294:342-350. 29. Mentzer RM Jr, Oz MC, Sladen RN, Graeve AH, Hebeler RF Jr, Luber JM Jr, Smedira NG. Effects of perioperative nesiritide in patients with left ventricular dysfunction undergoing cardiac surgery:the NAPA Trial. J. Am. Coll. Cardiol. 2007; 49:716-726. 30. Chuasuwan A, Kellum JA. Cardio-renal syndrome type 3: epidemiology, pathophysiology, and treatment. Semin. Nephrol. 2012; 32:31-39. 31. Kelly KJ. Distant effects of experimental renal ischemia/reperfusion injury. J. Am. Soc. Nephrol. 2003; 14:1549-1558. 32. Coca SG, Singanamala S, Parikh CR. Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis. Kidney Int. 2012; 81:442-448. 33. Basile DP, Donohoe D, Roethe K, Osborn JL. Renal ischemic injury results in permanent damage to peritubular capillaries and influences long-term function. Am. J. Physiol. Renal Physiol. 2001; 281:F887-899. 34. Mariscalco G, Lorusso R, Dominici C, Renzulli A, Sala A. Acute kidney injury: a relevant complication after cardiac surgery. Ann. Thorac. Surg. 2011; 92:1539-1547. 35. Hillege HL, Nitsch D, Pfeffer MA, Swedberg K, McMurray JJV, Yusuf S, Granger CB, Michelson EL, Ostergren J, Cornel JH, de Zeeuw D, Pocock S, van Veldhuisen DJ. Renal function as a predictor of outcome in a broad spectrum of patients with heart failure. Circulation. 2006; 113:671-678. 36. Blasberg JD, Schwartz GS, Balaram SK. The role of gender in coronary surgery. Eur J

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Cardiothorac Surg. 2011; 40:715-721. 37. Saxena A, Dinh D, Smith JA, Shardey G, Reid CM, Newcomb AE. Sex differences in outcomes following isolated coronary artery bypass graft surgery in Australian patients: analysis of the Australasian Society of Cardiac and Thoracic Surgeons cardiac surgery database. Eur J Cardiothorac Surg. 2012; 41:755-762.



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Table 1. Characteristics of the study population in relation to acute kidney injury classified by

absolute increase in postoperative serum creatinine values.

Acute Kidney Injury stage

All patients No AKI 1 2 3

Number of patients 24018 21239 1428 927 424

Percent of study population 100 88.3 6.0 3.9 1.8

Age (SD), years 67 (9) 66 (9) 70 (9) 71 (9) 70 (9)

Female sex, n (%) 5078 (21) 4523 (21) 278 (20) 192 (21) 85 (20)

eGFR (SD), mL/min/1.73 m2 77 (21) 78 (20) 73 (23) 68 (26) 58 (25)

Preop. SCr (SD), mol/L 92 (26) 90 (22) 98 (33) 107 (40) 131 (64)

Preop. SCr (SD), mg/dL 1.0 (0.3) 1.0 (0.3) 1.1 (0.4) 1.2 (0.5) 1.5 (0.7)

Diabetes mellitus (%) 23 22 27 33 37

Hypertension (%) 57 56 65 72 77

Hyperlipidemia (%) 61 60 61 62 70

Peripheral vascular disease (%) 8.9 8.3 13 13 18

Current smoking (%) 18 18 15 18 15

COPD (%) 5.9 5.8 6.6 6.5 7.8

Prior MI (%) 36 35 40 43 52

Prior stroke (%) 4.8 4.4 6.9 7.0 12

Left ventricular function

Ejection fraction > 50 % (%) 73 74 68 64 61

Ejection fraction 30-50 % (%) 24 23 28 32 33

Ejection fraction < 30 % (%) 2.7 2.5 3.7 4.0 6.2

Internal thoracic artery use (%) 94 94 95 94 93

CABG without cardiopulmonary

bypass (%) 5.9 5.6 6.7 7.9 8.7

Year of surgery

2000-2004 (%) 56 56 56 59 55

2005-2008 (%) 44 44 44 41 45

AKI, acute kidney injury; SD, standard deviation; eGFR, estimated glomerular filtration rate; SCr, serum

creatinine; CABG, coronary artery bypass grafting; COPD, chronic obstructive pulmonary disease; MI,

myocardial infarction. Age, GFR, and serum creatinine values are given as means with standard deviations.

Acute kidney injury classified according to absolute raise in serum creatinine values. Stage 1; 0.3 to 0.5 mg/dL,

stage 2; 0.5 to 1 mg/dL, stage 3; >1 mg/dL.

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Table 2. Hazard ratios of first hospitalization for heart failure with 95 percent confidence intervals in

relation to acute kidney injury stage defined by absolute increase in postoperative serum creatinine

values*. Total number of patients n = 24 018.

Acute kidney injury

No kidney

injury 1 2 3

Number of patients (%) 21239 (88.4) 1428 (5.6) 927 (3.9) 424 (1.8)

Number of events (%) 997 (4.7) 141 (9.9) 122 (13.2) 65 (15.3)

HR (95% CI) HR (95% CI) HR (95% CI)

Crude 1.00 2.22 (1.86-2.65) 3.10 (2.57-3.74) 3.95 (3.08-5.08)

Adjustment for age and

sex 1.00 1.87 (1.57-2.23) 2.48 (2.05-2.99) 3.29 (2.56-4.23)

Multivariable adjustment† 1.00 1.60 (1.34-1.92) 1.87 (1.54-2.27) 1.98 (1.53-2.57)

* Acute kidney injury classified according to absolute increase in serum creatinine values. Stage 1; 0.3 to 0.5 mg/dL,

stage 2; 0.5 to 1 mg/dL, stage 3; >1 mg/dL. HR, hazard ratio; CI, confidence Interval. † Multivariable adjustment was

made for: age, sex, diabetes mellitus, left ventricular ejection fraction, estimated glomerular filtration rate, pre- and

postoperative myocardial infarction.

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Table 3. Hazard ratios of hospitalization for heart failure stratified by estimated glomerular filtration rate with 95

percent confidence intervals in relation to acute kidney injury*. Total number of patients n = 24 018.

Acute Kidney Injury

Total No kidney

injury AKI 1 AKI 2&3

All patients

Number of patients (%) 24 018 (100) 21 239 (100) 1428 (100) 1351 (100)

Number of events (%) 1325 (5.5) 997 (4.7) 141 (9.9) 187 (14)

Age groups†

eGFR 60

Number of patients (%) 19 430 (81) 17 684 (83) 1018 (71) 728 (54)

Number of events (%) 806 (4.1) 656 (3.7) 67 (6.6) 83 (11)

Risk of HF hospitalization (HR; 95% CI) 1.00 1.41 (1.10-1.82) 2.24 (1.78-2.83)

eGFR <60

Number of patients (%) 4588 (19) 3555 (17) 410 (29) 623 (46)

Number of patients hospitalized for HF (%) 519 (11) 341 (9.6) 74 (18) 104 (17)

Risk of HF hospitalization (HR; 95% CI) 1.00 1.82 (1.41-2.34) 1.70 (1.35-2.12)

* AKI; Acute kidney injury classified according to absolute raise in serum creatinine values. Stage 1; 0.3-0.5 mg/dL, stage

2&3; > 0.5 mg/dL. CI; confidence interval, HF; heart failure, HR; hazard ratio. † Multivariable adjustment was made for; age,

sex, diabetes mellitus, left ventricular ejection fraction, pre- and postoperative myocardial infarction.

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nts hospitalized for HF (%) 519 (11) 341 (9.6) 74

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21

Figure Legends

Figure 1. Selection criteria for the study population consisting of 24 018 patients undergoing

primary isolated coronary artery bypass grafting between January 1, 2000 and December 31,

2008 in Sweden.

Figure 2. Cumulative incidence for first hospitalization of heart failure. The curves represent

no kidney injury, and different stages of acute kidney injury. The inset shows the same data

on an enlarged y-axis.

Figure 3. Cumulative incidence of the composite endpoint of first hospitalization for heart

failure or death. The curves represent no kidney injury, and different stages of acute kidney

injury. The inset shows the same data on an enlarged y-axis.

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Daniel Olsson, Ulrik Sartipy, Frieder Braunschweig and Martin J. HolzmannFailure

Acute Kidney Injury Following Coronary Artery Bypass Surgery and Long-term Risk of Heart

Print ISSN: 1941-3289. Online ISSN: 1941-3297 Copyright © 2012 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation: Heart Failure published online December 10, 2012;Circ Heart Fail.

http://circheartfailure.ahajournals.org/content/early/2012/12/10/CIRCHEARTFAILURE.112.971705World Wide Web at:

The online version of this article, along with updated information and services, is located on the

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click Request Permissions in the middle column of the Web page under Services. Further information about thisEditorial Office. Once the online version of the published article for which permission is being requested is located,

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Supplemental Material

Supplemental Table 1. Hazard Ratios of first hospitalization for heart failure with 95 percent confidence intervals in

relation to acute kidney injury stage defined by the AKIN classification*. Total number of patients n = 24 018.

Acute kidney injury

No kidney

injury 1 2 3

Number of patients (%) 21 230 (88) 2452 (10) 278 (1.2) 58 (0.2)

Number of events (%) 997 (4.7) 282 (12) 40 (14) 6 (10)

HR (95% CI) HR (95% CI) HR (95% CI)

Crude 1.00 2.72 (2.66-2.78) 2.90 (2.74-3.08) 2.40 (2.09-2.75)

Adjustment for age and

sex 1.00 2.31 (2.26-2.37) 2.44 (2.30-2.58) 2.22 (1.93-2.54)

Multivariable adjustment† 1.00 1.69 (1.48-1.94) 2.33 (1.69-3.22) 1.87 (0.84-4.20)

* Acute kidney injury classified according to the Acute Kidney Injury Network classification. Stage 1; > 0.3 mg/dL

or 50-100% increase, stage 2; 100-200% increase, stage 3; > 200% increase of postoperative creatinine values. HR;

Hazard Ratio. CI; confidence Interval. † Multivariable adjustment was made for: age, sex, diabetes mellitus, left

ventricular ejection fraction, estimated glomerular filtration rate, pre- and post-operative myocardial infarction.

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