Cardiovascular Surgery

Acute Kidney Injury After Cardiac Surgery

Focus on Modifiable Risk Factors
Keyvan Karkouti, MD; Duminda N. Wijeysundera, MD; Terrence M. Yau, MD;
Jeannie L. Callum, MD; Davy C. Cheng, MD; Mark Crowther, MD; Jean-Yves Dupuis, MD;
Stephen E. Fremes, MD; Blaine Kent, MD; Claude Laflamme, MD; Andre Lamy, MD;
Jean-Francois Legare, MD; C. David Mazer, MD; Stuart A. McCluskey, MD; Fraser D. Rubens, MD;
Corey Sawchuk, MD; W. Scott Beattie, MD

Background—Acute kidney injury (AKI) after cardiac surgery is a major health issue. Lacking effective therapies, risk
factor modification may offer a means of preventing this complication. The objective of the present study was to identify
and determine the prognostic importance of such risk factors.
Methods and Results—Data from a multicenter cohort of 3500 adult patients who underwent cardiac surgery at 7 hospitals
during 2004 were analyzed (using multivariable logistic regression modeling) to determine the independent relationships
between 3 thresholds of AKI (⬎25%, ⬎50%, and ⬎75% decrease in estimated glomerular filtration rate within 1 week
Downloaded from http://circ.ahajournals.org/ by guest on February 4, 2017

of surgery or need for postoperative dialysis) with death rates, as well as to identify modifiable risk factors for AKI. The
3 thresholds of AKI occurred in 24% (n⫽829), 7% (n⫽228), and 3% (n⫽119) of the cohort, respectively. All 3
thresholds were independently associated with a ⬎4-fold increase in the odds of death and could be predicted with
several perioperative variables, including preoperative intra-aortic balloon pump use, urgent surgery, and prolonged
cardiopulmonary bypass. In particular, 3 potentially modifiable variables were also independently and strongly
associated with AKI. These were preoperative anemia, perioperative red blood cell transfusions, and surgical
reexploration.
Conclusions—AKI after cardiac surgery is highly prevalent and prognostically important. Therapies aimed at mitigating
preoperative anemia, perioperative red blood cell transfusions, and surgical reexploration may offer protection against
this complication. (Circulation. 2009;119:495-502.)
Key Words: surgery 䡲 cardiopulmonary bypass 䡲 kidney 䡲 risk factors

A cute kidney injury (AKI) is a highly prevalent and

prognostically important complication of cardiac sur-
gery. By most estimates, up to 30% of cardiac surgery
patients develop clinically relevant kidney injury.1 When the
injury is severe enough to necessitate dialysis, which is the
case for approximately 1% to 2% of patients,1 it confers an
⬇8-fold increase in the odds of death.2 Even when the injury
is relatively modest, it is independently associated with
markedly increased morbidity and mortality.3
Clinical Perspective p 502
To mitigate the burden of AKI after cardiac surgery,
numerous interventions have been tested, but none has proved
efficacious.1 In the absence of proven interventions, a
reasonable strategy would be to identify modifiable risk
factors for AKI in this setting. These modifiable risk
factors might, in turn, serve as therapeutic targets for
preventing AKI. Previous studies have identified several

Received April 16, 2008; accepted November 13, 2008.

From the Department of Anesthesia, Toronto General Hospital, University Health Network, University of Toronto (K.K., D.N.W., S.A.M., W.S.B.);
Department of Health Policy, Management, and Evaluation, University of Toronto (K.K.); Department of Surgery, Division of Cardiac Surgery, Toronto
General Hospital, University Health Network, University of Toronto (T.M.Y.); Department of Clinical Pathology; Sunnybrook Health Sciences Center;
University of Toronto (J.L.C.), Toronto, Ontario, Canada; Department of Anesthesia, University of Western Ontario, London, Ontario, Canada (D.C.C.);
Department of Medicine, Division of Hematology, McMaster University, Hamilton, Ontario, Canada (M.C.); Department of Anesthesia, University of
Ottawa, Ottawa, Ontario, Canada (J.-Y.D.); Department of Surgery, Division of Cardiac and Vascular Surgery, Sunnybrook Health Sciences Center,
University of Toronto, Toronto, Ontario, Canada (S.E.F.); Department of Anesthesia, Dalhousie University, Halifax, Nova Scotia, Canada (B.K.);
Department of Anesthesia, Sunnybrook Health Sciences Center, University of Toronto, Toronto, Ontario, Canada (C.L.); Department of Surgery, Division
of Cardiac Surgery, McMaster University, Hamilton, Ontario, Canada (A.L.); Department of Surgery, Division of Cardiac Surgery, Dalhousie University,
Halifax, Nova Scotia, Canada (J.-F.L.); Departments of Anesthesia and Critical Care, Keenan Research Center in the Li Ka Shing Knowledge Institute,
St Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada (C.D.M.); Department of Surgery, Division of Cardiac Surgery, University of
Ottawa, Ottawa, Ontario, Canada (F.D.R.); Department of Anesthesia, McMaster University, Hamilton, Ontario, Canada (C.S.).
Correspondence to Keyvan Karkouti, MD, Department of Anesthesia and Health Policy, Management, and Evaluation, Toronto General Hospital,
University of Toronto, 200 Elizabeth St, EN 3-402, Toronto, Ontario, Canada M5G 2C4. E-mail keyvan.karkouti@uhn.on.ca
© 2009 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.108.786913

495
 496 Circulation February 3, 2009
Table 1. Relationship of AKI With Length of Stay and Mortality
ⱕ25% Decrease
in eGFR
Variables (n⫽2631)
Median hospital length 7 (5, 9)
of stay, d (Q1, Q3)*
Mortality rates
n (%) 25 (1.0%)
Unadjusted OR (95% CI) Reference
Adjusted OR (95% CI)† Reference
Q1 indicates first quartile; Q3, third quartile.
*P⬍0.0001 for all comparisons against the group with ⱕ25% decrease in eGFR.
†Variables for which adjustments were made included gender, age, weight, shock, diabetes, myocardial infarction, peripheral
vascular disease, ventricular dysfunction, atrial fibrillation, renal dysfunction, preoperative laboratory abnormalities, antifibrinolytic
drug use, procedure type, urgency, CPB duration, deep hypothermic circulatory arrest, blood product transfusion, reexploration, and
intra-aortic balloon pump use, as well as postoperative stroke, myocardial infarction, acute respiratory distress syndrome, pneumonia,
sepsis, and deep sternal infection.
Models’ c-index⫽0.93; Hosmer-Lemeshow P⫽0.4.
Downloaded from http://circ.ahajournals.org/ by guest on February 4, 2017
important risk factors for AKI after cardiac surgery.4 –14
The primary purpose of most of these studies, however,
was prognostic risk stratification rather than risk modifi-
cation; hence, they focused on patient comorbidities and
nonmodifiable surgical factors. Consequently, we under-
took this retrospective observational multicenter study to
examine the prognostic importance of modifiable risk
factors for AKI after cardiac surgery.
Methods
Study Cohort
Data from a previously described multicenter cohort were used for
the present study.15,16 The cohort consisted of 3500 adult (⬎18 years
of age) patients who underwent cardiac surgery with cardiopulmo-
nary bypass (CPB) at 7 academic Canadian hospitals during 2004.
Each hospital contributed 500 consecutive patients, excluding infre-
quent procedures (heart transplantation, ventricular assist device
placement, and complex congenital abnormality repair). Additional
exclusion criteria for the present study were preoperative dialysis
dependence and missing preoperative or postoperative creatinine
values. For patients who underwent more than 1 relevant procedure
during the study period, only data on their initial surgery were
collected.
After research board approval at each hospital was received,
detailed perioperative data were collected retrospectively on patients
from clinical databases and hospital charts. Data were entered into a
computerized database, which was programmed to accept only
matching double-entry data that fell within prespecified ranges. All
queries were resolved by reference to the patients’ original records.
Dependent Variable
The primary dependent variable was AKI. Three thresholds for injury,
taken from the consensus-based RIFLE (Risk, Injury, Failure, Loss, and
End-stage kidney disease) criteria,17 were examined: (1) ⬎25% de-
crease in estimated glomerular filtration rate (eGFR); (2) ⬎50%
decrease in eGFR; and (3) ⬎75% decrease in eGFR. All thresholds also
included any patient who required dialysis during their postoperative
hospital stay. Glomerular filtration rate was estimated with the
Cockcroft-Gault equation,18 using preoperative creatinine and highest
creatinine concentration during the first week after surgery.
Independent Variables
Measured preoperative and intraoperative variables known to be or
that could potentially be associated with AKI or other adverse
outcomes were examined.
⬎25% Decrease ⬎50% Decrease ⬎75% Decrease
in eGFR or Dialysis in eGFR or Dialysis in eGFR or Dialysis
(n⫽829) (n⫽228) (n⫽119)
10 (6, 17) 14 (7, 27) 19 (6, 36)
83 (10%) 58 (25%) 46 (39%)
11.6 (7.4–18.3) 21.7 (14.4–32.6) 33.3 (21.3–52.0)
4.0 (2.3–6.7) 5.9 (3.6–9.8) 9.5 (5.4–16.9)
Statistical Analyses
SAS version 9.1 (SAS Institute, Inc, Cary, NC) was used for the
statistical analyses. Categorical variables were summarized as fre-
quencies and percentages and continuous variables as means and
SDs. The unadjusted associations of the 3 thresholds of AKI with
hospital length of stay and death rates were calculated (with the
Wilcoxon rank sum test and the ␹2 statistic, respectively). For death,
the adjusted associations with AKI were also calculated with
multivariable logistic regression modeling (backward stepwise se-
lection; P⬍0.1 criterion for variable retention). For the present
analysis, all preoperative and intraoperative variables related to
death, as well as important measured postoperative complications
(myocardial infarction, stroke, respiratory failure, serious infections,
blood product transfusions, and reexploration), were assessed as
covariates.
Multivariable logistic regression modeling was also performed to
assess the adjusted associations of measured perioperative variables
with the 3 thresholds of AKI. Initially, bivariate analyses (using the
␹2 statistic for categorical variables and the t test or Wilcoxon rank
sum test for continuous variables) were performed to identify which
variables were associated with the dependent variables. The mathe-
matical relationships between the continuous predictor variables and
AKI were assessed with cubic spline functions.19,20 Variables that
were not linearly related were either mathematically transformed,
categorized along clinically sensible cut points, or converted into
multiple dichotomous variables.21
All clinically sensible variables with P⬍0.3 in the bivariate
analyses were entered into multivariable logistic regression models.
Subsequent retention in the models was determined by backward
stepwise selection, in which P⬍0.1 was the criterion for variable
retention. A Pearson correlation matrix of variables was used to
identify collinear independent variables.21
Model discrimination and calibration were assessed by the c-index
and the Hosmer-Lemeshow statistic (larger probability value means
better calibration), respectively. Bootstrap resampling22 was used to
assess the stability of the models as follows: 100 computer-generated
samples, each including 3450 patients, were derived from the study
cohort by random selection with replacement, and the models were
refitted for each sample. The retention rates of the variables in the
bootstrap models were measured. The center effect was analyzed by
inclusion of the center (categorized as low-, medium-, and high-rate
centers) as a covariate in the logistic regression models and by
reconstruction of the logistic regression models with generalized
estimating equations.23
The authors had full access to and take full responsibility for the
integrity of the data. All authors have read and agree to the
manuscript as written.
 Karkouti et al
Downloaded from http://circ.ahajournals.org/ by guest on February 4, 2017
Figure. Spline function graphs of the unadjusted relationships between selected continuous variables and probability of AKI (⬎50%
decrease in eGFR or dialysis). Dotted lines are the 95% CIs.
Results
After the exclusion criteria were applied, 3460 patients were
included in the study. Of these, 829 (24%) met the first, 228
(7%) met the second, and 119 (3%) met the third threshold of
AKI. As can be seen in Table 1, all 3 thresholds of AKI were
associated with increased length of stay and death. The lowest
threshold of ⬎25% decrease in eGFR, for example, was asso-
ciated with a 4-fold increase in the risk-adjusted odds of death.
The Figure shows the unadjusted relationships (using
spline function curves) of selected continuous independent
variables with a ⬎50% decrease in eGFR (other thresholds
had similar relationships; results not shown). The bivariate
associations of patient- and procedure-related variables with
AKI are shown in Table 2 (associations with other thresholds
were similar; results not shown); variables with P⬍0.3 were
included in the multivariable analyses. No 2 variables had a
Pearson correlation coefficient ⬎0.45, which suggests that
collinearity was not an issue in the logistic regression
analyses. Nine patients with missing values were excluded
from the multivariable analyses.
The results of the multivariable analyses for the 3 thresh-
olds of AKI are presented in Table 3. The models demon-
strated good discrimination and calibration; furthermore, they
remained stable during bootstrap resampling. The addition of
interaction terms or of the center did not influence the models
Acute Kidney Injury After Cardiac Surgery 497
significantly. Accounting for clustering also did not have a
significant effect on the models.
Although the most predictive risk factors in the models
were CPB duration and intra-aortic balloon pump before
surgery, 3 potentially modifiable and interrelated risk factors
(preoperative anemia, perioperative red blood cell [RBC]
transfusions, and the need for reexploration) were strongly
associated with AKI in all 3 models. The Pearson correlation
coefficients among these variables were ⬇0.3 (P⬍0.0001).
Discussion
In the present multicenter cohort, AKI occurred commonly
and, even when mild, was independently associated with
increased mortality rates. This shows that the burden of AKI
in modern cardiac surgery remains high. Furthermore, it
provides a multicenter validation of the clinical relevance of
the RIFLE classification in cardiac surgery.17
As in previous studies,1,4 –14,24 –27 we found several inde-
pendent risk factors for AKI. Some of the risk factors, such as
the comorbidities diabetes mellitus, preexisting kidney dis-
ease, and left ventricular dysfunction, are clearly nonmodifi-
able. Others, such as the presence of an intra-aortic balloon
pump and CPB duration, may be modifiable, but not readily
and only in selected cases. For example, in patients with
intra-aortic balloon pumps, it may at times be possible to
 498 Circulation February 3, 2009

Table 2. Characteristics of the Study Cohort

ⱕ25% Decrease ⬎25% Decrease ⬎50% Decrease ⬎75% Decrease
in eGFR in eGFR or Dialysis in eGFR or Dialysis in eGFR or Dialysis
Variables (n⫽2631) (n⫽829) (n⫽228) (n⫽119) P*
Patient-related variables
Female sex 628 (24) 229 (28) 61 (27) 31 (26) 0.03
Age, y 65⫾11 66⫾11 68⫾12 69⫾11 ⬍0.0001
Weight, kg 81⫾16 83⫾19 83⫾19 82⫾19 0.0001
Diabetes (type 1 or 2), n (%) 719 (27) 310 (37) 87 (38) 44 (37) ⬍0.0001
Hypertension, n (%) 1724 (66) 580 (70) 162 (71) 83 (70) 0.02
Chronic obstructive pulmonary disease, n (%) 253 (10) 107 (13) 28 (12) 17 (14) 0.007
Cerebrovascular disease, n (%) 253 (10) 97 (12) 30 (13) 16 (13) 0.08
Peripheral vascular disease, n (%) 290 (11) 103 (12) 20 (9) 11 (9) 0.3
Preoperative atrial fibrillation, n (%) 206 (8) 120 (14) 45 (20) 26 (22) ⬍0.0001
Recent (⬍30 days) myocardial infarction, n (%) 465 (18) 171 (21) 58 (25) 34 (29) 0.06
Recent (⬍5 days) heart catheterization, n (%) 622 (24) 223 (27) 72 (32) 42 (35) 0.06
⬍0.0001
Downloaded from http://circ.ahajournals.org/ by guest on February 4, 2017

Left ventricular dysfunction (ejection fraction 371 (14) 175 (21) 57 (25) 35 (29)
⬍40%), n (%)
Preoperative intra-aortic balloon pump, n (%) 49 (2) 76 (9) 32 (14) 22 (18) ⬍0.0001
Preoperative hemoglobin, g/dL 13.6⫾1.6 13.0⫾1.9 12.5⫾2.1 12.3⫾2.2 ⬍0.0001
Preexisting renal insufficiency (eGFR ⬍60 698 (27) 264 (32) 103 (45) 70 (59) 0.003
mL/min), n (%)
Preexisting coagulopathy (INR ⬎1.5), n (%) 76 (3) 52 (6) 22 (10) 11 (9) ⬍0.0001
Preexisting thrombocytopenia (platelet count 165 (6) 91 (11) 35 (15) 22 (18) ⬍0.0001
⬍150⫻109/L), n (%)
Use of ACE inhibitor or receptor blocker 1541 (59) 462 (56) 121 (54) 67 (57) 0.2
therapy before surgery, n (%)
Procedure-related variables
Hospital, n (%) 0.005
1 387 (15) 103 (12) 26 (11) 17 (14)
2 365 (14) 129 (16) 31 (14) 18 (15)
3 374 (14) 120 (14) 53 (23) 30 (25)
4 385 (15) 112 (14) 19 (8) 11 (9)
5 400 (15) 92 (11) 30 (13) 20 (17)
6 364 (14) 133 (16) 43 (19) 17 (14)
7 356 (14) 140 (17) 26 (11) 6 (5)
Procedure ⬍0.0001
Isolated aortocoronary bypass surgery, n (%) 1860 (71) 480 (58) 113 (50) 58 (49)
Single valve surgery, n (%) 234 (9) 66 (8) 19 (8) 11 (9)
Other surgery, n (%) 537 (20) 283 (34) 96 (42) 50 (42)
Urgent surgery, n (%) 367 (14) 187 (23) 65 (29) 39 (33) ⬍0.0001
Redo surgery, n (%) 175 (7) 90 (11) 33 (14) 22 (18) ⬍0.0001
CPB duration, min 103⫾42 129⫾65 151⫾87 155⫾88 ⬍0.0001
Deep hypothermic circulatory arrest, n (%) 61 (2) 28 (3) 12 (5) 7 (6) 0.09
Received aprotinin, n (%) 704 (27) 283 (34) 95 (42) 55 (46) ⬍0.0001
Lowest hematocrit during CPB, % 24⫾3 23⫾4 23⫾4 22⫾4 ⬍0.0001
Median perioperative (day 0 or 1) RBC 0 (0, 2) 2 (0, 4) 3 (1, 6) 4 (1, 7) ⬍0.0001
transfusion, U (Q1, Q3)
Postoperative reexploration, n (%) 111 (4) 109 (13) 47 (21) 31 (26) ⬍0.0001
INR indicates international normalized ratio of the prothrombin time; eGFR, estimated glomerular filtration rate.
*Comparisons between patients with ⱕ25% in eGFR and ⬎25% in eGFR or on dialysis.
Continuous variables are shown as mean⫾SD unless otherwise stated.
 Karkouti et al Acute Kidney Injury After Cardiac Surgery 499

Table 3. Independent Predictors of AKI

⬎25% Decrease in eGFR or Dialysis ⬎50% Decrease in eGFR or Dialysis ⬎75% Decrease in eGFR or Dialysis

Variable OR (95% CI) Wald ␹2 (P) Retained, %* OR (95% CI) Wald ␹2 (P) Retained, %* OR (95% CI) Wald ␹2 (P) Retained, %*
Patient-related factors
Age, y 63% 7 (0.04) 100% 0%
⬍60 Reference
60–70 1.13 (0.74–1.72)
⬎70 1.64 (1.07–2.49)
BSA, m2 18 (0.0001) 100% 9 (0.009) 100% 8 (0.02) 100%
⬍1.7 Reference Reference Reference
1.7–2.1 1.22 (0.95–1.57) 1.25 (0.82–1.92) 1.51 (0.86–2.63)
⬎2.1 1.82 (1.34–2.46) 2.15 (1.25–3.69) 2.87 (1.37–6.00)
Diabetes 1.47 (1.22–1.76) 17 (⬍0.0001) 100% 1.48 (1.08–2.03) 6 (0.01) 100% 2%
Hypertension 1.20 (0.99–1.44) 4 (0.06) 74% 1% 1%
Atrial fibrillation 1.65 (1.26–2.16) 14 (0.0002) 100% 1.67 (1.12–2.49) 6 (0.01) 100% 1.74 (1.04–2.90) 4 (0.04) 99%
Left ventricular dysfunction 1.14 (1.03–1.26) 7 (0.009) 100% 1.16 (0.99–1.37) 3 (0.07) 98% 1.37 (1.11–1.69) 9 (0.003) 100%
Preoperative IABP 3.39 (2.25–5.11) 34 (⬍0.0001) 100% 3.13 (1.86–5.27) 18 (⬍0.0001) 100% 3.08 (1.68–5.64) 13 (0.0003) 100%
Renal insufficiency 30% 1.44 (0.97–2.08) 4 (0.05) 100% 3.38 (2.10–5.45) 25 (⬍0.0001) 100%
Downloaded from http://circ.ahajournals.org/ by guest on February 4, 2017

Thrombocytopenia 1.42 (1.05–1.91) 5 (0.02) 100% 1.47 (0.94–2.31) 3 (0.09) 91% 1.69 (0.97–2.97) 3 (0.07) 97%
Baseline hemoglobin 18 (0.0005) 100% 18 (0.0006) 100% 8 (0.04) 98%
ⱖ14 g/dL Reference Reference Reference
12–13.9 g/dL 1.23 (1.07–1.49) 1.06 (0.73–1.54) 1.00 (0.58–1.67)
10–11.9 g/dL 1.63 (1.25–2.12) 1.65 (1.07–2.54) 1.82 (1.04–3.17)
⬍10 g/dL 1.99 (1.29–3.08) 2.94 (1.66–5.23) 1.83 (0.84–3.95)
Procedure-related factors
Urgent surgery 1.28 (1.02–1.64) 5 (0.03) 100% 1.38 (0.97–1.98) 3 (0.08) 97% 1.54 (0.96–2.46) 3 (0.06) 93%
Reexploration 1.95 (1.40–2.71) 16 (⬍0.0001) 100% 1.99 (1.28–3.09) 9 (0.002) 100% 2.53 (1.46–4.40) 11 (0.0009) 100%
CPB duration (per 15 min) 1.11 (1.08–1.14) 57 (⬍0.0001) 100% 1.12 (1.08–1.16) 38 (⬍0.0001) 100% 1.08 (1.03–1.13) 12 (0.0006) 100%
Aprotinin 0% 1% 1.52 (0.99–2.31) 4 (0.05) 100%
CPB hematocrit ⬍20% 1.41 (1.07–1.84) 6 (0.01) 100% 0% 0%
Perioperative RBCs (per unit) 1.08 (1.05–1.12) 21 (⬍0.0001) 100% 1.08 (1.04–1.13) 15 (⬍0.0001) 100% 1.08 (1.03–1.13) 10 (0.001) 100%
C-index 0.72 0.81 0.84
Hosmer-Lemeshow P 0.2 0.4 0.8
BSA indicates body surface area; IABP, intra-aortic balloon pump.
*As obtained by bootstrap modeling. For variables that did not remain in the main model but remained in some of the bootstrap models, only the retention rate is shown.

delay the surgery until after the pump is explanted, and in
high-risk patients who are anticipated to require prolonged
CPB support, it may be possible to perform a less extensive
surgery to reduce CPB duration. Use of aprotinin, a recently
withdrawn antifibrinolytic drug that previously has been
shown to be linked with renal dysfunction,28 –30 was also
independently but not strongly associated with AKI in the
present study.
Of note, we identified 3 potentially modifiable and inter-
related variables that were independently and strongly asso-
ciated with AKI. These variables were preoperative anemia,
perioperative RBC transfusions, and postoperative reexplora-
tion. Before we explore the possible mechanisms by which
these variables may contribute to kidney injury after cardiac
surgery or the strategies by which they may be modified, it is
first necessary to provide an overview of the pathogenesis of
AKI in this setting.
Pathogenesis of AKI in Cardiac Surgery
An important cause of AKI in cardiac surgery,31,32 as well as
in other settings,33 is cellular ischemia, which results in
tubular epithelial and vascular endothelial injury and activa-
tion.34,35 Cardiac surgery heightens the risk of ischemic
kidney injury by several processes. Normally, kidney perfu-
sion is autoregulated such that glomerular filtration rate is
maintained until the mean arterial blood pressure falls below
80 mm Hg.35 Mean arterial blood pressure during cardiac
surgery is often at the lower limits or below the limits of
autoregulation, especially during periods of hemodynamic
instability.1 In addition, many cardiac surgery patients have
impaired autoregulation due to existing comorbidities (eg,
advanced age, atherosclerosis, chronic hypertension, or
chronic kidney disease), administration of drugs that impact
kidney autoregulation (eg, nonsteroidal antiinflammatory
drugs, ACE inhibitors, angiotensin receptor blockers, and
radiocontrast agents), or a proinflammatory state (see be-
low).35 In patients with impaired autoregulation, kidney
function may deteriorate even when the mean arterial blood
pressure is within the normal range.35
Another process by which cardiac surgery may contribute
to ischemic kidney injury is by inciting a strong systemic
inflammatory response.1 Proinflammatory events during car-
diac surgery include operative trauma, contact of the blood
components with the artificial surface of the CPB circuit,
 500 Circulation February 3, 2009
ischemia-reperfusion injury, and endotoxemia.1,36,37 Inflam-
mation plays a central role in the development of ischemic
kidney injury,34,35 and it is thought that the systemic inflamma-
tory response caused by cardiac surgery is similarly deleterious.1
Finally, cardiac surgery may further predispose patients to
ischemic kidney injury through the generation of free hemoglo-
bin and iron from hemolysis that occurs during CPB.1
The present findings, as well as those of others, support the
importance of these processes. Specifically, variables associ-
ated with impaired kidney perfusion, CPB duration, and
hemodynamic instability have repeatedly (including in the
present study) been shown to be associated with kidney injury
after cardiac surgery.1
Role of Anemia, RBC Transfusion,
and Reexploration
The kidney can generally tolerate isolated insults such as
hypoperfusion extremely well; for kidney injury to occur, a
Downloaded from http://circ.ahajournals.org/ by guest on February 4, 2017
combination of several insults or risk factors, or multiple hits,
is thought to be necessary.38 In cardiac surgery, anemia, RBC
transfusion, and reexploration may represent the additional
insults that culminate in AKI.
Anemia
We, and others, have shown that perioperative anemia in
cardiac surgery is independently associated with various
adverse outcomes, including kidney injury.15,39 Anemia may
contribute to kidney injury by reducing renal oxygen deliv-
ery, worsening oxidative stress, and impairing hemostasis.
Tissue oxygen delivery is directly related to arterial oxygen
content, which is primarily dependent on the hemoglobin
concentration.40 Anemia would therefore decrease oxygen
delivery to the kidneys, especially to the vulnerable renal
medulla, where the normal partial pressure of oxygen in the
renal tissue is very low.40 The adverse consequences of
anemia are likely enhanced further during cardiac surgery,
during which, for reasons outlined earlier, the kidney is more
prone to renal hypoperfusion.35
Anemia may enhance renal oxidative stress, because RBCs
serve important antioxidant functions.40 Anemia impairs he-
mostasis because normal platelet function is dependent on the
presence of an adequate (but as yet undetermined) hemoglo-
bin concentration.41,42 In cardiac surgery, during which patients
are already at increased risk for bleeding due to CPB-related
hemostatic defects,43 the added burden of anemia-induced plate-
let dysfunction may lead to excessive bleeding, which in turn
may necessitate multiple RBC transfusions and reexploration,
both of which are associated with AKI.
RBC Transfusion
Although the intended therapeutic effect of RBC transfusion
is to improve organ function by increasing tissue oxygen
delivery, there is increasing evidence that transfused RBCs
may actually contribute to organ injury in susceptible pa-
tients, likely because of changes that occur to RBCs during
storage.44 During storage, RBCs become less deformable,
undergo ATP and 2,3-diphosphoglycerate depletion, lose
their ability to generate nitric oxide, have increased adhesive-
ness to vascular endothelium, release procoagulant phospho-
lipids, and accumulate proinflammatory molecules, as well as
free iron and hemoglobin.45– 48 As a result, transfused stored
RBCs may impair tissue oxygen delivery, promote a proin-
flammatory state, exacerbate tissue oxidative stress, and
activate leukocytes and the coagulation cascade.45,46,48 In
susceptible patients, such as those undergoing cardiac sur-
gery, these changes can lead to organ dysfunction, with the
kidney seemingly at particularly high risk for injury.44
Reexploration
Surgical reexploration after cardiac surgery is independently
associated with various adverse outcomes, including kidney
injury.49 Although the mechanisms by which reexploration
can cause kidney injury have not been fully elucidated, it is
likely a safe assumption that they involve exacerbation of
many of the factors outlined above, such as hemodynamic
instability and operative trauma. Surgical reexploration is
also inextricably linked to both anemia and RBC transfusion,
because the principal reason for reexploration after cardiac
surgery is coagulopathy (which is exacerbated by anemia),
which leads to excessive blood loss (and massive RBC
transfusion).43
Clinical and Research Implications
If the observed association between these 3 factors—anemia,
transfusion of stored RBCs, and coagulopathy requiring
surgical reexploration—and AKI after cardiac surgery is
causal, then it would follow that treating or avoiding these
factors would reduce AKI after cardiac surgery. Several
low-risk, low-cost, perioperative measures that can be readily
implemented to help mitigate the occurrence or effects of
these factors include preoperative discontinuation of drugs
that impair coagulation, minimization of bloodletting and
hemodilution, expeditious surgery, administration of antifi-
brinolytic drugs, and aggressive investigation and treatment
of excessive blood loss. Other potential measures include use
of intravenous iron or erythropoietin-stimulating agents to
treat anemia before surgery, limiting RBC transfusions to
units that have been stored for short durations, or adminis-
tering hemostatic agents such as recombinant activated factor
VII early in the course of blood loss. Because of their high
costs, unproven effectiveness, possible risks, and logistical
issues related to their implementation, however, the safety,
efficacy, and cost-effectiveness of these measures must be
assessed before their routine use can be considered.
Study Limitations
There are several limitations to be considered when interpret-
ing the present study. First, postoperative renal function was
estimated with the Cockcroft-Gault equation, which uses
serum creatinine and weight (as a measure of muscle mass) to
estimate renal function after surgery.18 During the postoper-
ative period, however, these estimates may not be accurate
because of imbalances between creatinine production and
elimination, which can be caused by various factors, includ-
ing changing renal function, muscle breakdown and injury,
liver dysfunction, and various medications.50 Second, be-
cause only patients undergoing cardiac surgery with CPB
were included in the present study, our results cannot be
 Karkouti et al
generalized to other populations. Third, because this was a
retrospective observational study, causality could not be
determined. Thus, it is quite possible that AKI does not
increase the risk of death but is simply associated with death.
It is also possible that modifying any of the identified risk
factors for AKI will not influence the risk of AKI. Fourth, the
effects of unknown or unmeasured confounders on the
observed associations between the risk factors and AKI (eg,
perioperative use of nephrotoxic drugs), as well as between
AKI and death (eg, liver dysfunction), cannot be ruled out.
Fifth, neither the cause nor the duration of preoperative
anemia, each of which has prognostic implications, was
known. Sixth, the duration of follow-up was limited to the
period of hospitalization. Thus, postdischarge complications
could not be accounted for in the present analysis.
Conclusions
This multicenter, retrospective study found 3 potentially
modifiable, interrelated risk factors—preoperative anemia,
Downloaded from http://circ.ahajournals.org/ by guest on February 4, 2017
perioperative RBC transfusions, and postoperative reexplora-
tion—that were independently associated with AKI after
cardiac surgery. Future studies should determine the benefits
of therapies aimed at mitigating these factors.
Sources of Funding
Funding for this project was provided by the Canadian Institutes of
Health Research and Canadian Blood Services through an operating
grant and by Novo Nordisk through an unrestricted research grant.
Disclosures
None.
References
1. Rosner MH, Okusa MD. Acute kidney injury associated with cardiac
surgery. Clin J Am Soc Nephrol. 2006;1:19 –32.
2. Chertow GM, Levy EM, Hammermeister KE, Grover F, Daley J. Inde-
pendent association between acute renal failure and mortality following
cardiac surgery. Am J Med. 1998;104:343–348.
3. Lassnigg A, Schmidlin D, Mouhieddine M, Bachmann LM, Druml W,
Bauer P, Hiesmayr M. Minimal changes of serum creatinine predict
prognosis in patients after cardiothoracic surgery: a prospective cohort
study. J Am Soc Nephrol. 2004;15:1597–1605.
4. Wijeysundera DN, Karkouti K, Dupuis JY, Rao V, Chan CT, Granton JT,
Beattie WS. Derivation and validation of a simplified predictive index for
renal replacement therapy after cardiac surgery. JAMA. 2007;297:
1801–1809.
5. Palomba H, de Castro I, Neto AL, Lage S, Yu L. Acute kidney injury
prediction following elective cardiac surgery: AKICS score. Kidney Int.
2007;72:624 – 631.
6. Mehta RH, Grab JD, O’Brien SM, Bridges CR, Gammie JS, Haan CK,
Ferguson TB, Peterson ED. Bedside tool for predicting the risk of post-
operative dialysis in patients undergoing cardiac surgery. Circulation.
2006;114:2208 –2216.
7. Thakar CV, Arrigain S, Worley S, Yared JP, Paganini EP. A clinical score
to predict acute renal failure after cardiac surgery. J Am Soc Nephrol.
2005;16:162–168.
8. Provenchere S, Plantefeve G, Hufnagel G, Vicaut E, de Vaumas C,
Lecharny JB, Depoix JP, Vrtovsnik F, Desmonts JM, Philip I. Renal
dysfunction after cardiac surgery with normothermic cardiopulmonary
bypass: incidence, risk factors, and effect on clinical outcome. Anesth
Analg. 2003;96:1258 –1264.
9. Grayson AD, Khater M, Jackson M, Fox MA. Valvular heart operation is
an independent risk factor for acute renal failure. Ann Thorac Surg.
2003;75:1829 –1835.
10. Eriksen BO, Hoff KR, Solberg S. Prediction of acute renal failure after
cardiac surgery: retrospective cross-validation of a clinical algorithm.
Nephrol Dial Transplant. 2003;18:77– 81.
Acute Kidney Injury After Cardiac Surgery 501
11. Janssen DPB, Noyez L, van Druten JAM, Skotnicki SH, Lacquet LK.
Predictors of nephrological morbidity after coronary artery bypass
surgery. Cardiovasc Surg. 2002;10:222–227.
12. Conlon PJ, Stafford-Smith M, White WD, Newman MF, King S, Winn
MP, Landolfo K. Acute renal failure following cardiac surgery. Nephrol
Dial Transplant. 1999;14:1158 –1162.
13. Mangano CM, Diamondstone LS, Ramsay JG, Aggarwal A, Herskowitz
A, Mangano DT. Renal dysfunction after myocardial revascularization:
risk factors, adverse outcomes, and hospital resource utilization. Ann
Intern Med. 1998;128:194 –203.
14. Chertow GM, Lazarus JM, Christiansen CL, Cook F, Hammermeister
KE, Grover F, Daley J. Preoperative renal risk stratification. Circulation.
1997;95:878 – 884.
15. Karkouti K, Wijeysundera DN, Beattie WS; RBC Investigators. Risk
associated with preoperative anemia in cardiac surgery: a multicenter
cohort study. Circulation. 2008;117:478 – 484.
16. Karkouti K, Wijeysundera DN, Beattie WS, Callum JL, Cheng D, Dupuis
JY, Kent B, Mazer D, Rubens FD, Sawchuk C, Yau TM. Variability and
predictability of blood product use in cardiac surgery: a multicentre study.
Transfusion. 2007;47:2081–2088.
17. Bellomo R, Kellum JA, Ronco C. Defining and classifying acute renal
failure: from advocacy to consensus and validation of the RIFLE criteria.
Intensive Care Med. 2007;33:409 – 413.
18. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum
creatinine. Nephron. 1976;16:31– 41.
19. Devlin TF, Weeks BJ. Spline functions for logistic regression modeling.
In: Proceedings of the 11th Annual SAS Users Group International
Conference. Cary, NC: SAS Institute Inc; 1986:646 – 651.
20. Harrell FE. SAS macros and data step programs useful in survival anal-
ysis and logistic regression. 1999. Available at: http://biostat.mc.
vanderbilt.edu/twiki/bin/view/Main/SasMacros. Accessed October 15,
2008.
21. Katz MH. Multivariable Analysis: A Practical Guide for Clinicians. 1st
ed. Cambridge, United Kingdom: Cambridge University Press; 1999.
22. Efron B, Tibshirani RJ. Estimates of bias. In: Cox DR, Hinkley DV, Reid
N, Rubin DB, Silverman BW, eds. An Introduction to the Bootstrap. New
York, NY: Chapman & Hall; 1993:124 –140.
23. Allison PD. Logit analysis of longitudinal and other clustered data. In:
Allison PD, ed. Logistic Regression Using SAS System: Theory and
Application. Cary, NC: SAS Institute and Wiley; 1991:179 –216.
24. Kuitunen A, Vento A, Suojaranta-Ylinen R, Pettila V. Acute renal failure
after cardiac surgery: evaluation of the RIFLE classification. Ann Thorac
Surg. 2006;81:542–546.
25. Wigfield CH, Lindsey JD, Munoz A, Chopra PS, Edwards NM, Love RB.
Is extreme obesity a risk factor for cardiac surgery? An analysis of
patients with a BMI ⬎ or ⫽40. Eur J Cardiothorac Surg. 2006;29:
434 – 440.
26. Quader MA, McCarthy PM, Gillinov AM, Alster JM, Cosgrove DM III,
Lytle BW, Blackstone EH. Does preoperative atrial fibrillation reduce
survival after coronary artery bypass grafting? Ann Thorac Surg. 2004;
77:1514 –1522.
27. Bailey D, Phan V, Litalien C, Ducruet T, Merouani A, Lacroix J, Gauvin
F. Risk factors of acute renal failure in critically ill children: a prospective
descriptive epidemiological study. Pediatr Crit Care Med. 2007;8:29 –35.
28. Karkouti K, Beattie WS, Dattilo KM, McCluskey SA, Ghannam M,
Hamdy A, Wijeysundera D, Fedorko L, Yau TM. A propensity score
case-control comparison of aprotinin and tranexamic acid in high-
transfusion-risk cardiac surgery. Transfusion. 2006;46:327–338.
29. Brown JR, Birkmeyer NJ, O’Connor GT. Meta-analysis comparing the
effectiveness and adverse outcomes of antifibrinolytic agents in cardiac
surgery. Circulation. 2007;115:2801–2813.
30. Fergusson DA, Hebert PC, Mazer CD, Fremes S, MacAdams C, Murkin
JM, Teoh K, Duke PC, Arellano R, Blajchman MA, Bussieres JS, Cote D,
Karski J, Martineau R, Robblee JA, Rodger M, Wells G, Clinch J,
Pretorius R. A comparison of aprotinin and lysine analogues in high-risk
cardiac surgery. N Engl J Med. 2008;358:2319 –2331.
31. Yeboah ED, Petrie A, Pead JL. Acute renal failure and open heart
surgery. BMJ. 1972;1:415– 418.
32. Krian A. Incidence, prevention, and treatment of acute renal failure
following cardiopulmonary bypass. Int Anesthesiol Clin. 1976;14:
87–101.
33. Liano F, Pascual J; Madrid Acute Renal Failure Study Group. Epidemi-
ology of acute renal failure: a prospective, multicenter, community-based
study. Kidney Int. 1996;50:811– 818.
 502 Circulation February 3, 2009

34. Sutton TA, Fisher CJ, Molitoris BA. Microvascular endothelial injury and
dysfunction during ischemic acute renal failure. Kidney Int. 2002;62:
1539 –1549.
35. Abuelo JG. Normotensive ischemic acute renal failure. N Engl J Med.
2007;357:797– 805.
36. Paparella D, Yau TM, Young E. Cardiopulmonary bypass induced
inflammation: pathophysiology and treatment: an update. Eur J Cardio-
thorac Surg. 2002;21:232–244.
37. Laffey JG, Boylan JF, Cheng DCH. The systemic inflammatory response
to cardiac surgery. Anesthesiology. 2002;97:215–252.
38. Flemming B, Seeliger E, Wronski T, Steer K, Arenz N, Persson PB.
Oxygen and renal hemodynamics in the conscious rat. J Am Soc Nephrol.
2000;11:18 –24.
39. Kulier A, Levin J, Moser R, Rumpold-Seitlinger G, Tudor IC,
Snyder-Ramos SA, Moehnle P, Mangano DT. Impact of preoperative
anemia on outcome in patients undergoing coronary artery bypass graft
surgery. Circulation. 2007;116:471– 479.
40. Nangaku M. Chronic hypoxia and tubulointerstitial injury: a final common
pathway to end-stage renal failure. J Am Soc Nephrol. 2006;17:17–25.
41. Valeri CR, Khuri S, Ragno G. Nonsurgical bleeding diathesis in anemic
thrombocytopenic patients: role of temperature, red blood cells, platelets,
and plasma-clotting proteins. Transfusion. 2007;47(suppl):206S–248S.
42. Valeri CR, Cassidy G, Pivacek LE, Ragno G, Lieberthal W, Crowley JP,
Khuri SF, Loscalzo J. Anemia-induced increase in the bleeding time:
Downloaded from http://circ.ahajournals.org/ by guest on February 4, 2017
implications for treatment of nonsurgical blood loss. Transfusion. 2001;
41:977–983.
43. Despotis G, Eby C, Lublin DM. A review of transfusion risks and optimal
management of perioperative bleeding with cardiac surgery. Transfusion.
2008;48:2S–30S.
44. Koch CG, Li L, Sessler DI, Figueroa P, Hoeltge GA, Mihaljevic T,
Blackstone EH. Duration of red-cell storage and complications after
cardiac surgery. N Engl J Med. 2008;358:1229 –1239.
45. Almac E, Ince C. The impact of storage on red cell function in blood
transfusion. Best Pract Res Clin Anaesthesiol. 2007;21:195–208.
46. Tinmouth A, Fergusson D, Yee IC, Hebert PC. Clinical consequences of
red cell storage in the critically ill. Transfusion. 2006;46:2014 –2027.
47. Comporti M, Signorini C, Buonocore G, Ciccoli L. Iron release, oxidative
stress and erythrocyte ageing. Free Radic Biol Med. 2002;32:568 –576.
48. Cardo LJ, Hmel P, Wilder D. Stored packed red blood cells contain a
procoagulant phospholipid reducible by leukodepletion filters and
washing. Transfus Apher Sci. 2008;38:141–147.
49. Moulton MJ, Creswell LL, Mackey ME, Cox JL, Rosenbloom M. Reex-
ploration for bleeding is a risk factor for adverse outcomes after cardiac
operations. J Thorac Cardiovasc Surg. 1996;111:1037–1046.
50. Bloor GK, Welsh KR, Goodall S, Shah MV. Comparison of predicted
with measured creatinine clearance in cardiac surgical patients. J Car-
diothorac Vasc Anesth. 1996;10:899 –902.

CLINICAL PERSPECTIVE
Acute kidney injury (AKI) after cardiac surgery is a serious complication that is closely associated with postoperative
death. In previous studies that evaluated risk factors for AKI, most of the identified risk factors were not modifiable (eg,
diabetes mellitus, preexisting kidney disease). In the present multicenter study of 3500 adult patients undergoing cardiac
surgery in 2004, we focused on identifying potentially modifiable risk factors for postoperative AKI. We found that AKI,
as defined by consensus-based criteria (⬎25%, ⬎50%, and ⬎75% decrease in estimated glomerular filtration rate or need
for dialysis within 1 week of surgery), was independently associated with a ⬎4-fold increase in death rates. Three common
and potentially modifiable variables (preoperative anemia, red blood cell transfusions, and surgical reexploration) were
highly associated with AKI, even after adjustment for other perioperative risk factors (eg, preoperative intra-aortic balloon
pump, cardiopulmonary bypass duration). Given these results, we propose that randomized trials are now needed to
determine whether interventions that modify these risk factors might also prevent AKI after cardiac surgery.
 Acute Kidney Injury After Cardiac Surgery: Focus on Modifiable Risk Factors
Keyvan Karkouti, Duminda N. Wijeysundera, Terrence M. Yau, Jeannie L. Callum, Davy C.
Cheng, Mark Crowther, Jean-Yves Dupuis, Stephen E. Fremes, Blaine Kent, Claude Laflamme,
Andre Lamy, Jean-Francois Legare, C. David Mazer, Stuart A. McCluskey, Fraser D. Rubens,
Corey Sawchuk and W. Scott Beattie
Downloaded from http://circ.ahajournals.org/ by guest on February 4, 2017

Circulation. 2009;119:495-502; originally published online January 19, 2009;

doi: 10.1161/CIRCULATIONAHA.108.786913
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2009 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539

The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circ.ahajournals.org/content/119/4/495

Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial
Office. Once the online version of the published article for which permission is being requested is located,
click Request Permissions in the middle column of the Web page under Services. Further information about
this process is available in the Permissions and Rights Question and Answer document.

Reprints: Information about reprints can be found online at:

http://www.lww.com/reprints

Subscriptions: Information about subscribing to Circulation is online at:

http://circ.ahajournals.org//subscriptions/