Update on the Beans: How to Keep Them Going
Duminda N. Wijeysundera, MD PhD FRCPC
Department of Anesthesia, University of Toronto
Prognostic Importance
Acute kidney injury (AKI) is an important postoperative complication of cardiac surgery. Even
after accounting for comorbidities and other postoperative complications, AKI following cardiac
surgery is associated with increased postoperative mortality, regardless of whether the kidney
injury is severe enough to require renal replacement therapy.1-5 Even small postoperative
elevations in creatinine concentration following cardiac surgery (e.g., 0.3 to 0.5 mg/dL) are
associated with increased 30-day postoperative mortality.3
Mechanisms for Perioperative Acute Kidney Injury
Therapies for preventing perioperative AKI should be considered based on the potential
underlying mechanisms of AKI after cardiac surgery. There are several mechanisms for
perioperative AKI, several of which are responsible in any individual affected patient.
1. Renal ischemia due to reduced perfusion and acute anemia. Acute anemia, even with
adequate perfusion pressure, predisposes the kidneys to hypoxic injury.6
2. Ischemia-reperfusion injury
3. Inflammation caused by the surgical stress response and cardiopulmonary bypass (CPB)
4. Emboli – both microemboli and macroemboli. Examples include microemboli generated
during CPB and atheroemboli generated by manipulation of the ascending aorta.
5. Nephrotoxins – both exogeneous and endogeneous (e.g., angiographic contrast
administered before surgery,7 free hemoglobin released by intra-operative hemolysis8)
Defining Acute Kidney Injury Using Changes in Creatinine
The diagnosis of AKI, as well as staging of its severity, is based on either of two consensus-based
criteria, namely RIFLE and AKIN. Both criteria involve assessment of changes in creatinine or
estimated glomerular filtration rate (eGFR), as well as changes in urine output.
Application of the AKIN criteria involves two steps – an initial diagnosis of AKI based on
changes over 48 hours – and a staging of AKI based on changes within a seven day period. 9
Diagnosis
An abrupt (within 48 hours) reduction in kidney function currently defined as
an absolute increase in serum creatinine of more than or equal to 0.3 mg/dl (≥
26.4 μmol/l), a percentage increase in serum creatinine of more than or equal
to 50% (1.5-fold from baseline), or a reduction in urine output (documented
oliguria of less than 0.5 ml/kg per hour for more than six hours).
AKIN Stage
AKIN Stage 1
Serum Creatinine Criteria (based on changes in a seven day period)
Increase in serum creatinine of more than or equal to 0.3 mg/dl (≥ 26.4
μmol/l) or increase to more than or equal to 150% to 200% (1.5- to 2-fold)
from baseline
1
AKIN Stage 2
AKIN Stage 3
Increase in serum creatinine to more than 200% to 300% (> 2- to 3-fold) from
baseline
Increase in serum creatinine to more than 300% (> 3-fold) from baseline
OR serum creatinine of more than or equal to 4.0 mg/dL (≥ 354 μmol/L) with
an acute increase of at least 0.5 mg/dL (44 μmol/L) OR requirement for renal
replacement therapy
The RIFLE criteria define severity or stage of AKI based on changes in creatinine or eGFR
observed within the previous 1 to 7 days.10
RIFLE Stage
Creatinine or eGFR Criteria (based on changes in prior one to seven
days)
Risk
Increase in serum creatinine X 1.5 or GFR decrease >25%
Injury
Serum creatinine X 2 or GFR decreased >50%
Failure
Serum creatinine X 3, or serum creatinine >4 mg/dl (>354 μmol/L)
with an acute rise >0.5 mg/dL (>44 μmol/L) or GFR decreased >75%
Loss
Complete loss of kidney function >4 weeks
End-stage kidney disease End stage renal disease for >3 months
Either criterion can be used to diagnose and classify AKI – both approaches have shown validity
in that patients with increasing severity of AKI (based on either classification system) also have
increasingly worse prognosis.11,12 Nonetheless, the AKIN criteria may lead to some overdiagnosis of AKI, especially when applied to individuals who meet AKIN Stage 1 criteria, but do
not meet any RIFLE criteria.11 In addition, both classification systems suffer from the limitations
of using creatinine as a marker of acute changes in kidney function – including influence by
factors aside from kidney function (e.g., age, sex, muscle mass, ethnicity, diet), delayed
response following acute changes in kidney function, and lack of guidance on the site of kidney
injury (e.g., tubular versus glomerular injury). Despite these limitations, either classification
system can be used to identify postoperative AKI in the clinical setting, to define outcomes in
research related to AKI, and to compare outcomes or quality of care related to AKI.
Alternative Markers of Acute Kidney Injury
Given the limitations of using creatinine as a marker of AKI, there is increasing interest in
alternative biomarkers, especially one that can provide early indications of AKI.13 Such
biomarkers could allow for initiation of early treatment of AKI. This approach has theoretical
benefits, especially since early renal recovery after AKI is associated with improved long-term
survival after cardiac surgery.14 Early detection of AKI could allow for the appropriate targeted
use of novel interventions such as allogeneic bone marrow derived human mesenchymal stem
cells to promote early recovery of renal function after AKI.
Of potential biomarkers that have been evaluated, the most promising is urinary
neutrophil gelatinase-associated lipocalin (NGAL) – which is a marker of renal tubular injury. In
a meta-analysis of studies performed in cardiac surgery patients, the urinary NGAL had a pooled
area under the receiver-operating-characteristic (ROC) curve for predicting AKI (diagnosed
2
based on changes in creatinine) of 0.75 (95% CI, 0.70 to 0.87).15 Despite this promise, the
diagnostic performance of NGAL is not consistent, with several studies reporting poor
accuracy.16,17 Alternative biomarkers include cystatin C (marker of glomerular filtration) and
urinary IL-18 (marker of inflammation). While all individual biomarkers continue to have
limitations, the combination of biomarkers, with or without clinical risk factors, may represent
the most accurate approach for early identification of patients with AKI.18,19
Interventions for Preventing Perioperative Acute Kidney Injury
Overall, there are few proven drug interventions for preventing injury to the kidneys during
surgery.20 Some interventions showing potential promise are described below.
1. Interventions for Preventing Renal Ischemia
If impaired renal perfusion is an important mechanism for perioperative AKI, optimizing renal
oxygen delivery may mitigate the risk of this complication. A systematic review of randomized
trials found that “goal-directed therapy” based on hemodynamic optimization significantly
reduce the risk of perioperative AKI (odds ratio 0.64; 95% CI 0.50 to 0.83; P = 0.0007). 21.
Similarly, several cohort studies have found that reduced intra-operative hematocrits,
especially levels of 0.20 or lower,22,23 were associated with increased risks of perioperative AKI.
Other authors have further suggested that the increased risk depends not on the absolute level
to which hemoglobin concentration falls, but rather its relative decline from the baseline
concentration.24 Specifically, the risk of adverse perioperative outcomes increases once
hemoglobin concentrations drops by 50% or greater.24
Nonetheless, it remains unclear whether some of the potential interventions for
treating impaired renal perfusion are themselves safe for the kidneys. For example, the usual
treatment for acute anemia, namely red cell transfusion, is itself associated with an increased
risk of AKI.2 Notably, a randomized trial of restrictive versus liberal red cell transfusion
strategies in cardiac surgery found no difference in rates of perioperative AKI.25 In addition,
some authors have raised concerns about using hydroxyethyl starches to optimize
hemodynamics because these colloids may themselves also cause AKI.26
An alternative approach to optimizing renal perfusion is to use pharmacologic agents
that increase renal perfusion. Although still widely used, low-dose dopamine does not prevent
AKI, although it does increase urine output (which may be a clinically useful effect in specific
circumstances).27 Conversely, fenoldopam, which is a selective dopamine-1-receptor
antagonist, has shown some promise in preventing AKI after cardiac surgery. A systematic
review of randomized trials in cardiac surgery found that fenoldopam significantly reduced both
renal replacement therapy (odds ratio 0.37; CI, 0.23 to 0.59) and in-hospital death (odds ratio
0.46; CI, 0.29 to 0.75).28 These findings were confirmed in a more recent systematic review
focused only on placebo-controlled randomized trials.29 Especially since perioperative AKI has a
multifactorial etiology, such large risk reductions from fenoldopam alone are implausible. A
large randomized trial is warranted, and is presently being undertaken (NCT00621790).
Atrial natriuretic peptide (ANP) has multiple potentially beneficial effects, including
increased glomerular filtration, natriuresis, diuresis, and inhibition of the renin-angiotensinaldosterone axis. A systematic review of randomized trials in cardiac surgery has shown
reductions in progression to renal replacement therapy with ANP.30 These findings have been
supported by three recent trials in cardiac surgery patients with normal preoperative kidney
3
function, preoperative ventricular dysfunction, and preoperative renal impairment. 31-33 These
promising results support an evaluation of ANP in a large multicenter randomized trial.
2. Reducing Harmful Effects of CPB
Cardiopulmonary bypass may cause perioperative AKI through a range of mechanisms,
including generation of microemboli, induction of a systemic inflammatory response, and
production of atheroemboli through manipulation of the ascending aorta. Thus, simply avoiding
CPB through procedures such as off-pump coronary artery bypass (OPCAB) may theoretically
reduce the risk of perioperative AKI. A recent systematic review of relevant randomized trials
found that OPCAB significantly reduced AKI (odds ratio 0.27; CI, 0.13 to 0.54) but had no
statistically significant effect on the need for renal replacement therapy (odds ratio, 0.31; CI,
0.06 to 1.59). However, this analysis was limited by the very heterogeneous definitions of AKI in
the relatively few included trials (5 trials with 438 participants).34 By comparison, a single large
randomized trial (2203 participants) of off-pump versus on-pump coronary artery bypass graft
surgery found no difference in rates of renal replacement therapy (relative risk 0.90; CI, 0.37 to
2.20).35 Nonetheless, this specific trial recruited participants at very low baseline risk for AKI,
thus potentially explaining their negative findings. Conversely, a subsequent multicenter trial of
4752 participants found that OPCAB significantly reduced risks of mild AKI (AKIN Stage 1 or
RIFLE-Risk categories), but had no significant effect on risks of renal replacement therapy. 36
3. Avoidance of Nephrotoxins
A straightforward approach for preventing AKI may be to avoid or minimize the impact of
nephrotoxic agents. Angiographic contrast is one such nephrotoxin to which most cardiac
surgery patients are exposed. A cohort study evaluated the relationship between perioperative
AKI, time interval between contrast exposure and surgery, dose of contrast, and preoperative
renal function.7 The risk of postoperative AKI was increased substantially if surgery was
performed within 5 days after administration of high-doses (>1.4 mL/kg) of angiographic
contrast. Similarly, as indicated above, it is likely prudent to avoid the use of hydroxyethyl
starches in cardiac surgery patients at increased risk of perioperative AKI.37
Free hemoglobin and free iron from the hemolysis of red cells during CPB may be
another important nephrotoxin to which cardiac surgery patients are exposed. 8,38 A recent pilot
randomized trial suggested that preoperative (as opposed to intra-operative) transfusion of red
cells to anemic cardiac surgery patients (who were invariably going to require transfusion) may
mitigate some these physiologic risk factors, although the impact of such a strategy on risks of
AKI itself remains unknown.39 An initial pilot randomized trial (100 participants) also found that
sodium bicarbonate administration, which helps to alkalinize the urine and thereby remove free
hemoglobin, also prevented AKI after cardiac surgery (odds ratio 0.43; CI, 0.19-0.98), as defined
by a 25% increase in creatinine concentrations over baseline levels.40 Despite these initial
promising results, two subsequent randomized trials, one with 427 participants and another
with 350 participants,41,42 did not replicate these initial positive findings. At present, therefore,
there are not compelling data to support using sodium bicarbonate to prevent AKI.
4
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