European Journal of Cardio-thoracic Surgery 35 (2009) 854—863

www.elsevier.com/locate/ejcts

Review

Acute kidney injury following cardiac surgery: impact of early versus late
haemofiltration on morbidity and mortality
Maqsood Elahi a, Sanjay Asopa a, Axel Pflueger b, Nadey Hakim c, Bashir Matata d,*
a
Wessex Cardiothoracic Centre, Institute of Developmental Sciences, General Hospital, Southampton, United Kingdom
b
Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, MN, USA
c
West London Renal and Transplant Centre, Hammersmith Hospital, London, United Kingdom
d
Liverpool Heart & Chest Hospital NHS Trust, Thomas Drive, Liverpool, L14 3PE, United Kingdom

Received 21 July 2008; received in revised form 11 November 2008; accepted 12 December 2008; Available online 11 February 2009

Summary
Various forms of renal replacement therapies (RRT) are available to treat acute kidney injury (AKI) after cardiac surgery. The objective of this
review is to assess the incidence of postoperative AKI that necessitates the application of haemofiltration in adult patients undergoing cardiac
operations with cardiopulmonary bypass (CPB), to determine the factors that influence the outcome in these patients. In addition, the review
aims to assess the outcomes of postoperative early haemofiltration as compared to late intensive haemofiltration. Different forms of RRT such as
intermittent haemodialysis, continuous haemofiltration, or hybrid forms which combine advantages of both are now available for application in
cardiac surgery patients, and will be discussed in this article. The underlying disease, its severity and stage, the aetiology of AKI, clinical and
haemodynamic status of the patient, the resources available, and different costs of therapy may all influence the choice of the RRTstrategy. AKI,
with its risk of uraemic complications, represents an independent risk factor for adverse outcomes in critically ill patients after cardiac surgery.
Whether early initiation of RRT is associated with improved survival is unknown, and also clear guidelines on RRT durations are still lacking. In
particular, it remains unclear whether haemodynamically unstable patients who develop septic shock pre- and postoperatively can benefit from
early RRT initiation. In addition, it is not known whether in AKI patients undergoing cardiac surgery RRT modalities can eliminate significant
amounts of clinically relevant inflammatory mediators. This review gives an update of information available in the literature on possible
mechanisms underlying AKI and the recent developments in continuous renal replacement treatment modalities.
# 2008 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

Keywords: Angiotensin II; Renal replacement therapy; Acute renal failure; Cardiopulmonary bypass; Oxidative stress; Inflammation

1. Introduction importance of establishing the natural history of the

Acute kidney injury (AKI) occurs in significant numbers of
patients undergoing cardiopulmonary bypass (CPB) surgery
for coronary artery disease [1—5]. Depending on the
definitions, AKI may occur in up to 30% of post-cardiotomy
patients [4,5]. Renal injury during cardiac surgery appears to
be mechanistically related to pre-existing renal dysfunction,
diabetes mellitus, ventricular dysfunction, older age,
hypertension, microembolic and macroembolic processes,
inflammatory mediators, prolonged CPB time, sensitivity to
sympathetic stimulation, and perturbation in renovascular
resistance and flow [1—3].
Although AKI incidence is relatively low it is of major
concern that when it occurs it is associated with high
morbidity and mortality. The continued poor outcomes
associated with acute renal failure (ARF) highlight the
* Corresponding author.
E-mail address: matata_bashir@hotmail.com (B. Matata).
1010-7940/$ — see front matter # 2008 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.ejcts.2008.12.019
condition, in the hope that will lead to the preoperative
identification of high-risk patients. This would permit the
early implementation of appropriate interventions such as
intra- or postoperative renal replacement therapy and
establish the efficacy of such modalities. The establishment
of continuous renal replacement therapy (CRRT) has been
proposed as a means of reducing the in-hospital mortality
in patients who develop postoperative AKI. In this review
we focus primarily on the literature dealing with renal
complications occurring in the perioperative phase of cardiac
surgery. This is an area of major uncertainty, and controversy.
The main issue is centred on the definition of AKI and ARF.
There is currently a unanimous agreement that renal
complications severely impact upon the patient’s manage-
ment and outcome. Specifically it has an impact on the
method of renal replacement therapy i.e. dialysis (based
on the diffusion principle) or haemofiltration (based on
convention), the dose of renal replacement therapy (RRT;
Urea KT/V for dialysis vs haemofiltration flow (ml/kg/h)),
and the timing of RRT (early vs late). Here we discuss the
 M. Elahi et al. / European Journal of Cardio-thoracic Surgery 35 (2009) 854—863
mechanisms leading to the induction of AKI postoperatively
and focus on the different modalities of CRRT available.
Furthermore, we have discussed the merits of early and late
CRRT on morbidity and mortality rates for patients with AKI
post-cardiac surgery.
2. Prevalence and incidences
Renal dysfunction following cardiac surgery is well
recognised, particularly that of ischaemic origin. The
spectrum varies from sub-clinical injury to well established
renal failure requiring RRT. Patients who develop AKI have
higher rates of mortality and their management requires
significantly greater resource utilisation particularly for those
patients on chronic dialysis [6]. Historically, the incidence of
AKI is reported to be at 5%, however, up to 2% of the patients
who develop AKI would require RRT, [7] a mode of treatment
that was introduced in the 1980s [8]. Recent evidence suggests
that even a 20% change in plasma creatinine post-cardiac
surgery has a significant impact on postoperative outcomes
[9—11]. The development of mild to moderate AKI is also
associated with a mortality rate of 10—20% [12—14]. Previously
[15] we reported in a cohort of 1245 patients undergoing
isolated coronary artery bypass surgery (CABG) over a year that
5% of patients with impaired preoperative renal function
(creatinine >150 mg/dl) develop AKI post-CPB. Furthermore
this is associated with a mortality of 11% as compared to 1.6% in
patients with normal renal function [15]. Considering the need
for open-heart surgery worldwide and the high patient
numbers with postoperative ARF, it is of great surprise that
to date little attention has been paid to the management of
patients who develop this complication.
AKI is the standard term for an abrupt and sustained
decrease in renal function resulting in retention of
nitrogenous (urea and creatinine) and non-nitrogenous waste
products. Depending on the severity and duration of the renal
dysfunction, this accumulation is accompanied by metabolic
disturbances, such as metabolic acidosis and hyperkalaemia,
changes in body fluid balance, and effects on many other
organ systems. Definitions of AKI have varied from the severe
(i.e. require dialysis) or by an increase in serum creatinine
level >0.5 mg/dl (44 mmol/l) or a 25% increase from baseline
within the first five postoperative days [14]. The variation in
definitions is further compounded by a lack of consensus
on indications for and timing of dialysis, which have been
shown to improve outcome if initiated early in some studies
[15—19]. In 2004, the Acute Dialysis Quality Initiative
workgroup [20], proposed a multilevel classification system
for AKI identified by the acronym RIFLE (risk, injury, failure,
loss of kidney function, and end-stage kidney disease). In the
intensive medicine arena, several studies have used this
consensual definition for assessing whether outcomes
progressively worsened with the severity of AKI [21]. Ricci
et al. [22] recently conducted a literature search from
August 2004 to June 2007 on 24 studies in which the RIFLE
classification was used to define AKI. In 13 studies, patient-
level data on mortality were available for risk, injury, and
failure patients, as well as those without AKI (non-AKI). Over
71,000 patients were included in the analysis of published
reports. With respect to non-AKI, there appeared to be a
855
stepwise increase in relative risk (RR) for death going from
risk (RR = 2.40) to injury (RR = 4.15) to failure (6.37,
p < 0.0001 for all); however, the element of patient
population heterogeneity was noted in interpreting the
results. The authors concluded that the RIFLE classification is
a simple, readily available clinical tool to classify AKI in
different populations and suggested that even mild degrees
of kidney dysfunction may have a negative impact on
outcome [22].
Furthermore, many of the patients undergoing urgent
CABG have been undergoing coronary angiography prior to
surgery and are exposed to the additional risk of contrast
nephropathy. Contrast nephropathy has been associated with
a high cardiovascular mortality of nearly 40% without the
need for dialysis and 45% when the patient has been on
haemodialysis [22]. In the study of Gruberg et al. [23]
the greatest risk factors for 1-year mortality were need for
hospital dialysis, rise in serum creatinine, diabetes, and the
need for coronary vein grafting. In addition, Iakovou et al. [24],
demonstrated in 8628 patients, that the amount of contrast
agent and female gender were additional risk factors for a
1-year mortality of greater than 30%. Also, Rihal et al. [25]
found a 22% hospital mortality and 12% 1-year mortality in
patients with ARF after undergoing a coronary angioplasty.
3. Risk factors for post-cardiac surgery acute renal
injury
Several risk factors have been associated with the
occurrence of postoperative AKI. Renal hypoperfusion/
ischaemic injury particularly of the renal medulla seem to
be an important, if not the main, mechanism leading to this
complication. The partial oxygen tension in the renal medulla
is only 10—20% of the partial oxygen tension in the renal
cortex; hence these areas are most susceptible to injury from
renal hypoperfusion.
The causes for renal hypoperfusion and subsequent AKI are
variable and include: pre-existing chronic renal insufficiency
[26], older age [26], previous cardiovascular surgery [27],
tissue oedema [28], micro-embolism [29], endothelial
dysfunction [30], a generalised inflammatory response as a
consequence of the CPB circuit [31] and an increased
susceptibility to renal ischaemia injury, e.g. diabetes [32—
35], CPB time [36], duration of cross-clamp time, duration of
hypothermia, perioperative hypotension, duration of sur-
gery, increased generation of reactive oxygen species [37],
pre-existing reduction in renal blood flow [38], pre-existing
anaemia, co-existing morbidities such as hypovolaemia,
congestive heart failure, requirements of vasopressure
support, congenital heart disease [39] and the exposure to
nephrotoxic agents/drugs (aminoglycosides, vancomycin,
contrast dye) in the immediate preoperative period. For
example, in the heart transplant settings, calcineurin
inhibitors have been implicated in the development of
chronic renal injury [40]. Though numerous variables were
identified as predictors of AKI, information is still lacking
regarding the specific risk factors associated with the level of
preoperative renal function. Lombardi and Ferreiro [41] have
reported that the variables that are independently asso-
ciated with the onset of AKI were age, diabetes, preoperative
856 M. Elahi et al. / European Journal of Cardio-thoracic Surgery 35 (2009) 854—863
use of diuretics, non-scheduled surgery, CPB time, CPB mean
arterial pressure, haemodilution, postoperative use of
norepinephrine and EuroSCORE. The authors concluded that
the difference in risk factors associated with postoperative
AKI was primarily dependent on the degree of baseline renal
function. The authors also suggested that the degree of
preoperative renal function was a predictor of AKI only in
patients with CKD stages 3—4 [41]. Other well known risk
factors for AKI in this setting such as the use of diuretics and
the level of haemodilution during CPB are potentially
modifiable.
4. Possible mechanisms of post-cardiac surgery AKI
The pathogenetic mechanisms that lead to renal ischae-
mia are complex and involve numerous signal transduction
pathways. The development of AKI as a result of renal
ischaemia depends on degree and duration of the ischaemic
event and the functionality of countervailing mechanism.
Prolonged renal arteriolar vasoconstriction is perpetuated by
hypovolaemia, dehydration, increased levels of vasocon-
strictors (adenosine, angiotensin, aldosterone, endothelin,
catecholamines, and thromboxanes) as well as a decrease in
atrial natriuretic peptide (ANP) and nitric oxide-dependent
renal vasorelaxation [32—35,42]. For example, endothelial
dysfunction of the diabetic renal vasculature is characterised
by an impaired nitric oxide-dependent and prostaglandin-
dependent vasorelaxation [32—35]. Hence, adenosine-
induced vasoconstriction of the afferent arterioles, which
occurs as a result of mitochondrial ATP hydrolysis during renal
ischaemia [43], is markedly exacerbated in the diabetic renal
vasculature and causes a much more profound ischaemia-
induced reduction of renal blood flow when compared with
non-diabetic conditions. This apparent increase in risk for
developing AKI in the diabetic milieu is linked to a higher
sensitivity of the renal vasculature to adenosine-induced
renal vasoconstriction via adenosine A1 receptors, as a result
of a diminished renal prostaglandin- and nitric oxide-
dependent vasodilatory capacity [43,44]. A diminished nitric
oxide-dependent renal vasodilation has been observed in
both renal cortical and papillary capillaries in the early onset
of experimental diabetes long before the onset of a
measurable renal impairment quantified by a diminished
glomerular filtration rate or proteinuria [35].Hence, patients
with diabetes may be more susceptible to renal ischaemia
injury as a result of cardiopulmonary bypass surgery than
non-diabetics long before the onset of progressed stages of
diabetic nephropathy such as an elevated serum creatinine or
albuminuria, and therefore every patient with diabetes
should be considered high-risk to develop CPB surgery-
induced AKI.
5. Continuous renal replacement therapy for
postoperative acute kidney injury
CRRT is further subdivided into venovenous and arter-
iovenous categories, offers continuous and steady fluid
removal and uraemic toxin clearance. Their intensity can
easily be titrated to prevent or treat volume overload rapidly.
For example, a series of studies have revealed that
haemofiltration improves heart and lung functions in patients
with ARF and cardiac shock after heart surgery [44,45]. This
can reduce the need of inotropic support, which also
contributes to patients’ survival [44,45]. This method
provides better control of fluid status, improves uraemia,
and also ultrafiltrates toxic proteins such as myocardial
depressant factors. Overall, haemofiltration also helps in
improving the ventricular function by restoring the myocar-
dial water content (MWC) within normal limits [46]. Schiffl
et al. reported that MWC, which normally ranges from 78%
under normal conditions, could increase to more than 82% in
pathologic states [47]. Experimental studies of CPB have
shown that a variety of myocardial injuries are associated
with an increase in MWC, LV mass and decrease in LV
compliance [45].
5.1. Venovenous (VV) renal replacement therapies
5.1.1. Continuous venovenous haemofiltration (CVVH)
CVVH with the aid of a blood pump provides solute
removal by convection across a membrane. It offers high
volume ultrafiltration using replacement fluid, which can be
administered pre-filter or post-filter. The pump guarantees
adequate blood flow to maintain required ultrafiltration
rates. Venous blood access is usually femoral, jugular or
subclavian using a double lumen cannula. In patients with
thrombocytopenia or excessive bleeding due to any other
cause, heparin is replaced with continuous prostacyclins
infusion. This mode is used for removal of fluid and middle
sized molecules. As the ultrafiltration rate is high, replace-
ment electrolyte solution is required to maintain haemody-
namic stability (Fig. 1).
5.1.2. Continuous venovenous haemodialysis (CVVHD)
CVVHD utilises a blood pump and a venous access site for
removal of solutes by diffusion. Dialysate is pumped in
counter flow to the blood. CVVHDs are new modifications of
continuous replacement therapy, most useful in patients who
are haemodynamically compromised. They offer a smooth
way of instituting dialysis treatment where conventional
dialysis is difficult to perform (Fig. 2).
Fig. 1. CVVH (continuous venovenous haemofiltration).
Continuous haemofiltration with the aid of a blood pump provides solute
removal by convection. It offers high volume ultrafiltration using replacement
fluid, which can be administered pre-filter or post-filter. The pump guarantees
adequate blood flow to maintain required UF rates. Venous blood access is
usually femoral, jugular or subclavian using a double lumen cannula.
 M. Elahi et al. / European Journal of Cardio-thoracic Surgery 35 (2009) 854—863
Fig. 2. CVVHD (continuous venovenous haemodialysis). This technique uses an
infusion pump, haemodialysis membrane and dialysate solution as well as the
same blood access circuitry as the CVVH technique. As with the CAVHD system,
adding the dialysis membrane and the dialysate solution increases the effi-
ciency of the procedure. The process of continuous diffusion dialysis in CVVHD
is less effective than the CAVHD because the lower pressure venous system
does not filter as much blood per unit of time. The use of a pump-driven
venovenous circuit in CVVHD permits blood flows that are both higher and more
constant than provided by an arteriovenous circuit. In addition, the elimina-
tion of the need for a large bore arterial catheter eliminates the associated
risks of arterial thrombosis and arterial bleeding.
5.1.3. Continuous venovenous haemodialfiltration
(CVVHDF)
CVVHDF (Fig. 3) utilises a blood pump and a venous access
site for removal of solutes by diffusion and convection
simultaneously. It offers high volume ultrafiltration using
replacement fluid, which can be administered pre-filter or
post-filter. Simultaneously, dialysate is pumped in counter
flow to blood. This mode is used where large amounts of fluid
are removed and replaced per hour, as a means of ‘cleaning’
the plasma, for example to remove inflammatory cytokines.
This is a continuous process of removal by convective flow of
fluids of uraemic toxins from the blood. It requires use of
substitution fluid to prevent excess fluid loss. It is usually
performed at ultrafiltration rates greater than 8 ml/min.
CVVHDFs have a better cytokine clearance in the haemofil-
tration settings for postoperative septic patients.
5.2. Arteriovenous (AV) renal replacement therapies
5.2.1. Continuous arteriovenous haemodialysis (CAVHD)
This is a continuous diffusion process of removing uraemic
toxins from blood into a sterile dialysate fluid. Blood flows
Fig. 3. CVVHDF (continuous venovenous haemodialfiltration). Continuous hae-
modialfiltration with the aid of a blood pump provides solute removal by
diffusion and convection simultaneously. It offers high volume ultrafiltration
using replacement fluid, which can be administered pre-filter or post-filter.
Simultaneously, dialysate is pumped in counter flow to blood.
857
Fig. 4. CAVHD (continuous arteriovenous haemodialysis). This technique uses
an infusion pump, haemodialysis membrane and dialysate solution as well as
the same blood access circuitry as the CAVH technique. An infusion pump
pushes a continuous trickle of sterile dialysis fluid into the dialysate compart-
ment of a haemodialyser membrane. The blood/dialysate interface is the
haemodialysis membrane. CAVHD uses the process of continuous diffusion
dialysis to rid the body of fluid, electrolytes, and nitrogenous wastes. The
preferred arterial access site is the common femoral artery.
spontaneously through an AV shunt or femoral cannulation of
an artery and vein. Dialysis fluid is usually maintained
between 15 and 35 ml/min. Blood and dialysis fluid flows are
counter-current to maximise diffusion. CAVHD was developed
to augment the solute clearances obtainable with continuous
arteriovenous haemofiltration (CAVH). Although CAVH pro-
vides excellent volume control, solute clearances are
frequently insufficient to provide satisfactory control of
azotemia, particularly in hypercatabolic patients. CAVHD is
similar to CAVH with one exception: the addition of the
continuous perfusion of dialysate through the haemofilter
counter-current to the direction of blood flow, most
commonly at a rate of 1—2 l/h. As a result, the technical
requirements for the satisfactory performance of CAVHD are
similar to those of CAVH (Fig. 4).
To clarify the quality and the benefits from each system of
continuous renal replacement therapy, the advantages and
disadvantages of the described modalities are summarised in
Table 1.
6. Benefits of continuous renal replacement therapy on
maintaining post-surgery haemodynamic stability
The introduction and development of CRRT represents one
of the very important changes in patient management in the
intensive care unit (ICU). Application of the type of
continuous renal replacement therapy treatment is usually
tailored to the patient’s need including patient character-
istics, urgency of treatment, haemodynamic tolerance and
vascular access. Intermittent haemodialysis and haemofil-
tration are regarded as complementary techniques, inter-
changeable in critically ill patients with AKI according to
circumstances. While scientific criteria for the initiation of
renal replacement therapy in AKI patients is still not yet
defined, most renal physicians believe it is reasonable to
prefer modalities that prevent physiological derangements
as opposed to that of post-hoc correction. In addition,
nutrition should be considered as an integral part of all renal
replacement therapy prescription taking into account the
858 M. Elahi et al. / European Journal of Cardio-thoracic Surgery 35 (2009) 854—863

Table 1
Summary of the different modalities from each system of CRRT.

Modality Mechanism Advantages Disadvantages

CVVH Solute removal by convection
CVVHD Solute removal by diffusion
CVVHDF Solute removal by simultaneous
diffusion and convection
CAVHD Continuous diffusion process
High volume UF using replacement fluid
Best where conventional dialysis is difficult
Removes uraemic toxins & ‘cleans’ the
plasma especially in septic patients
Augments nitrogenous waste clearance &
provides excellent volume control
Haemodynamic stability can be compromised due to high UF rate
Less effective due to lower pressure: does not filter as blood/unit
of time
Haemodynamic stability can be compromised due to ultrahigh
UF rate
Solute clearance is insufficient to provide satisfactory control of
azotemia in hypercatabolic patients

UF: ultrafiltrate.

degree of catabolism [44]. Peritoneal dialysis (PD) for
instance although recommended for AKI it is not suitable
for adult critically ill patients because of high rates of
associated peritoneal infections, poor to inadequate solute
clearance leading to less than optimal uraemic controls. PD
also impedes diaphragmatic movements and is associated
with pulmonary and cardiac dysfunction [45]. Overall,
intermittent haemodialysis is associated with haemodynamic
instability and therefore haemofiltration is considered the
safer modality for treatment of AKI in the critical care setup.
This is because the profound systemic hypotension, which
accompanies haemodialysis, is highly undesirable for the
recovering kidneys [46].
Compared with other forms of uraemic therapies, volume
control is continuous and adaptable to the changing
circumstances during CRRT. CRRT avoids swings in the
intravascular volumes, maintains blood pressure and pre-
vents treatment-associated renal injury. Thus CRRT achieves
a much superior uraemic control when compared with other
forms of treatments for renal impairment [47]. Investigators
from Cleveland Clinic have shown that the larger delivery
dose (expressed as litres of whole body clearance for various
solutes such as urea) is associated with a better outcome in
critically ill patients [48]. CRRT also allows a greater
metabolic control to be achieved and thus provides a
platform for an aggressive, protein rich nutritional policy
to improve daily nitrogen balance, thus having possible
favourable effects on immune function and overall outcome.
CRRT is ideally suited for patients with significant cardiac
diseases such as patients with congestive cardiac failure not
responding to diuretics. Studies have shown that CRRT helps
to restore dry body weight, improve urine output, decrease
the activation of neurohormones and prolong the oedema-
free time [49]. In cardiac surgical patients CRRT helps
decrease myocardial oedema, reduce left ventricular end
diastolic pressure by optimising the Frank—Starling relation-
ship and improving myocardial performance by removing
circulating myocardial depressants [50,51].
7. Elimination of inflammatory cytokines and
anaphylatoxins by continuous renal replacement
therapy
CRRT has added pumps to increase the filtration rates and
sometimes combines primarily convective compound trans-
port (by haemofiltration) with diffusive transport (with an
additional dialysis cycle) across a hydrophobic membrane.
Hydrophobic membranes have an asymmetric structure,
allowing solutes of a wide range of molecular weights (cut-off
30 kDa) to be eliminated by convection. Small molecules
(creatinine, urea, electrolytes) pass with high sieving
coefficients. Also, small molecules like interleukin-8 (IL-8)
of molecular weight 8 kDa, the anaphylotoxin complement
C3a (9 kDa) and b2-microglobulin (11 kDa) have a high sieving
coefficient [52]. A profound decrease in the sieving
coefficient was observed at a molecular weight of about
20 kDa in animal studies [53].
TNF-alpha (MW 52 kDa) a key mediator of sepsis is unlikely
to pass the commonly used filters owing to the size. Clinical
studies have given conflicting evidence of its removal with
some studies suggesting no changes in the plasma TNF-alpha
level [54,55], while some showing substantial [56] to minimal
clearance [57]. Some studies have shown an increase in the
plasma levels due to the passage through the haemofilter [58].
The plasma levels of TNF-alpha change during the course of
illness and therefore depend on the time of initiation of CRRT
as well as the amount eliminated by the haemofiltration.
Similarly contradictory results exist for interleukin-6 (IL-
6), MW 26 kDa with some studies showing a presence in the
dialysis effluents [59], while others showing no IL-6 [57].
Recent prospective studies have shown that CRRT does not
have a significant impact on serum IL-6 levels despite
significant transfer of IL-6 from blood into dialysate [60].
Other studies have demonstrated that CRRTwith high-volume
haemofiltration (8 l/h) improved the cardiac index, which
was related to improved survival [61]. In septic patients the
myocardial depression is manifested as biventricular dilation
and a low ejection fraction [62]. Incubation of spontaneously
beating cardiomyocytes with serum from patients with septic
shock induced cardiac contractility, and correlated with the
in vivo low ventricular ejection fraction measured [63].
8. Effect of timing of continuous renal replacement
therapy on operative outcomes
Although there is continuing debate on the underlying
mechanisms by which CRRT improves survival, there is also no
international consensus on important issues such as the
indication and timing of initiation of CRRT due to the absence
of relevant guidelines and an international consensus on the
definition of ARF [64]. Acute renal failure increases risk of
death after cardiac surgery [4—8]. Until recently, it was not
known whether small subtle changes in renal function could
have an impact on operative outcomes. To address this,
Lassnigg et al. [10] studied the association between small
serum creatinine changes after surgery and mortality,
 M. Elahi et al. / European Journal of Cardio-thoracic Surgery 35 (2009) 854—863
independently of other established perioperative risk
indicators. In a prospective cohort study involving 4118
patients undergoing cardiac and thoracic aortic surgery, the
effect of changes in serum creatinine within 48 h post-
operatively on 30-day mortality was analysed. Of the 2441
patients in whom serum creatinine decreased, early
mortality was 2.6% in contrast to 8.9% in patients with
increased postoperative serum creatinine values. Patients
with large decreases showed progressively increasing 30-day
mortality. Mortality was lowest in patients in whom serum
creatinine decreased by a maximum of 0.3 mg/dl but
increased to 6% in patients in whom serum creatinine
remained unchanged. Mortality was highest in patients with a
creatinine increase 0.5 mg/dl in all groups, including those
patients who received postoperative RRT. After cardiac and
thoracic aortic surgery, 30-day mortality was lowest in
patients with a slight postoperative decrease in serum
creatinine. Interestingly, even a minimal increase in serum
creatinine was associated with a substantial decrease in
survival. The authors [10] suggested that even a mild change
in the renal function may have an effect on the operative
outcomes and then concluded that elevated creatinine may
be an independent indicator for risk of death.
In another study, Schiffl et al. [65] reported the effect of
daily intermittent haemodialysis, as compared with conven-
tional (alternate-day) intermittent haemodialysis, on survi-
val among patients with acute renal failure. The authors
suggested in a cohort of 160 patients with acute renal failure
assigned to receive daily or conventional intermittent
haemodialysis, that daily haemodialysis resulted in better
control of uraemia, fewer hypotensive episodes during
haemodialysis, and more rapid resolution of acute renal
failure (mean [SD], 9  2 vs 16  6 days; p = 0.001) than did
conventional haemodialysis. The mortality rate, according to
the intention-to-treat analysis, was 28% for daily dialysis and
46% for alternate-day dialysis ( p = 0.01). Indeed, in a
multiple regression analysis, it was found that less frequent
haemodialysis (on alternate days, as opposed to daily) was an
independent risk factor for death.
In contrast, Bouman et al. in 2003 [66] studied the effects
of the initiation time of continuous venovenous haemofiltra-
Table 2
Studies showing the advantage of early initiation of CRRT.
Author Patient numbers CRRT initiated
early (average days)
Elahi et al. [15] 64 cardiac surgery 0.78  0.2 days
patients needing CRRT
Bent et al. [16] 65 cardiac surgery 2.38 days
patients needing CRRT
Luckraz et al. [19] 98 cardiac surgery 2.08  1.66
patients needing CRRT
Gettings et al. [17] 100 trauma patients 10.5 since hospital
needing CRRT admission
Abbreviations: Dop: dopamine; Adre: adrenaline; Amin: aminophylline; Frus: frusemide; IABP: intra-aortic balloon pump counter pulsation; CRRT: continuous renal
replacement treatment.
859
tion and of the ultrafiltrate rate in patients with circulatory
and respiratory insufficiency developing early oliguric acute
renal failure. This was a randomised, controlled, two-centre
study. A total of 106 ventilated severely ill patients who were
oliguric despite massive fluid resuscitation, inotropic sup-
port, and high-dose intravenous diuretics were randomised
into three groups. Thirty-five patients were treated with
early high-volume haemofiltration (72—96 l per 24 h), 35
patients with early low-volume haemofiltration (24—36 l per
24 h), and 36 patients with late low-volume haemofiltration
(24—36 l per 24 h). The authors concluded that survival at day
28 was 74.3% in early high-volume haemofiltration, 68.8% in
early low-volume haemofiltration, and 75.0% in late low-
volume haemofiltration, hereby in critically ill patients with
oliguric acute renal failure, survival at 28 days and recovery
of renal function were not improved using high ultrafiltrate
volumes or early initiation.
Other recent studies however, have shown that introduc-
tion of CRRT early in the course of treatment may improve
survival [15—18; Table 2]. Bent et al. [16] treated 65
consecutive patients with early and intensive CVVH after
cardiac surgery (mean operation to CVVH time, 2.38 days;
pump-controlled ultrafiltration rate, 2 l/h). They observed
that in 32.3% of patients, intra-aortic balloon counter-
pulsation was required and 20% of patients were emergen-
cies. Using an outcome prediction score specific for acute
renal failure, the predicted risk of death was 66% and actual
mortality was 40% ( p = 0.003). The authors concluded that
early and aggressive CVVH is associated with better than
predicted survival in severe acute renal failure after cardiac
operations. Using readily available clinical data, the outcome
of such patients can be predicted before CVVH is applied.
Gettings et al. [17] retrospectively demonstrated in their
review that an early initiation of CRRT, based on pre-CRRT
blood urea nitrogen (BUN), might improve the rate of survival
of trauma patients who develop ARF. The mean BUN of the
early and late starters was 42.6 and 94.5 mg/dl, respectively
( p < 0.0001). CRRT was initiated earlier in the hospital
course of early starters compared to late starters (hospital
day 10.5 vs 19.4; p < 0.0001). Admission laboratory values
for BUN, serum creatinine, lactate, and bilirubin as well as
CRRT initiated Medications at CRRT initiation Limitations
late (average days)
2.55  2.2 days Dopa 6 out of 58 Retrospective study
Adre 20 out of 44
Amin 11 out of 53
Frus 27 out of 37
N/A IABP = 32.3% Retrospective study
Ventilation = 58.5%
Hypotension despite inotropes = 40%
N/A IABP = 40% Retrospective study
Tracheostomy for prolonged
ventilation = 32%
19.4 since Survival rate significantly increased Retrospective study
hospital admission among early starters compared to
late starters (39.0 vs 20.0%, p = 0.041)
860 M. Elahi et al. / European Journal of Cardio-thoracic Surgery 35 (2009) 854—863
fluid and blood requirements in the first 24 h were
statistically the same for the two groups, suggesting a
similar risk for developing acute renal failure. Survival rate
was significantly increased among early starters compared to
late starters (39.0 vs 20.0%, respectively, p = 0.041).
Recently we conducted a retrospective study [15] on adult
patients who had undergone consecutive cardiac surgical
procedures. Sixty-four patients out of 1264 (5%) developed
ARF and required postoperative CVVH. The hospital mortality
was 43% in patients that received late CVVH (group I) as
compared with 22% in patients on early CVVH (group II,
p < 0.05), with an overall mortality associated with ARF of
1.5%. The mean time between the operation and the
initiation of CVVH was 2.55  2.2 days in group I and
0.78  0.2 days in group II ( p < 0.001). The mean duration of
CVVH was 4.57  11.4 days in group I and 4.61  2.0 days in
group II ( p = NS). Advanced age ( p = 0.013), elevated
preoperative creatinine ( p = 0.002), postoperative pulmon-
ary oedema ( p = 0.01), sepsis ( p = 0.001), multiple organ
failure ( p = 0.031), hypotension ( p = 0.031) and preopera-
tive renal failure ( p < 0.05) were the independent factors
influencing the poor postoperative outcome and cardiac
instability. We concluded that early and aggressive use of
CVVH was associated with better than expected survival in
patients that develop severe ARF after cardiac operations.
Similarly, Van Den Noortgate et al. [67] evaluated the
influence of age on the risk factors for in-hospital mortality in
patients with cardiac surgery-induced ARF. They reported
that the outcome in the elderly patients requiring dialysis
due to ARF post-cardiac surgery is comparable with the
outcome in a younger population. No significant difference
was found in severity of disease between the elderly and the
younger. Variables predicting mortality in the elderly are the
presence of multiple organ failure (MOF), mechanical
ventilation and hypotension 24 h before starting CRRT. They
suggested that age per se is not a reason to withhold CRRT in
elderly patients with ARF following cardiac surgery.
Not many studies have looked at the outcome of
postoperative renal dysfunction with or without the need
for CRRT and the long-term outcome. A recent study by Loef
et al. [68] investigated in-hospital and long-term prognosis of
patients with postoperative renal deterioration and 843
patients who underwent cardiac surgery with CPB were
included. Postoperative renal function deterioration
(increase in serum creatinine in the first postoperative week
of at least 25%) occurred in 145 (17.2%) patients. In these
patients, in-hospital mortality was 14.5%, vs 1.1% in patients
without deterioration in renal function ( p < 0.001). Multi-
variate analysis indicated a significant association between
in-hospital mortality with postoperative renal function
impairment, re-exploration, and postoperative stroke,
duration of operation, age, and diabetes. After a follow-up
period of 100 months mortality was significantly increased in
the patients with impaired renal function (n = 124) as
compared with those without renal function deterioration
(hazard ratio 1.83; 95% confidence interval 1.38—3.20). Also
after adjustment for other associated independent risk
factors, the risk of death in patients with postoperative
impaired renal function deterioration remained elevated
(hazard ratio 1.63; 95% confidence interval 1.15—2.32). This
elevated risk of death in the longer term was independent of
whether renal function had recovered at discharge from
hospital. They concluded that postoperative renal function
deterioration in cardiac surgical patients not only results in
increased in-hospital mortality but also adversely affects
long-term survival. Although this study has highlighted the
consequences of renal functional deterioration the authors
did not shed any light on the potential underlying mechan-
isms. None of the survivors in Loef’s study [68] developed
end-stage renal disease however, details on timing of
initiation of CRRT and the levels of long-term renal function
were not provided, making it difficult to ascertain whether
the episodes of AKI were associated with a progressive
decline in renal function and also if early initiation of CRRT
had any beneficial effects on survival.
9. Effect of duration and intensity of continuous renal
replacement therapy
Some recently published randomised studies have failed
to demonstrate outcome improvement with more intense
RRT [69,70]. Palevsky et al. [69] studied critically ill patients
with acute kidney injury requiring intensive renal support in
terms of mortality, improvement in recovery of kidney
function, or reduction in the rate of non-renal organ failure
as compared with less-intensive therapy involving a defined
dose of intermittent haemodialysis three times per week and
continuous renal-replacement therapy at 20 ml/kg h. In this
study critically ill patients with acute kidney injury and
failure of at least one non-renal organ or sepsis received
intensive or less-intensive renal-replacement therapy. The
primary end point was death from any cause by day 60. In
both study groups, haemodynamically stable patients under-
went intermittent haemodialysis, and haemodynamically
unstable patients underwent continuous venovenous hae-
modialfiltration or sustained low-efficiency dialysis. Patients
receiving the intensive treatment strategy underwent
intermittent haemodialysis. Low-efficiency dialysis was six
times per week and continuous venovenous haemodialfiltra-
tion at 35 ml/kg of body weight per h. For patients receiving
the less-intensive treatment strategy, the corresponding
treatments were provided thrice weekly and at 20 ml/kg h.
The rate of death from any cause by day 60 was 53.6% with
intensive therapy and 51.5% with less-intensive therapy (odds
ratio, 1.09; 95% confidence interval, 0.86—1.40; p = 0.47).
The results appear to suggest the possibility that the duration
of application of intense versus less-intense RRT did not
affect the outcomes.
Tolwani et al. [70] studied the effect of dosage of CVVHDF
on survival in patients with ARF. Two hundred critically ill
patients with ARF were randomly assigned to receive CVVHDF
with pre-filter replacement fluid at an effluent rate of either
35 ml/kg h (high dosage) or 20 ml/kg h (standard dosage).
The primary study outcome, survival to the earlier of either
intensive care unit discharge or 30 days, was 49% in the high-
dosage arm and 56% in the standard-dosage arm (odds ratio
0.75; 95% confidence interval 0.43—1.32; p = 0.32). Among
hospital survivors, 69% of those in the high-dosage arm
recovered renal function compared with 80% of those in the
standard-dosage arm ( p = 0.29); therefore, a significant
difference in patient survival or renal recovery was not
 M. Elahi et al. / European Journal of Cardio-thoracic Surgery 35 (2009) 854—863
detected between patients receiving high-dosage or stan-
dard-dosage CVVHDF. The observations in these studies raise
concerns as to the issues surrounding the definition of ARF,
whether inappropriate patient selection criteria were used,
whether results from different treatment modalities are
comparable in different patient groups and whether the
studies were adequately powered.
10. Conclusions
Observations from several studies reinforce the notion
that there are many unresolved issues relating to post-
operative AKI. The time has come for the implementation of
a consensus on the standard definition of AKI that is
sensitive and specifically defines this complication. This will
permit an accurate assessment of the impact of AKI on
outcomes, and allow comparison of patients across centres
worldwide. The preoperative risk assessment scores will
need to be re-validated prospectively using the standar-
dised definitions and should incorporate emerging knowl-
edge of patient characteristics and the care elements. In
this regard a prognostic score system for AKI would help
anticipate patient treatment. To develop such a predictive
score for AKI following cardiac surgery, Palomba et al. [71]
recently evaluated 603 patients for AKI (defined as serum
creatinine above 2.0 mg/dl or an increase of 50% above
baseline value). The authors included age greater than 65,
pre-operative creatinine above 1.2 mg/dl, pre-operative
capillary glucose above 140 mg/dl, heart failure, combined
surgeries, CPB time above 2 h, low cardiac output, and low
central venous pressure as variables and reported good
calibration and validation of their scoring system [72].
Clinical predictors and biochemical markers identified for
the development of AKI can only explain a part of this
individual risk. Another tool to predict the risk of AKI and to
improve individualised patient care focuses on the identi-
fication of early predictive biomarkers such as urine
neutrophils gelatinase-associated lipocalin (NGAL), urinary
IL-8, and liver fatty acid-binding protein [73,74]. Further-
more, genetic risk factors must not be forgotten, chances
are that some gene products might be involved in the
development of AKI. Unfortunately, to date our knowledge
of the relationship between genetic diversity and the
susceptibility to and the severity of AKI remains limited.
There is some evidence to suggest that sepsis and
cardiopulmonary bypass-associated complications involves
polymorphism of genes that participate in the control of
inflammatory or vasomotor processes [75—77]. Future
studies could be designed to identify high-risk individuals
based on standardised score. This could lead to initiation of
timely interventions that might prevent or ameliorate renal
injury and improve operative outcomes. A key element is
the dissemination of information across the continuum of
care. This calls for multidisciplinary collaboration among
cardiac surgeons, nephrologists, and allied personnel
involved in patient care who may not be aware of study
findings published in selective society journals. This has
thus far limited the adaptation of study findings into clinical
practice. We conclude that future progress in this area will
depend primarily on the choices we make now.
861
References
[1] 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—62.
[2] Chertow GM, Lazarus JM, Christiansen CL, Cook EF, Hammermeister KE,
Grover F, Daley J. Preoperative renal risk stratification. Circulation
1997;95:878—84.
[3] Page US, Washburn T. Using tracking data to find complications that
physicians miss: the case of renal failure in cardiac surgery. Jt Comm J
Qual Improv 1997;23:511—20.
[4] Anderson RJ, O’Brien M, MaWhinney S, VillaNueva CB, Moritz TE, Sethi
GK, Henderson WG, Hammermeister KE, Grover FL, Shroyer AL. Mild renal
failure is associated with adverse outcome after cardiac valve surgery. Am
J Kidney Dis 2000;35:1127—34.
[5] Mack MJ, Brown PP, Kugelmass AD, Battaglia SL, Tarkington LG, Simon AW,
Culler SD, Becker ER. Current status and outcomes of coronary revascu-
larization 1999 to 2002: 148,396 surgical and percutaneous procedures.
Ann Thorac Surg 2004;77:761—6.
[6] Leacche M, Rawn JD, Mihaljevic T, Lin J, Karavas AN, Paul S, Byrne JG.
Outcomes in patients with normal serum creatinine and with artificial
renal support for acute renal failure developing after coronary artery
bypass grafting. Am J Cardiol 2004 1;93:353—6.
[7] Kellerman PS. Perioperative care of the renal patient. Arch Intern Med
1994;154:1674—88.
[8] Kramer P, Kaufhold G, Grone HJ, Wigger W, Rieger J, Matthaei D, Stokke T,
Burchardi H, Scheler F. Management of anuric intensive care patients with
arteriovenous hemofiltration. Int J Artif Organs 1980;3:225—7.
[9] Ryckwaert F, Boccara G, Frappier JM, Colson PH. Incidence, risk factors,
and prognosis of a moderate increase in plasma creatinine early after
cardiac surgery. Crit Care Med 2002;30:1495—8.
[10] 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—605.
[11] Suen WS, Mok CK, Chiu SW, Cheung KL, Lee WT, Cheung D, Das SR, He GW.
Risk factors for the development of acute renal failure (ARF) requiring
dialysis in patients undergoing cardiac surgery. Angiology 1998;49:789—800.
[12] Schwilk B, Wiedeck H, Stein B, Reinelt H, Treiber H, Bothner U. Epide-
miology of acute renal failure and outcome of haemofiltration in intensive
care. Int Care Med 1997;23:1204—11.
[13] Massoudy P, Wagner S, Thielmann M, Herold U, Kottenberg-Assenmacher
E, Marggraf G, Kribben A, Philipp T, Jakob H, Herget-Rosenthal S. Acute
renal failure in patients with coronary heart disease: coronary artery
bypass surgery and acute kidney injury—impact of the off-pump techni-
que. Nephrol Dial Transplant 2008;23(9):2853—60.
[14] Burns KE, Chu MW, 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(3):342—50.
[15] Elahi MM, Lim MY, Joseph RN, Dhannapuneni RR, Spyt TJ. Early hemofil-
tration improves survival in post-cardiotomy patients with acute renal
failure. Eur J Cardiothorac Surg 2004;26:1027—31.
[16] Bent P, Tan HK, Bellomo R, Buckmaster J, Doolan L, Hart G, Silvester W,
Gutteridge G, Matalanis G, Raman J, Rosalion A, Buxton BF. Early and
intensive continuous hemofiltration for severe renal failure after cardiac
surgery. Ann Thorac Surg 2001;71:832—7.
[17] Gettings LG, Reynolds HN, Scalea T. Outcome in post-traumatic acute
renal failure when continuous renal replacement therapy is applied early
vs late. Intensive Care Med 1999;25:805—13.
[18] Demirkilic U, Kuralay E, Yenicesu M, Caglar K, Oz BS, Cingoz F, Gunay C,
Yildirim V, Ceylan S, Arslan M, Vural A, Tatar H. Timing of replacement
therapy for acute renal failure after cardiac surgery. J Card Surg
2004;19:17—20.
[19] Luckraz H, Gravenor MB, George R, Taylor S, Williams A, Ashraf S, Argano
V, Youhana A. Long and short-term outcomes in patients requiring con-
tinuous renal replacement therapy post cardiopulmonary bypass. Eur J
Cardiothorac Surg 2005;27:906—9.
[20] Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P, Acute Dialysis
Quality Initiative workgroup. Acute renal failure — definition, outcome
measures, animal models, fluid therapy and information technology
needs: the Second International Consensus Conference of the Acute
Dialysis Quality Initiative (ADQI) Group. Crit Care 2004;8(August
(4)):R204—12.
862 M. Elahi et al. / European Journal of Cardio-thoracic Surgery 35 (2009) 854—863
[21] Lameire N, Van Biesen W, Vanholder R. Acute renal failure. Lancet 2005;
365:417—30.
[22] Ricci Z, Cruz D, Ronco C. The RIFLE criteria and mortality in acute kidney
injury: a systemic review. Kidney Int 2008;73:538—46.
[23] Gruberg L, Mintz GS, Mehran R, Gangas G, Lansky AJ, Kent KM, Pichard AD,
Satler LF, Leon MB. The prognostic implications of further renal function
deterioration within 48 h of interventional coronary procedures in
patients with pre-existent chronic renal insufficiency. J Am Coll Cardiol
2000;36:1542—8.
[24] Iakovou I, Dangas G, Mehran R, Lansky AJ, Ashby DT, Fahy M, Mintz GS,
Kent KM, Pichard AD, Satler LF, Stone GW, Leon MB. Impact of gender on
the incidence and outcome of contrast-induced nephropathy after per-
cutaneous coronary intervention. J Invasive Cardiol 2003;15:18—22.
[25] Rihal CS, Textor SC, Grill DE, Berger PB, Ting HH, Best PJ, Singh M, Bell
MR, Barsness GW, Mathew V, Garratt KN, Holmes Jr DR. Incidence and
prognostic importance of acute renal failure after percutaneous coronary
intervention. Circulation 2002;105:2259—64.
[26] Kilo J, Margreiter JE, Ruttmann E, Laufer G, Bonatti JO. Slightly elevated
serum creatinine predicts renal failure requiring hemofiltration after
cardiac surgery. Heart Surg Forum 2005;8:34—8.
[27] De Moreas Lobo EM, Burdmann EA, Abdulkader RCRM. Renal function
changes after elective cardiac surgery with cardiopulmonary bypass.
Renal Failure 2000;22:487—97.
[28] Amirhamzeh MMR, Dean DA, Jia CX, Cabreriza SE, Starr JP, Sardo MJ,
Chalik N, Dickstein ML, Spotnitz MH. Iatrogenic myocardial oedema:
increased diastolic compliance and time course of resolution in vivo.
Ann Thorac Surg 1996;62:737—43.
[29] Piriou V, Claudel JP, Bastien O, Ross S, Lehot JJ. Severe systemic cho-
lesterol embolisation after open heart surgery. Br J Anaesth 1996;77:
277—80.
[30] Verrier DE, Boyle EM. Endothelial cell injury in cardiovascular surgery.
Ann Thorac Surg 1996;62:915—22.
[31] Gu YJ, de Vries AJ, Boonstra PW, Van Oeveren W. Leukocyte depletion
results in improved lung function and reduced inflammatory response
after cardiac surgery. J Thorac Cardiovasc Surg 1996;112:494—500.
[32] Pflueger AC, Schenk F, Osswald H. Increased sensitivity of the renal
vasculature to adenosine in streptozotocin-induced diabetes mellitus
rats. Am J Physiol 1995;269:529—35.
[33] Pflueger AC, Gross JM, Knox FG. Adenosine-induced renal vasoconstric-
tion in diabetes mellitus rats: role of prostaglandins. Am J Physiol
1999;277:1410—7.
[34] Pflueger AC, Osswald H, Knox FG. Adenosine-induced renal vasoconstric-
tion in diabetes mellitus rats: role of nitric oxide. Am J Physiol
1999;276:340—6.
[35] Pflueger AC, Larson TS, Hagl S, Knox FG. Role of nitric oxide in intrarenal
hemodynamics in experimental diabetes mellitus in rats. Am J Physiol
1999;277:725—33.
[36] Doddakula K, Al-Sarraf N, Gately K, Hughes A, Tolan M, Young V, McGovern
E. Predictors of acute renal failure requiring renal replacement therapy
post cardiac surgery in patients with preoperatively normal renal func-
tion. Interact Cardiovasc Thorac Surg 2007;6:314—8.
[37] Zhu J, Yin R, Shao H, Dong G, Luo L, Jing H. N-acetylcysteine to
ameliorate acute renal injury in a rat cardiopulmonary bypass model.
J Thorac Cardiovasc Surg 2007;133:696—703.
[38] Lema G, Meneses G, Urzua J, Jalil R, Canessa R, Moran S, Irarrazaval
MJ, Zalaquett R, Orellana P. Effects of extracorporeal circulation on
renal function in coronary surgical patients. Anaesth Analg 1995;81:
446—51.
[39] Fleming F, Bohn D, Edwards H, Cox P, Geary D, McCrindle BW, Williams
WG. Renal replacement therapy after repair of congenital heart disease
in children. A comparison of hemofiltration and peritoneal dialysis. J
Thorac Cardiovasc Surg 1995;109:322—31.
[40] Groetzner J, Kaczmarek I, Landwehr P, Mueller M, Daebritz S, Lamm P,
Meiser B, Reichart B. Renal recovery after conversion to a calcineurin
inhibitor-free immunosuppression in late cardiac transplant recipients.
Eur J Cardiothorac Surg 2004;25:333—41.
[41] Lombardi R, Ferreiro A. Risk factors profile for acute kidney injury after
cardiac surgery is different according to the level of baseline renal
function. Ren Fail 2008;30:155—60.
[42] Sladen R, Prough D. Peri-operative renal protection. Crit Care Clin 1997;
9:314—31.
[43] Pflueger A, Larson TS, Nath KA, King BF, Gross JM, Knox FG. Role of
adenosine in contrast media-induced acute renal failure in diabetes
mellitus. Mayo Clin Proc 2000;75:1275—83.
[44] van Bommel EF. Renal replacement therapy for acute renal failure on the
intensive care unit: coming of age? Neth J Med 2003;61:239—48.
[45] Ronco C, Bellomo R, Ricci Z. Continuous renal replacement therapy in
critically ill patients. Nephrol Dial Transplant 2001;16:67—72.
[46] Conger JD. Does hemodialysis delay recovery from ARF? Semin Dial
1990;3:146—8.
[47] Schiffl H, Lang SM, Konig A, Held E. Dose of intermittent haemodialysis
and outcome of acute renal failure: a prospective randomised study. J Am
Soc Nephrol 1997;8:290.
[48] Paganini EP, Tapolay M, Goormastic M, Halstenberg W, Kozlowski L,
Leblanc M, Lee JC, Moreno L, Sakai K. Establishing a dialysis therapy/
patient outcome link in intensive care unit acute dialysis for patients with
acute renal failure. Am J Kidney Dis 1996;28:81—9.
[49] Cipolla CM, Grazi S, Rimondini A, Susini G, Guazzi M, Della Bella P, Guazzi
MD. Changes in circulating norepinephrine with hemofiltration in
advanced congestive heart failure. Am J Cardiol 1990 15;66:987—94.
[50] Caprioli R, Favilla G, Palmarini D, Comite C, Gemignani R, Rindi P, Cioni L.
Automatic continuous venovenous hemodialfiltration in cardiosurgical
patients. ASAIO J 1993;39:606—8.
[51] Blake P, Hasegawa Y, Khosla MC, Fouad-Tarazi F, Sakura N, Paganini EP.
Isolation of ‘‘myocardial depressant factor(s)’’ from the ultrafiltrate of
heart failure patients with acute renal failure. ASAIO J 1996;42:911—5.
[52] Hoffmann JN, Faist E. Removal of mediators by continuous hemofiltration
in septic patients. World J Surg 2001;25:651—9.
[53] Gohl H, Buck R, Strathmann H. Basic features of the polyamide mem-
branes. Contrib Nephrol 1992;96:1—25.
[54] Sander A, Armbruster W, Sander B, Daul AE, Lange R, Peters J. Hemofil-
tration increases IL-6 clearance in early systemic inflammatory response
syndrome but does not alter IL-6 and TNF alpha plasma concentrations.
Intensive Care Med 1997;23:878—84.
[55] Sanchez-Izquierdo JA, Perez Vela JL, Lozano Quintana MJ, Alted Lopez E,
Ortuno de Solo B, Ambros Checa A. Cytokines clearance during venovenous
hemofiltration in the trauma patient. Am J Kidney Dis 1997;30:483—8.
[56] Bellomo R, Tipping P, Boyce N. Continuous veno-venous hemofiltration
with dialysis removes cytokines from the circulation of septic patients.
Crit Care Med 1993;21:522—6.
[57] Heidemann SM, Ofenstein JP, Sarnaik AP. Efficacy of continuous arter-
iovenous hemofiltration in endotoxic shock. Circ Shock 1994;44:183—7.
[58] Tonnesen E, Hansen MB, Hohndorf K, Diamant M, Bendtzen K,
Wanscher M, Toft P. Cytokines in plasma and ultrafiltrate during
continuous arteriovenous haemofiltration. Anaesth Intensive Care
1993;21:752—8.
[59] Bellomo R, Tipping P, Boyce N. Interleukin-6 and interleukin-8 extraction
during continuous venovenous hemodialfiltration in septic acute renal
failure. Ren Fail 1995;17:457—66.
[60] Heering P, Morgera S, Schmitz FJ, Schmitz G, Willers R, Schultheiss HP,
Strauer BE, Grabensee B. Cytokine removal and cardiovascular hemody-
namics in septic patients with continuous veno-venous hemofiltration.
Intensive Care Med 1997;23:288—96.
[61] Honore PM, Jamez J, Wauthier M, Lee PA, Dugernier T, Pirenne B, Hanique
G, Matson JR. Prospective evaluation of short-term, high-volume iso-
volemic hemofiltration on the hemodynamic course and outcome in
patients with intractable circulatory failure resulting from septic shock.
Crit Care Med 2000;28:3581—7.
[62] Parker MM, McCarthy KE, Ognibene FP, Parrillo JE. Right ventricular
dysfunction and dilatation, similar to left ventricular changes, charac-
terize the cardiac depression of septic shock in humans. Chest 1999;
97:126—31.
[63] Hoffmann JN, Werdan K, Hartl WH, Jochum M, Faist E, Inthorn D. Hemofil-
trate from patients with severe sepsis and depressed left ventricular
contractility contains cardiotoxic compounds. Shock 1999;12:174—80.
[64] Ricci Z, Ronco C, D’Amico G, De Felice R, Rossi S, Bolgan I, Bonello M,
Zamperetti N, Petras D, Salvatori G, Dan M, Piccinni P. Practice patterns in
the management of acute renal failure in the critically ill patient: an
international survey. Nephrol Dial Transplant 2006;21:690—6.
[65] Schiffl H, Lang SM, Fischer R. Daily hemodialysis and the outcome of acute
renal failure. N Engl J Med 2002;346:305—10.
[66] Bouman CS, Oudemans-Van Straaten HM, Tijssen JG, Zandstra DF, Kese-
cioglu J. Effects of early high-volume venovenous hemofiltration on
survival and recovery of renal function in intensive care patients with
acute renal failure: a prospective, randomised trial. Crit Care Med
2002;30:2205—11.
[67] Van Den Noortgate N, Mouton V, Lamot C, Van Nooten G, Dhondt A,
Vanholder R, Afschrift M, Lameire N. Outcome in a post-cardiac surgery
 M. Elahi et al. / European Journal of Cardio-thoracic Surgery 35 (2009) 854—863
population with acute renal failure requiring dialysis: does age make a
difference? Nephrol Dial Transplant 2003;18:732—6.
[68] Loef BG, Epema AH, Smilde TD, Henning RH, Ebels T, Navis G, Stegeman
CA. Immediate postoperative renal function deterioration in cardiac
surgical patients predicts in-hospital mortality and long-term survival.
J Am Soc Nephrol 2005;16:195—200.
[69] Palevsky PM, Zhang JH, O’Connor TZ, Chertow GM, Crowley ST, Choudhry
D, Finkel K, Kellum JA, Paganini E, Schein RMH, Smith MW, Swanson KM,
Thompson BT, Vijayan A, Watnick S, Star RA, Peduzzi P. Intensity of renal
support in critically ill patients with acute kidney injury. N Engl J Med
2008;359:1—14.
[70] Tolwani AJ, Campbell RC, Stofan BS, Lai KR, Oster RA, Wille KM. Standard
versus high dose CVVHDF for ICU-related acute renal failure. J Am Soc
Nephrol 2008;19:1233—8.
[71] 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—31.
[72] Bennett M, Dent CL, Ma Q, Dastrala S, Grenier F, Workman R, Syed H, Ali S,
Barasch J, Devarajan P. Urine NGAL predicts severity of acute kidney
863
injury after cardiac surgery: a prospective study. Clin J Am Soc Nephrol
2008;3:665—73.
[73] Parikh CR, Mishra J, Thiessen-Philbrook H, Dursun B, Ma Q, Kelly C, Dent
C, Devarajan P, Edelstein CL. Urinary IL-18 is an early predictive bio-
marker of acute kidney injury after cardiac surgery. Kidney Int 2006;
70:199—203.
[74] Portilla D, Dent C, Sugaya T, Nagothu KK, Kundi I, Moore P, Noiri E,
Devarajan P. Liver fatty acid-binding protein as a biomarker of
acute kidney injury after cardiac surgery. Kidney Int 2008;73:
465—72.
[75] Elahi MM, Gilmour A, Matata BM, Mastana SS. A variant of position-308 of
the tumour necrosis factor alpha gene promoter and the risk of coronary
heart disease. Heart Lung Circ 2008;17:14—8.
[76] Isbir SC, Tekeli A, Ergen A, Yilmaz H, Ak K, Civelek A, Zeybek U, Arsan S.
Genetic polymorphisms contribute to acute kidney injury after coronary
artery bypass grafting. Heart Surg Forum 2007;10(6):E439—44.
[77] Yates RB, Stafford-Smith M. The genetic determinants of renal impairment
following cardiac surgery. Semin Cardiothorac Vasc Anesth 2006;10(4):
314—26.