Abstract
Background : Renal complications following cardiac surgery are
fairly common and may require renal replacement therapy. Most of such
cases recover with either conservative management or temporary, short
period requirements for renal replacement therapy. Several studies
highlight compelling evidence for such complications to be recognised
and managed promptly.
Aim: In this review, we aim to address the identified risk
factors and pathophysiology of cardiac surgery associated renal injury.
Furthermore, data regarding acute kidney injury and the long-term renal
complications post-cardiac surgery will also be analysed.
Methods: A comprehensive review of literature was conducted
using appropriate keywords on search engines of SCOPUS, Wiley, PubMed,
and SAGE Journals.
Conclusion: Various risk factors during the periods of surgery
have been identified to be linked to the occurrence of these adverse
outcomes. Many of these factors have been identified through extensive
research and are modifiable while several others are still unclear or
needs deeper understanding and studies.
Introduction
Renal complications following cardiac surgery are well recognized, with
acute kidney injury (AKI) being the most prevalent. Cardiac
surgery-associated acute kidney injury (CSA-AKI) has an incidence
varying from 7-28% in adult patients.1 The incidence
of AKI in paediatric patients following congenital heart surgery is even
higher; with an incidence of 40% in this age group. AKI is also linked
to the rapid progression of chronic kidney failure, which poses as
long-term renal complications post-cardiac surgery.2These adverse outcomes are associated with increased morbidity,
premature mortality, longer hospital stays, and incur higher hospital
fees. Multiple studies conducted, confirm the connection between the
severity of AKI post cardiovascular surgery and the probability of
death.3
Acute kidney injury is generally defined as a rapid deterioration in
kidney function resulting in structural and functional damage. AKI
normally creates an upsurge in serum creatinine value as well as in
blood urea nitrogen concentration. However, due to the delay in the rise
of these values, AKI is more commonly manifested clinically by a
deterioration in the value of the urine output.4
Multiple classification systems are designed to stage AKI. Few common
classifications used are the RIFLE or AKIN criteria. RIFLE is the
acronym for Risk, Injury, Failure, Loss, and End-stage kidney disease.
Patients are classified either by their glomerular filtration rate or
urine output. The AKIN classification is essentially a revised edition
of the RIFLE with a few important changes; a) elimination of GFR
criteria, b) lower serum creatinine threshold for the diagnosis of AKI,
and c) reduced duration for diagnosing AKI (changed from 7 days to 48
hours).3 These criteria rely heavily on serum
creatinine which may prove inaccurate as the value has a gap in the rise
and involves the reduction of 50% of kidney function in order for it to
be elevated in the serum. Hence, several biomarkers are coming to light,
such as neutrophil gelatinase-associated lipocalin (NGAL),
interleukin-18 (IL-18), and kidney injury molecule-1, which indicate
kidney damage or inflammation. A study by Jayaraman et al. showed that
NGAL has a higher sensitivity of detecting intrinsic AKI at 24 hours
based on the RIFLE criteria than compared to
creatinine.1
In our review, we have summarized AKI in further depth relating to its
incidence, aetiologies as well as management. Although AKI has been
extensively researched, the research on CKD remains fairly minimal. This
review also aims to shed light on CKD, its associated risk factors, and
methods of reducing the chances of complications.
Pathophysiology
The pathophysiology of cardiac surgery-associated acute kidney injury
(CSA-AKI) is not fully understood. However, it is reasonable to accept
that several factors contribute to postoperative renal damage. Adverse
renal outcomes can be the consequence of several assaults that happened
before, during, and after the surgery.5 A few
important mechanisms of CSA-AKI include peri-operative renal ischaemia,
reperfusion injury, cardiopulmonary bypass (CPB)-induced haemolysis,
pigment nephropathy, oxidative stress, and
inflammation.6 A figure adapted from Yuan et al. has
been included in this review to further understand the mechanism of
acute kidney injury (Figure 1).10
The highly regulated renal perfusion system consists of a shunt that
helps maintain electrolyte and water concentration gradients in the
renal medulla for tubule and collecting system reabsorption but renders
the renal medulla and corticomedullary junction hypoxic relative other
tissues. This may act as a protective mechanism for oxidative injury but
increases susceptibility to ischemia. Surgery may alter renal perfusion
hence damaging tubules at the corticomedullary junction and medulla.
Furthermore, aorta cannulation and cross-clamping increase atheroemboli
to the kidneys, further exacerbating ischemia, and inducing
inflammation. Renal oxygenation may also be impaired due to sympathetic
nervous system activation, the endogenous release of circulating
catecholamines, and the induction of the renin-angiotensin-aldosterone
cascade.10
Intraoperatively, many factors may alter renal perfusion, such as the
vasodilatory effects of anaesthesia, the usage of diuretics, and blood
loss which overall accentuates the effect of hypoperfusion on the
kidneys. Following a prolonged period of ischaemia, restoration of blood
flow may also cause reperfusion injury in which renal tissues are
further damaged due to the induction of oxidative stress. Oxidative
stress increases the generation of proinflammatory mediators hence
inflicting renal damage.6 Another cause of renal
injury is by nephrotoxins, such as the usage of iodine contrast dye
during coronary angiography.7
Elevated postoperative plasma concentrations of inflammatory cytokines
are significantly associated with a higher risk of developing AKI.
Evidence suggests that plasma IL-6 and IL-10 may serve as biomarkers for
perioperative outcomes. Although the mechanism behind the inflammation
is not completely understood, it may be caused due to a combination of
factors including contact activation from the exposure of blood to the
CBP circuit, ischemia-reperfusion injury, and oxidative
damage.10
Furthermore, the usage of cardiopulmonary bypass (CPB) itself may evoke
renal damage due to the trigger of systemic inflammatory response
syndrome (SIRS), the consequences of changes in blood flow and renal
vasomotor tone as well as the formation of microemboli. SIRS during CPB
is elicited by the contact of blood with the foreign material of the
bypass circuit and prompts widespread inflammation and renal damage. CPB
also alters the pressure for effective renal blood flow by altering
renal vasomotor tone, hence further risking the kidneys to ischemia and
reperfusion damages. Haemolysis induced by CPB also worsens SIRS and
induces the generation of microemboli, which directly destruct
capillaries in the kidneys.10
Additionally, both hemoglobinemia and myoglobinemia are independent
predictors of postoperative AKI. Billings et al., in their study,
demonstrated that postoperative AKI is associated with both enhanced
intraoperative hemeprotein release and enhanced lipid peroxidation. The
study found that patients who had developed AKI had twice the
plasma-free hemoglobin at the end of CPB than those who did not, despite
having similar AKI risk profiles and identical CPB durations in each
group. Hence, data suggests that hemolysis and high concentrations of
plasma-free hemoglobin, through induction of subsequent injurious
mechanisms or from direct effects, may contribute to the development of
AKI post-cardiac surgery.12
Risk Factors
A variety of risk factors have been identified in the past through
multiple studies. The occurrence of renal complications after cardiac
surgery is a result of multifactorial risk factors that eventually can
lead to reduced renal function. For this review, risk factors leading to
acute kidney injury have been classified as preoperative,
intraoperative, and postoperative as summarized in Table 1.
Preoperative:
Anaemia is recognised as a critical risk factor as it further increases
the vulnerability of the kidneys to ischaemia and injury during cardiac
surgery.5 Another predictor for cardiac
surgery-associated renal complications is the presence of comorbidities
such as insulin-requiring diabetes mellitus, pre-existing chronic kidney
disease, and chronic obstructive pulmonary disease
(COPD).1 Pre-existing heart conditions such as
congestive cardiac failure and left ventricular heart impairment also
predispose to renal complications post-heart surgery.1,
7 A study by Ortega-Loubon et al. showed that an extremely reduced left
ventricular ejection fraction of <40% is a remarkable risk
factor associated with the postoperative renal complication. Moreover,
the study also identified other risk factors as being old age and
pre-existing kidney disease.7
Intraoperatively :
Blood transfusion was discovered to have a harmful effect on kidney
function post-surgery. This was hypothesised as the changes in the
structure and function of the red blood cells during storage leads to
ineffective oxygenation.8 Another risk factor of
CSA-AKI is cardiopulmonary bypass (CPB) itself due to the initiation of
systemic inflammation.5 Prolonged cardiac surgery,
aortic cross-clamping, and vasopressors also predispose to renal
complications by changing renal perfusion, causing oxidative stress, and
inducing inflammation.3, 5
Postoperative:
Risk factors are also found tied to the risk of renal complications. The
usage of nephrotoxic antibiotics, such as vancomycin and aminoglycosides
were found to significantly increase the risk of renal adversity. Hence,
the avoidance of using such drugs and administering less nephrotoxic
antibiotics post-surgery will reduce the risk of a
complication.8 Hypotension post-surgery, longer
mechanical ventilation, and the administration of antihypertensive also
amplify the susceptibility of adverse renal outcomes.7
Long-term and Short-term Complications of Cardiac Surgery
Aforementioned, acute kidney injury is a long-recognised complication
after cardiac surgery resulting in a higher morbid-mortality. The
condition is characterized by a sudden deterioration of kidney function
indicated by a reduced glomerular filtration rate (GFR). A summary of
the studies used for the purpose of this review has been provided in
Table 2. A retrospective study conducted by Vellinga et al. analysed 565
patients undergoing cardiac surgery for AKI. Results showed that 14.7%
of the patients developed AKI with a significant difference in age,
preoperative estimated glomerular filtration rate, and chronic kidney
disease between the CS-AKI group and the control
population16
Additionally, perioperative renal dysfunction proves to be a major
determinant of both operative and long-term mortality, following cardiac
surgery. Postoperative AKI not only extends hospitalization days but
also becomes an important independent prognostic risk factor. It is
essential to identify high-risk patients for developing AKI in order to
provide appropriate support in terms of fluid management, hemodynamic
support, adjunctive pharmacologic therapy, or early aggressive use of
therapy (RRT).6
In patients undergoing cardiac surgery, baseline and pre-existing
comorbidities and functional status are important factors that should be
taken into consideration as they can determine the likelihood of
developing AKI postoperatively. Amini et al., in their study analysed
the risk factors of AKI after coronary artery bypass grafting surgery
(CABG). Results concluded that patients that developed AKI had longer
ventilation times, ICU, and hospitalization days. They also found a
strong association between advanced age, diabetes, on-pump surgery, red
blood cell transfusion, and prolonged mechanical ventilation and
development of AKI.16 Many of these risk factors such
as advanced age, hypertension, hyperlipidaemia, and peripheral vascular
disease, and not modifiable.17
Mizuguchi et al. demonstrate the occurrence of AKI in patients with no
pre-existing kidney disease to be 4.4% and those with pre-existing
chronic kidney disease to be 4.8% proving that the degree of AKI can
identify patients who will have a higher risk of progression to acute
kidney disease.18 These patients may benefit from a
close follow-up of renal function because they are at risk of
progressing to chronic kidney disease. Rosner et al. suggest that the
usage of preoperative intro-aortic balloon pump in conditions of low
cardiac output and insult is associated with the development of
postoperative AKI.19
A retrospective study conducted by Han et al. concluded that aetiologies
responsible for the development of AKI included cardiogenic hypotension
(46.3%), multiorgan failure (2.8%), respiratory failure (3.7%),
haemolysis (7.4%), drug-induced interstitial pneumonia (0.9%), and
other unknown causes (38.9%).8 Similarly, in 2015,
Mao et al. investigated the occurrence, severity, and outcomes of acute
kidney injury in octogenarians following heart valve surgery. Nearly
half of the cohort studied developed AKI after valve replacement with
significant functional impairment and reduced
survival.9 Moreover, aortic cross-clamp, CPB, and
blood transfusions and vasopressors are unique to cardiac surgery;
however, are associated with an increased risk of developing AKI.
Predominantly, postoperative AKI occurs due to haemodynamic instability,
nephrotoxic, inotropic, and vasoconstrictor drugs, and systemic
inflammation. Moreover, patients with congestive heart failure or left
ventricular dysfunction postoperatively have an impaired ejection
fraction, and perfusion pressure to the kidneys and hence are at a
higher risk of developing AKI.19
Management
Rosner et al. suggest identifying patients who are at high risk for AKI
is critical to its prevention and management.12 This
can be carried out by utilizing well-established risk stratification
systems for cardiac surgery patients. The best-validated scores predict
severe AKI requiring dialysis and include the Cleveland Clinic Score and
the Mehta Score.20,21 Another systematic review
reiterated these findings, concluding that the Cleveland Clinic model
has been the most widely used and has shown high discrimination in most
of the tested populations.21
However, a prospective study by Bernie et al. analyzed data from 30,000
subjects undergoing cardiac surgery in the UK to develop a model using
KDIGO criteria for predicting all stages of AKI. The model’s risk
prediction score of any stage of AKI (AUC, 0.74 (95% CI: 0.72-0.76))
exhibited better discrimination compared with the Cleveland Clinic Score
and equivalent discrimination to the Mehta Score. This is the first risk
score that accurately identified patients at risk of any stage
AKI.23
Although preventative strategies are limited, current evidence supports
the maintenance of renal perfusion, and intravascular volume while
avoiding venous congestion, administration of balanced salt instead of
high-chloride intravenous fluids. Additionally, limiting cardiopulmonary
bypass exposure.6 Traditional treatment options mainly
focus on attenuating ischemia, reducing intrarenal inflammation, and
supportive care. Patients who have developed AKI following cardiac
surgery should be enterally or parenterally fed 20-30
kcal/kg/day.22 In cases where AKI is severe enough to
require RRT, higher caloric intake via protein supplementation may be
necessary with glycemic control indicated in patients developing
AKI.25, 26
Cases wherein AKI becomes severe, RRT is required to treat hyperkalemia,
remove excess fluid, treat uremia, or reverse
acidosis.27 A meta-analysis conducted by Liu et al.
indicated that early initiation of RRT for patients with AKI after
cardiac surgery was associated with lower 28-day mortality and shorter
ICU length of stay.27 Likewise, a 2013 study
contrasting early versus late RRT initiation in critically ill patients
established that early RRT was associated with lower mortality (51.5 vs.
77.9% p=0.001) and reduced time of the ventilator (12.8 vs. 18.9 days,
p-0.03).28
Of note, failure to respond to RRT may be associated with a combination
of risk factors including older age, intraoperative and postoperative
blood transfusions, non-emergent surgery, gender, and increased
preoperative serum creatinine (s-Cr ) and uric acid levels. However, it
is widely accepted that the benefits of achieving haemodynamic stability
with the use of RRT and potential improvement in renal function outweigh
the risks.20
Another potential treatment is alkaline phosphatase. Although its exact
mechanism of action is unknown, it is likely to be related to
dephosphorylation and thereby detoxification of detrimental molecules
involved in the pathogenesis of acute kidney injury. Results from a
randomized controlled trial conducted in 2012 found that intravenous
administration of recombinant alkaline phosphatase increase creatinine
clearance from 50 ± 27 ml/minute at baseline to 108 ± 73 ml/minute after
treatment in the alkaline phosphatase group versus from 40 ± 37 to
65 ± 30 ml/minute in the placebo group (p=0.01). Despite the promising
results, this did not translate into a decreased need for
RRT.30
Long Term Complications
It is increasingly recognised that AKI after cardiac surgery is
associated with long term complications such as CKD and end-stage renal
disease (ESRD).31 The phases of kidney disease
progression from normal kidney function through AKI, and CKD have been
summarized in Figure 2.7 Between 0.6% to 5% of
cardiac surgery patients will need dialysis postoperatively. This puts
them at a higher mortality rate of 25% in contrast to 2% among
patients who do not need dialysis.32 In a study
conducted by Lo et al., AKI patients requiring dialysis had a 28-fold
increased risk of progressing to stage 4 CKD or ESRD compared to
hospitalized patients without AKI.33 RRT is used for
the management of severe AKI or oliguric renal failure. Evidence from
trials suggests that RRT lowers the risk of uraemia, hyperkalaemia, and
promotes overall haemodynamic stability in cardiac
patients.27 Surgical patients with higher baseline
eGFR are more likely to recover with RRT. Despite this, findings from a
cohort study examining the likelihood of recovery on RRT revealed that
there are fewer benefits available for heart failure patients,
regardless of baseline eGFR. This can be due to challenges in fluid
management, and potential for haemodialysis induced myocardial injury in
heart failure patients. 34