Intensive Care Med (2015) 41:514516

DOI 10.1007/s00134-014-3596-x

Johan Martensson
R. Bellomo

WHATS NEW IN INTENSIVE CA RE

Whats new in perioperative renal dysfunction?

Received: 8 November 2014

Accepted: 2 December 2014
Published online: 8 January 2015
Springer-Verlag Berlin Heidelberg and ESICM 2014
J. Martensson
R. Bellomo
Department of Intensive Care, Austin Hospital,
Melbourne, VIC, Australia
J. Martensson
Section of Anaesthesia and Intensive Care Medicine,
Department of Physiology and Pharmacology,
Karolinska Institutet, Stockholm, Sweden
R. Bellomo ())
Department of Epidemiology and Preventive Medicine,
Australian and New Zealand Intensive Care Research Centre,
School of Preventive Medicine and Public Health,
Monash University, Melbourne, VIC, Australia
e-mail: rinaldo.bellomo@austin.org.au;
rinaldo.bellomo@monash.edu
Tel.: ?61-3-94965992

Introduction
The increasing incidence of acute kidney injury (AKI) is
approaching epidemic status worldwide. Moreover, AKIassociated mortality remains high. More people die with
AKI than from breast cancer, prostate cancer, heart failure
and diabetes combined [1]. In addition, the development
of chronic and end-stage kidney disease and cardiovascular morbidity are now recognised as long-term
consequences of the AKI syndrome [2]. After sepsis,
major surgery is the most common AKI-trigger. However,
the mechanisms responsible for postoperative AKI remain
poorly defined. Thus, perioperative AKI is an area of
intense research. In particular, potential biomarkers of

early tubular stress as well as promising therapies to

prevent and ameliorate AKI are under active
investigation.

AKI predictors and preoperative assessment

The risk of postoperative AKI depends on patient susceptibility, extent and type of surgery-induced injury,
exposure to nephrotoxic drugs and perioperative haemodynamic management. Advanced age and chronic kidney
disease (CKD), two risk factors which often coexist, are
recognised as the most important patient-related risk
factors for AKI [3]. The incidence of both postoperative
AKI and mortality increase exponentially with decreasing
baseline glomerular filtration rate (GFR). Other clinical
and biochemical risk factors are listed in Table 1.
Surgical trauma and procedures such as cardiopulmonary bypass trigger the production and release of
cytokines, reactive oxygen species and labile free iron [4].
These biologically injurious events induce the tubular cell
synthesis of proteins involved in cytoprotective mechanisms. For example, tissue inhibitor of metalloproteinases2 (TIMP-2) and insulin-like growth factor-binding protein-7 (IGFBP7) induce G1 cell-cycle arrest, which
appears to prevent injured cells from dividing until tubular
injury has resolved [5]. Neutrophil gelatinase-associated
lipocalin (NGAL) and hepcidin are involved in iron
homeostasis and have the ability to reduce extracellular
iron-induced cell-injury [4]. Liver fatty acid-binding protein (L-FABP) limits the toxic effects of oxidative
intermediates on cellular membranes by binding lipid
oxidation products. Finally, kidney injury molecule-1
(KIM-1) facilitates the regeneration of injured tubules.
These proteins can be quantified in urine and have been
extensively studied as early biomarkers of AKI. The role
of single biomarkers in the management of postoperative

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Table 1 Perioperative risk stratification, prevention and management of acute kidney injury
Preoperative

Intra- and postoperative

Screening for risk factors

Age [65 years
Male sex
Black race
Obesity (body mass index [40 kg/m2)
Chronic kidney disease
Liver disease
Congestive heart failure
Peripheral vascular disease
Diabetes mellitus
Hypertension
Malignancy
Chronic obstructive pulmonary disease
Anaemia
Hypoalbuminemia
Baseline biochemistry
Serum creatinine and estimated GFR
Urinary albumin to creatinine ratio
Serum albumin
Haemoglobin
Urinary biomarkers?a

AKI preventive strategies

Avoid hypotension
Avoid synthetic colloids and hyperchloremic solutions
Avoid fluid overload and high central venous pressure
Minimise use of nephrotoxic drugs
Low-dose atrial natriuretic peptide infusion?a
Postoperative monitoring
At least daily serum creatinine measurements
Urine output hourly
Urinary biomarker panels?a
TIMP-2 9 IGFBP7
KIM-1 ? IL-18
NGAL ? L-FABP
Postoperative AKI treatment
Infection control
Low-dose atrial natriuretic peptide infusion?a
CRRT if diuretics insufficient to treat impending fluid overload and/or venous congestion

GFR Glomerular filtration rate, TIMP-2 tissue inhibitor of fatty acid-binding protein, CRRT continuous renal replacement
metalloproteinases-2, IGFBP7 insulin-like growth factor-binding therapy
protein-7, KIM-1 kidney injury molecule-1, IL-18 interleukin-18, a Suggestion with limited evidence in the literature
NGAL neutrophil gelatinase-associated lipocalin, L-FABP liver

AKI, however, remains unclear due to a lack of therapies

and because the performance of individual biomarkers
appears to vary significantly according to the population
studied.
In contrast, biomarker panels added to clinical risk
models seem to be more robust in predicting postoperative AKI. A combination of urinary TIMP-2, IGFBP7 and
a six-parameter clinical model was recently shown to
accurately predict AKI after cardiac surgery [area under
the receiver operating characteristics curve (AuROC)
0.97, 95 % confidence interval (CI) 0.921.00] [5]. In
addition, the combined use of NGAL and L-FABP predicted cardiac surgery-associated AKI with an AuROC of
0.93 (95 % CI 0.870.99) [6]. Finally, KIM-1 and interleukin-18 used in combination predicted severe AKI or
death (AuROC 0.93, 95 % CI 0.790.98) [7]. Nonetheless, the utility of these biomarkers in postoperative care
will continue to depend on their ability to trigger specific
interventions.

Perioperative management of patients with or at risk

of AKI
Although hypotension is a strong, independent and
potentially avoidable contributor to renal damage [8], a
safe blood pressure threshold for individual patients
remains to be determined. Perioperative blood pressure
deficit (decrease in blood pressure relative to the patients

preoperative values) may be especially important in

patients with impaired renal autoregulation, such as the
elderly and patients with CKD or chronic hypertension.
This concept was highlighted in the SEPSISPAM trial
where, in septic shock patients with chronic hypertension,
a target mean arterial pressure (MAP) of 6570 mmHg
increased the need for renal replacement therapy (RRT)
compared to a MAP of 8085 mmHg [9].
Fluid administration is widely used to prevent and
treat perioperative hypotension. There is, however,
uncertainty about the optimal use of fluids to achieve and
maintain haemodynamic stability. Previous studies have
suggested a reduction in postoperative complications
when haemodynamic algorithms are used to guide fluid
therapy and vasoactive support. The most recent and
largest trial conducted to date, however, failed to demonstrate a reduction in the composite outcome of
complications, including AKI and 30-day mortality when
cardiac output-guided fluid and dopexamine therapy were
compared to standard care in major gastrointestinal surgery [10]. Notably, such goal-directed therapy did not
reduce the overall volume of fluids administered
(approximately 4 l). Indeed, the association of fluid
accumulation and venous congestion with worsening
kidney function has been repeatedly emphasised in critically ill patients [11]. Whether, a more restrictive fluid
strategy can improve patient-centred outcomes in highrisk patients undergoing major abdominal surgery is
currently being explored in a large multicenter randomised trial (the RELIEF trial; ClinicalTrials.gov Identifier:

516

NCT01424150). Finally, the choice of fluid clearly

impacts renal outcome. Owing to their nephrotoxic
effects, administration of hydroxyethyl starches and hyperchloremic solutions, such as 0.9 % saline, should be
avoided in patients at risk of postoperative AKI [12, 13].
The link between tubular injury and reduced GFR is
incompletely understood. Impaired chloride reabsorption
by injured tubules causing increased chloride delivery to
macula densa and constriction of the afferent arteriole
may provide a pathophysiological connection between
tubular injury and reduced GFR. This tubuloglomerular
feedback can theoretically be counteracted by renal
vasodilators, such as atrial natriuretic peptide (ANP) and
fenoldopam. Results from small single-centre randomised
controlled trials (RCTs) suggest that perioperative lowdose infusion of ANP prevents AKI after major surgery
[14]. Although such low-grade evidence does not justify
routine perioperative ANP infusion in high-risk patients,
its utility deserves further investigation in large trials. The

putative benefits of fenoldopam, however, have been

refuted in a recent large multicentre double-blind RCT,
where fenoldopam infusion failed to attenuate the course
of mild AKI or decrease the need for RRT after cardiac
surgery [15].
In conclusion, AKI is a preventable and partly modifiable postoperative complication. Avoiding blood
pressure deficits, nephrotoxic drugs or fluids, fluid overload and venous congestion are important protective
measures to attenuate the risk of postoperative AKI and to
enhance renal recovery when such AKI occurs. Optimisation of intrarenal haemodynamics may play a role in the
future prevention and treatment of AKI. The measurement of biomarkers of renal tubular stress may be equally
important to trigger earlier intervention and monitor
future therapies.
Conflicts of interest None.

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