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Intensive care medicine and renal transplantation 1
Management of patients at risk of acute kidney injury
Jill Vanmassenhove, Jan Kielstein, Achim Jörres, Wim Van Biesen
Acute kidney injury (AKI) is a multifaceted syndrome that occurs in different settings. The course of AKI can be
variable, from single hit and complete recovery, to multiple hits resulting in end-stage renal disease. No interventions
to improve outcomes of established AKI have yet been developed, so prevention and early diagnosis are key. Awareness
campaigns and education for health-care professionals on diagnosis and management of AKI—with attention to
avoidance of volume depletion, hypotension, and nephrotoxic interventions—coupled with electronic early warning
systems where available can improve outcomes. Biomarker-based strategies have not shown improvements in
outcome. Fluid management should aim for early, rapid restoration of circulatory volume, but should be more limited
after the first 24–48 h to avoid volume overload. Use of balanced crystalloid solutions versus normal saline remains
controversial. Renal replacement therapy should only be started on the basis of hard criteria, but should not be
delayed when criteria are met. On the basis of recent evidence, the risk of contrast-induced AKI might be overestimated
for many conditions.
Introduction
Acute kidney injury (AKI) is a clinical syndrome that is
associated with many conditions. Interventional
treatments for established AKI have been disappointing.
Although renal replacement therapy (RRT) is the
mainstay of treatment for advanced AKI, RRT is
potentially harmful and not readily available in all
settings and regions. Awareness of and care for patients
with AKI are suboptimal.^1 In most cases AKI is
attributable to simple causes such as volume depletion,
hypotension, and exposure to nephrotoxic medications.^2
Accordingly, attention has shifted in the past decade
from treatment to prevention, early detection, and
proactive management of AKI to avoid further damage
in the short term and long term. AKI is often a
continuum of kidney injury rather than a single-hit,
freestanding condition (figure 1). Chronic kidney
disease (CKD) is an important risk factor in AKI
development and AKI in turn predisposes patients
to CKD.
This Series paper will describe the strategies used to
identify patients at risk of AKI and assess the potential
effect of management strategies that aim to decrease the
effect of nephrotoxicity and improve outcomes.
Identification of patients at risk and early
diagnosis of AKI
Risk prediction for and early identification of AKI are
key in the attempt to reduce the burden of AKI.^3
Prevention should not only apply to patients with a
generic increased risk of AKI (table 1), but also to
patients with impending and even established AKI to
avoid additional kidney damage or delay in recovery. For
patients at increased risk of AKI and those with
impending and established AKI, use of interventions
Key messages
- Acute kidney injury (AKI) is a preventable condition, but
implementation of current preventive strategies is
suboptimal.
- Education and awareness of AKI should be improved for
non-nephrologist health-care providers.
- AKI is a continuum, and prevention of additional damage
to an already injured kidney is crucial.
- Patients who have recovered from AKI should be followed
up because some might have an accelerated course of
chronic kidney disease.
- Avoidance of nephrotoxicity and volume depletion is key
for prevention of AKI in patients in hospital.
- Use of electronic alerts—eg, when serum creatinine values
rise—for identification of patients at high-risk of AKI and
for drug-dose adaptations are useful if these alerts are
coupled to a specific course of action and awareness
campaigns in the framework of a care bundle.
- For prevention of contrast-induced AKI, patients at
intermediate risk might benefit from oral volume
expansion schedules. In high-risk patients, intravenous
volume expansion is preferable.
Search strategy and selection criteria
We searched MEDLINE and the Cochrane database of
Systematic Reviews for articles published between
Jan 1, 2010, and Sept 31, 2016, without language restrictions.
We used MeSH terms and key words for acute kidney injury
and fine-tuned this search according to the following topics
using appropriate boolean operators: biomarkers, risk
prediction models, prevention, statins, electronic alerts,
ischaemic preconditioning, and early start. We primarily
included publications from the past 5 years. Articles not
retrieved by the search that were regarded as highly relevant
by the authors were added to the reference list (for full search
strategy see appendix).
Lancet 2017; 389: 2139– This is the first in a Series of two papers about intensive care medicine and kidney transplantation Renal Division, Ghent University Hospital, Ghent, Belgium (J Vanmassenhove MD, Prof W Van Biesen MD) ; Medical Clinic V, Nephrology, Hypertension and Blood Purification, Academic Teaching Hospital Braunschweig, Braunschweig, Germany (Prof J Kielstein MD) ; and Department of Medicine 1, Nephrology, Transplantation and Medical Intensive Care, University Witten/Herdecke, Medical Centre Cologne Merheim, Cologne, Germany (Prof A Jörres MD) Correspondence to: Prof Wim Van Biesen, Renal Division, Ghent University Hospital, 9000 Ghent, Belgium wim.vanbiesen@ugent.be
See Online for appendix
that are potentially nephrotoxic should be balanced
against their expected benefit.
The course, severity, and outcome of AKI can be very
different from patient to patient and from situation to
situation (figure 1). This variation is determined by the
presence or absence of pre-existing underlying CKD
(acute episode in chronically ill patients vs acute episode
in previously healthy patients) and thus the initial GFR;
early detection and intervention (or not); and additional
nephrotoxic insults by drugs, hypotension, contrast
media, post renal causes, or infections. In the best case
(single hit in a previously healthy patient), kidney
function recovers completely; however, presence of
underlying chronic kidney disease, repetitive insults, and
inadequate detection or intervention can contribute to
incomplete recovery, which can lead to progressive CKD
and need for chronic RRT.
Risk prediction
Many risk prediction scores for AKI have been described
(see table 1 for externally validated scores and appendix
for all risk prediction scores). Most are limited to a
specific setting, so cannot be generalised outside that
setting. Even within a specific setting, heterogeneity
between populations can jeopardise the validity of risk
prediction. External validation in large multicentre
cohorts is thus necessary before risk prediction models
can be adapted in clinical practice. In the post cardiac
surgery population, the Cleveland Clinic Score provides
reasonably accurate predictions of RRT, but validated
scores predicting AKI without the need for RRT are
scarce. In the setting of major non-cardiovascular
surgery, most risk prediction models for AKI lack data
on the effect of their clinical implementation.^4 A
predictive score for AKI was developed from a large
database of routinely measured variables in a general
ward population with AKI incidence of 8·6%; internal
validation showed a sensitivity of 82% and a specificity
of 65%, but external validation has not yet been
checked.^5
AKI diagnostic classification criteria
Despite criticism,^6 the introduction of diagnostic
classification criteria for AKI has been a major step
forward. The KDIGO^7 diagnostic criteria for AKI can be
considered as a combination of the RIFLE^8 and AKIN^9
criteria. KDIGO also defined the concept of acute kidney
disease, which encompasses not only AKI, but also
conditions with persistent signs of renal damage for
more than 7 days and less than 90 days after the initial
insult, or conditions that do not fulfil the classic AKI
criteria.
Functional markers of AKI
The diagnostic classification criteria for AKI still rely on
functional markers of kidney activity such as glomerular
filtration rate (GFR) and urinary output. Currently, an
increase in serum creatinine is used as a surrogate
measure for a decrease in GFR. However, the
relationship between serum creatinine concentration
and GFR is not linear, and serum creatinine only starts
to rise when GFR has already decreased substantially.
Dilution due to fluid overload, decreased creatinine
generation due to reduced food intake, and decreased
muscle activity or sepsis can further increase the delay
in serum creatinine increase after onset of AKI.
Furthermore, the relationship between the clinical
course and the pathology of AKI is not well understood.
In a study by Chu and colleagues,^10 many patients with
histological evidence for AKI did not fulfil the clinical
criteria for AKI or acute kidney disease, mainly because
the serum creatinine increase was slower than the rate
of increase required to meet the AKI definition.
Early detection of AKI through monitoring of urinary
output is predictive of development of later AKI and is
associated with mortality.11,12^ In patients with sepsis,
oliguria flags up impending AKI before detectable
tubular injury occurs.^13 Assessment of urinary output in
6 h blocks is as effective as continuous urinary
monitoring for prediction of AKI,^11 and could be done in
general wards, where the gain of early AKI awareness
has most potential. Discriminative value of urinary
output for evolution of AKI can be enhanced by use of
the furosemide stress test, in which furosemide
(1·0 or 1·5 mg/kg) is administered intravenously as a
bolus. If the urinary output response is less than 100 mL
over the following 2 h, both the risk for progression to
Figure 1: The course of AKI over time (1) Preventive action can be taken when acute kidney injury (AKI) is discovered at an early stage, and progression to the need for renal replacement therapy (RRT; dotted blue line) can potentially be avoided (full black line). (2) During recovery from AKI, the kidneys are more susceptible to further injury, which can result in new deterioration of renal function (full black line) rather than recovery (green line). (3) Patients can recover their kidney function after starting RRT (full blue line). This recovery is often incomplete, which can result in progressive chronic kidney disease (CKD) and eventually end-stage kidney disease (ESKD; full lilac line). (4) Patients who have had a second AKI hit rarely recover their kidney function completely (full blue line), and have an increased risk of progressive CKD and evolution to ESKD over time (full lilac line). GFR=glomerular filtration rate.
Time
GFR
First hit Second hit
No Yes
Early detection and intervention
Need for RRT
(Near) complete recovery Incomplete recovery
Progressive CKD and ESKD
compared with the classic measurements, has been a
top priority. These biomarkers reflect either damage to
tubular cells (eg, N-acetyl β glucosaminidase,
glutathione S transferase, and alkaline phosphatase),
podocytes, or structural parts of the kidney (eg, F actin
and sodium–hydrogen exchanger 3); or enhanced
inflammatory crosstalk in the kidney (eg,
interleukins 18, 6, 10, and 5), upregulation of genes in
response to AKI (such as neutrophil gelatinase-
associated lipocalin [NGAL] and kidney injury
molecule-1), decreased proximal tubular reabsorption
(eg, retinol binding protein, cystatin C and β₂
microglobulin) or markers of cell cycle arrest (eg, tissue
inhibitor metalloproteinase-2 [TIMP-2] and insulin-like
growth factor binding protein-7 [IGFBF-7]). Use of
proteomics has facilitated development of panels of
biomarkers to increase diagnostic accuracy.^16
Biomarkers do not always translate usefully from the
research setting to clinical practice^17 for different
reasons. AKI is often not a single hit at a well defined
timepoint; the window of opportunity is mostly short,
and differs between biomarkers, so timing of sampling
becomes troublesome and nearly continuous sampling
might be required. None of the biomarkers are specific
for kidney disease and all biomarkers can be increased
by other underlying causes, irrespective of the presence
of kidney damage. Because it is unclear how much
damage is clinically relevant, the diagnostic threshold
for these biomarkers is unknown; improvements in
diagnostic sensitivity by use of biomarkers compared
with existing criteria might just reflect false positive
results.
Whether reported thresholds are relevant in all
conditions, irrespective of age, sex, other comorbidities,
and eventual presence of underlying chronic kidney
damage, is uncertain. Furthermore, technical issues
remain in sampling, storage, and handling of samples.
The test methods for measuring biomarkers need to be
validated and standardised, and the effect of issues such
as antibody configuration of the test clarified.
Whereas initial studies with NGAL in the well
defined setting of paediatric cardiac surgery were
promising,^18 later studies did not show an improvement
in diagnostic performance over existing criteria.19,
Outcome derivation cohort
Derivation model population
Derivation model
Sample size Events Discrimination AUC ROC
Calibration HL goodness of fit p value (Continued from previous page) Heart failure Forman et al (2004) >26·5 μmol/L sCr increase
Patients admitted to hospital with heart failure
1004 273 NR NR
Liver surgery Utsumi et al (2013) RIFLE criteria Living donor liver transplantation
200 121 NR NR
Slankamenac et al (2009) AKIN criteria Any type of liver resection
380 58 0 · 8 full model, 0 · 77 reduced model
0 · 75 for the reduced model General surgery Kheterpal et al (2009) AKI defined as an increase in sCr of >176· μmol/L from preoperative value or RRT need within 30 days of surgery
Major surgical procedures (excluding vascular, cardiac, urology, ophthalmology, paediatric, or obstetric)
57 080 561 0 · 80 (0·79–0·81) NR
Orthopaedic surgery Bell et al (2015) AKI according to KDIGO (based on sCr only)
Orthopaedic surgery 6220 672 0 · 74 (0·72–0·76) Calibration slope 1 · 0
Rhabdomyolysis McMahon et al (2013) AKI according to KDIGO (based on sCr only)
CPK >5000 IU within 72h of admission
See appendix for all available risk prediction models and studies listed. AUC ROC=area under receiver operating characteristic. HL=Hosmer-Lemeshow. AKI=acute kidney injury. RRT=renal replacement therapy. NR=not reported. STS=Society of Thoracic Surgeons. CABG=coronary artery bypass graft. CICSS=Continuous Improvement in Cardiac Surgery Study. CBP=cardiopulmonary bypass. NNECDSG=Northern New England Cardiovascular Disease Study Group. eGFR=estimated glomerular filtration rate. AKICS=acute kidney injury prediction following elective cardiac surgery. sCr=serum creatinine. CRATE=creatinine, lactic acid, cardiopulmonary bypass time, Euroscore. RIFLE=risk, injury, failure, loss of kidney function, and end-stage kidney disease. ACEF=age, creatinine, and rejection fraction. MRS=Mortality Risk Score. PCI=percutaneous coronary intervention. STEMI=ST-segment elevation myocardial infarction. AKIN=Acute Kidney Injury Network. KDIGO=Kidney Disease Improving Global Outcomes. CPK=creatine phosphokinase.
Table 1: Externally validated risk prediction models for AKI
NGAL is associated with inflammation so is not useful
in patients with sepsis.21,22^ In the Acute Kidney Injury
NGAL Evaluation of Symptomatic Heart Failure Study
(AKINESIS),^23 plasma NGAL was not superior to
serum creatinine for predicting AKI stage 2 or poor in-
hospital outcome in patients with decompensated
heart failure.
Cell cycle inhibitors appear to be an early signal of
renal injury. When cells are injured they respond by
shutting down and arresting their cell cycle to avoid cell
death and inflammation. Several large studies in
critically ill patients underlined the role of these
biomarkers for prediction of KDIGO stage 2 and 3
AKI.^24 The US Food and Drug Administration (FDA)
approved the use of [TIMP-2]*[IGFBP-7], but stressed
that the use of these markers is not a standalone test for
KDIGO stage 2 or 3 AKI and should not be used at point
of care.^25 Concerns about the usefulness of [TIMP-
2]*[IGFBP-7] for AKI prediction remain because these
markers are influenced by several other comorbidities^26
and do not outperform clinical measures.^15 Only when
biomarkers have clearly been shown to outperform a
standard clinical model and improve patient outcomes
will they be ready for implementation in clinical
practice. Only a handful of studies have incorporated
biomarkers as a clinical decision aid or risk stratification
tool and results from these studies have been
inconsistent.27–
Imaging techniques
The need for non-invasive tools to aid in (differential)
diagnosis, prediction of recovery, and unravelling of the
pathophysiology of AKI, have led to renewed interest in
ultrasound and functional MRI techniques.
Doppler resistive index (RI) has been used in different
settings for prediction of AKI as well as for identification
of prerenal azotaemia and for assessment of AKI
severity, and has shown promising results.31–33^ Changes
in renal perfusion can be assessed in different
pathological conditions by use of contrast-enhanced
ultrasonography (CEUS), which allows organ blood
quantification. This technique might allow assessment
of renal perfusion in response to different therapeutic
actions.34,
Several functional MRI techniques such as blood
oxygen level dependent (BOLD), arterial spin labelling
(ASL), and ultrasmall superparamagnetic iron oxide
particle (USPIO) MRI have also gained interest.^36 These
non-invasive techniques, which allow simultaneous
evaluation of renal morphology and renal function, are
based on the paramagnetic properties of deoxy-
haemoglobin (BOLD), magnetic labelling of water
protons (ASL), and administration of superparamagnetic
iron particles (USPIO).^36 BOLD MRI has been used in
patients with allografts to differentiate between acute
tubular necrosis and acute rejection; however, studies
have shown inconsistent results.37,38^ ASL^39 assesses renal
perfusion, USPIO^40 measures inflammation, and BOLD
MRI reflects tissue oxygen bioavailability—although it
cannot differentiate between changes in oxygen delivery
(renal blood flow), oxygen consumption (sodium
transport), and efficiency of oxygen use. BOLD MRI
works on the assumption that tissue oxygen levels are in
equilibrium with, and proportional to, blood oxygen
levels, but this premise has been questioned.^41
Furthermore, no standardised method to analyse renal
BOLD MRI data exists.^42 Doppler RI and CEUS have
several shortcomings as well.43–45^ RI measurement is
affected by numerous confounding factors such as
changes in intrarenal compliance, renal interstitial
pressure, heart rate, and intra-abdominal pressure.46,
Although CEUS can indicate substantial changes in
cortical perfusion, interobserver variability is high and
responses among patients are heterogeneous,
unpredictable, and have an unclear relationship with
patient characteristics.^47
Before these imaging techniques can be used in
clinical practice, larger studies in different settings and
patient groups, with standardisation of techniques, are
needed.
Electronic automated early warning systems
Care in AKI is often suboptimal and many opportunities
for AKI prevention are missed.^1 Although early
nephrology involvement seems beneficial,48,49^ non-
nephrologists should also be educated about AKI since
they are most likely to be the first or main health-care
professionals involved in care for patients with AKI.^50
Electronic automated early warning systems for AKI
are being developed and implemented. Such systems
require two essential steps: detection and alerting.
Detecting algorithms differ in the type of data (eg, sex,
age, and change of serum creatinine), the extent of data
sources (data collected during hospital admission or
previous data from external sources), and the decision
support rules they use. This heterogeneity results in
varying sensitivity, specificity, accuracy, and robustness.
Alerting systems can be passive (eg, a pop up in the
health record), active (a text message requiring reading
confirmation), or even interruptive (patient data cannot
be used further until action is taken). Furthermore, the
alert should be accompanied by clear instructions on
what action to take in response to the alert and
implementation of automated warning systems should
also include education and awareness campaigns.
Differences in approach for these steps might explain
why some systems work^51 and others do not;^52 an AKI
care bundle including the use of electronic alert
systems improved in-hospital mortality rates and
reduced odds for AKI deterioration,^51 whereas an
electronic alerting system used without well structured
instructions on how to follow up an alert did not
change practice and thus failed to improve patient
outcomes.^52
Optimisation of volume status
Restoration and maintenance of adequate systemic and
renal perfusion are key, and can be achieved by
administration of fluids and vasoactive drugs. However,
patients with early-stage AKI are at increased risk of
developing fluid overload because of oliguria. Fluid
overload is associated with increased mortality in
patients with AKI and does not contribute to restoration
of kidney function. Thus, a conflict exists between
adequate fluid resuscitation in hypotension and the
harmful consequences of fluid overload.^53 In any case
over zealous administration of intravenous fluids should
be avoided. Changes in fluid status can be independent,
and even occur in opposite directions, in the interstitial
space and intravascular compartment. Correct
assessment and monitoring of volume status is a major
challenge.
Early goal-directed therapy can prevent organ failure and
improve patient survival.^54 Implementation of protocolised
haemodynamic management strategies aiming to achieve
central venous pressures of 8–12 mm Hg rapidly, and more
restricted fluid loading later on, are recommended.7,55^ Three
large randomised trials56–58^ in patients with early septic
shock did not show benefit from early goal-directed therapy
versus control. However, mortality was substantially lower
in the treatment groups than in the control group in the
study by Rivers and colleagues,^54 suggesting that key
components such as rapid and adequate fluid resuscitation
and haemodynamic management have already become
standard care and led to an overall reduction in mortality.
Assessment of fluid status
Whereas oedema should be checked for in the ankles of
all patients, the thighs and buttocks should also be
assessed in those who are bedridden. Presence of
oedema does not exclude intravascular volume
depletion. Oliguria can indicate reduced renal
perfusion. The use of central venous pressure and
pulmonary artery catheters to assess volume status are
debated in critically ill patients because they do not
predict the response to a fluid challenge^59 or improve
outcome in the general intensive care unit (ICU)
population.^60 Pulse wave and pulse contour analysis
allows continuous monitoring of cardiac output and
beat-to-beat variations after administration of a fluid
bolus or during a passive leg raise test, and their use
might improve outcomes in patients undergoing high-
risk surgery.^61 In patients who are critically ill and on a
mechanical ventilator, dynamic measures such as
stroke volume variation and pulse pressure variation
can be used to identify hypovolaemia and fluid
responsiveness. Pulmonary congestion can be a sign of
genuine fluid overload in the circulating compartment
or of a failing heart. Volume depletion in the circulating
compartment can be assessed by ultrasonographic
measurement of the diameter and collapsibility of the
inferior vena cava.^62
Type of fluid to administer
Colloid solutions theoretically provide a longer duration
of plasma expansion compared with a similar volume
of crystalloid solutions. Randomised trials investigating
the use of crystalloids or colloids as the primary source
of volume resuscitation found no difference (albumin
vs crystalloid in the SAFE trial),^63 no difference in
mortality but higher need for RRT with colloids
(hydroxyethylstarch vs crystalloids in the CHEST
study),^64 or increased mortality with hydroxyethylstarch
versus Ringer’s lactate (in the 6S Trial).^65 In a meta-
analysis,^66 hydroxyethylstarch was associated with an
increase in mortality, AKI incidence, and use of RRT.
Therefore, the European Medicines Agency and the
FDA have issued warnings against the use of
hydroxyethylstarch solutions in patients who are
critically ill, and their use is now (correctly) no longer
recommended.
Excess levels of chloride in 0·9% saline solutions
might have adverse effects on acid–base homoeostasis
and renal function. In observational studies^67 a chloride-
restrictive strategy in patients who were critically ill was
associated with reduced incidence of AKI and need for
RRT, although these results were not confirmed in a
recent trial^68 in a general ICU population (including
mostly postsurgery patients). However as rather limited
amounts of fluids were applied, the recent trial might
have been false negative.
Avoidance of nephrotoxicity and further insult
AKI is often iatrogenic. Use of drugs that can contribute
to AKI, either directly or by inducing AKI through
haemodynamic factors, should be scrutinised,
especially in patients at high risk (eg, older patients,
those with volume depletion, or patients taking a
combination of non-steroidal anti-inflammatory drugs
[NSAIDs], diuretics, and renin-angiotensin-aldosterone
system [RAAS] blockers).^69 The duration and dose of
exposure should be minimised and, if appropriate,
therapeutic drug monitoring should be done (eg, in
patients given vancomycin or aminoglycosides).
Electronic alerts can increase awareness of these
dangerous combinations. Of note, even topical NSAIDs
increase the risk of AKI.^70
The argument that RAAS blockers should be stopped
in the perioperative setting or in cases of intercurrent
illness is controversial. In observational studies, an
association between continuing RAAS inhibitor
treatment preoperatively and reduced AKI incidence is
only found when the analysis is restricted to studies with
propensity matching and not in the overall patient
group.^71 The effect on AKI incidence of stopping rather
than continuing RAAS inhibitor treatment in the
perioperative period will be assessed in a systematic
review.^72 In the setting of cardiac surgery,^73 temporarily
stopping treatment with RAAS blockers prevented AKI
associated with cardiac surgery. Continuation versus
temporary suspension of treatment with RAAS
inhibitors^74 was associated with a higher incidence of
contrast-induced AKI, an effect more pronounced in
older patients and in those with pre-existing chronic
kidney disease. Stopping of RAAS inhibitor treatment
can be promoted provided the RAAS inhibition is
restarted after the intervention.^75
Intensity of glycaemic control in the perioperative
phase and in patients in the ICU has been a matter of
controversy. Early single-centre studies showed that
glycaemic control reduced mortality and incidence of
AKI, but later multicentre trials did not confirm these
findings.^76 Because long-term benefits of strict
glycaemic control are offset by the risk of hypoglycaemia,
modest glycaemic control—ie, achieving serum glucose
concentration of 8·3–10·0 mmol/L—is the preferred
strategy.
Many interventions for prevention of contrast-
induced AKI have shown inconsistent results except for
fluid loading with water and salt (table 2) and the use of
small volumes of contrast media. Whereas
hyperosmolar contrast media should be avoided, there
is insufficient evidence to prefer the use of iso-osmolar
over low-osmolar contrast media for prevention of
contrast-induced AKI.7,55^ For intravenous fluid
administration, the use of bicarbonate is not superior
to normal saline in prevention of this form of AKI.^77
Controversy remains about the appropriate schedule
for volume expansion, especially in patients with heart
failure, in whom the increased risk of AKI should be
balanced against increased risk of hypervolaemia.
Devices that aim to titrate the infusion rate to urinary
output during volume expansion report seemingly
promising results, but have often used suboptimal
control strategies.78–81^ Short, rapid volume expansion
with sodium bicarbonate before contrast-enhanced CT
was non-inferior to peri-procedural saline volume
expansion,^82 which is an important observation in view
of logistics and costs in the ambulatory setting; oral
fluids for volume expansion suffice in most patients
receiving intravenous contrast.83,84^ However, only two-
thirds of patients at risk of contrast-induced AKI are
Figure 2: Flowchart for prevention of contrast-induced (CI) AKI Several reports indicate that the risk of CI-AKI is similar in intra-arterial and intravenous contrast medium administration. eGFR=estimated glomerular filtration rate. NaCl=sodium chloride. *Use the lowest possible volume of contrast. There is no evidence for preference of low osmolar over iso-osmolar isotonic contrast medium. †Avoid contrast administration in patients with monoclonal gammapathies (relative contraindication). ‡Avoid repetitive contrast administration (<7 days after previous contrast administration). Reschedule if possible in case of recent (ie, within 72 h) use of non-steroidal anti-inflammatory drugs. There is no consensus on whether renin-angiotensin-aldosterone system blockers or diuretics should be stopped prior to contrast administration. Metformin should be stopped 48 h before the procedure and restarted 72 h after the procedure in high-risk patients. §Maximum rate of 300 mL/h before and 100 mL/h after contrast administration. Consider reducing fluid rate by half in patients with New York Heart Association class III or IV heart failure.
Administration of intravenous or intra-arterial contrast medium*
Risk stratification
Risk category
eGFR >60 mL/min per 1·73 m^2 †
Low risk of CI AKI Intermediate risk of CI AKI High risk of CI AKI
No diabetes or heart failure and eGFR 30–60 mL/min per 1·73 m 2 † OR Diabetes or heart failure and eGFR 45–60 mL/min per 1·73 m 2 †
No diabetes or heart failure and eGFR <30 mL/min per 1·73 m^2 † OR Diabetes or heart failure and eGFR <45 mL/min per 1·73 m^2 † OR Monoclonal gammapathy†
Course of action
Liberal fluid intake‡ 1 L over 12 h before contrast administration and 1 L over 12 h after contrast administration
Per oral volume expansion schedule‡ 1 g NaCI + 150 mL of H 2 O every hour from 2 h before until 6 h after contrast administration
Intravenous volume expansion with isotonic saline or sodium bicarbonate‡
- Isotonic saline: 1 L NaCI 0·9% over 12 h before and after contrast administration OR
- Sodium bicarbonate: 1 L glucose 5% + 150 mmol/L bicarbonate 8·4%/L, 3 mL/kg per h over 1 h before and 1 mL/kg per h during 6 h after contrast administration§
approach, it might be better to use the terminology
immediate start versus delayed start of RRT to indicate
the relation of the timing of RRT with the moment a
certain criterion has been met, rather than the
terminology early versus late. In a meta-analysis no
benefit of immediate start of RRT was observed when
randomised trials were included, whereas observational
cohort studies showed a 28% risk reduction in mortality,
with a high risk for publication bias.^109 Two recent large
trials presented conflicting results. The single centre
ELAIN study,^30 which assessed patients in ICU with AKI
stage 2 and with either severe sepsis or refractory fluid
overload, showed that immediate initiation of RRT
reduced 90-day mortality compared with delayed start of
RRT (44 of 112 patients in the immediate RRT initiation
group vs 65 of 119 patients in the delayed RRT initiation
group, hazard ratio 0·66, 95% CI 0·45–0·97). The
immediate group started RRT (100%) within 8 h of
inclusion, whereas the delayed group started within 12 h
of reaching AKI stage 3 (91%); only 9% of patients in this
group did not start RRT—so in reality, this protocol
tested the effect of delaying RRT in a patient group with
a clear indication for renal replacement. The multicentre
Artificial Kidney Initiation in Kidney Injury study
(AKIKI)^110 included patients in ICU who were critically ill
needing pressors or invasive ventilation with AKI stage 3,
but excluded patients who had a hard indication for RRT
at eligibility screening. In the early initiation group RRT
was started immediately after inclusion, whereas in the
late initiation group start of RRT was delayed until one of
the well defined hard criteria for starting RRT was met.
In effect, this study compared start of RRT based on
KDIGO stage 3 AKI criteria versus start of RRT based on
existing hard indications. In this setting, no advantage
for immediate start compared with delayed start of RRT
was observed (mortality at 60 days was 150 of 311 patients
vs 153 of 308 patients). In the delayed start group, 49% of
patients did not start RRT at all, and recovery of residual
diuresis was faster, and the occurrence of line infection
was lower than in patients in the immediate start group
(5% vs 10% of patients). This finding indicates that a too
precocious start of RRT is not helpful, and might
contribute further damage to an already injured kidney.
Given the vast heterogeneity of underlying clinical
scenarios and complications that patients with AKI have,
doubts remain about whether this clinical dilemma can
eventually be solved by decisive randomised trials.
Instead, a practical way to improve clinical care might lie
in the development of algorithms that provide a
framework of specific recommendations to assist
clinicians in their individual decision making.^111
CKD after AKI
Many patients who develop AKI will not have any follow-
up of their kidney function, although the risks of
recurrent AKI are well known.^112 Over the past decade,
evidence has accumulated suggesting that severe AKI
predisposes patients to faster progression of CKD later
on—especially if they have had multiple hits of AKI
or have pre-existing CKD (figure 1).^112 Therefore, it is
important that patients are actively involved in the
preservation of their kidney health and postdischarge
follow-up of kidney function is organised.
Contributors All authors contributed to writing the manuscript, discussing its content, and designing the tables and figures. JV performed the search strategies and the data extraction for tables 1 and 2. All authors have read and approved the final submitted version.
Declaration of interests JK received research grants and speaker fees from Fresenius Medical Care and Asahi Corporation. AJ received speaker fees and travel grants from Fresenius Medical Care and Gambro. WVB has received research grants, speaker fees and travel grants from Baxter, Fresenius Medical Care, Gambro, Leo Pharma, and Astellas. JV declares no competing interests.
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