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Acute Kidney Injury Prediction and Prevention: A Review of Studies and Interventions, Apuntes de Medicina

An overview of various studies on acute kidney injury (aki) prediction and prevention. It discusses the limitations of existing risk prediction models, diagnostic criteria, and the role of urinary biomarkers. The document also explores different interventions, such as furosemide stress test, urinary biomarkers, and various medications, to prevent aki. Each study is presented with details such as sample size, events, discrimination auc, and calibration hl.

Tipo: Apuntes

2018/2019

Subido el 10/12/2019

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Series
www.thelancet.com Vol 389 May 27, 2017
2139
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: 2139–51
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Onlineforappendix
pf3
pf4
pf5
pf8
pf9
pfa
pfd

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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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