REVIEWS

Global epidemiology and outcomes

of acute kidney injury
Eric A. J. Hoste   1*, John A. Kellum2, Nicholas M. Selby   3, Alexander Zarbock4,
Paul M. Palevsky   5, Sean M. Bagshaw6, Stuart L. Goldstein7, Jorge Cerdá8 and
Lakhmir S. Chawla9
Abstract | Acute kidney injury (AKI) is a commonly encountered syndrome associated with
various aetiologies and pathophysiological processes leading to decreased kidney function.
In addition to retention of waste products, impaired electrolyte homeostasis and altered drug
concentrations, AKI induces a generalized inflammatory response that affects distant organs.
Full recovery of kidney function is uncommon, which leaves these patients at risk of long-​term
morbidity and death. Estimates of AKI prevalence range from <1% to 66%. These variations can
be explained by not only population differences but also inconsistent use of standardized AKI
classification criteria. The aetiology and incidence of AKI also differ between high-​income and
low-​to-middle-​income countries. High-​income countries show a lower incidence of AKI than do
low-​to-middle-​income countries, where contaminated water and endemic diseases such as
malaria contribute to a high burden of AKI. Outcomes of AKI are similar to or more severe than
those of patients in high-​income countries. In all resource settings, suboptimal early recognition
and care of patients with AKI impede their recovery and lead to high mortality , which highlights
unmet needs for improved detection and diagnosis of AKI and for efforts to improve care for
these patients.

*e-​mail: eric.hoste@ugent.be
https://doi.org/10.1038/
s41581-018-0052-0
Acute kidney injury (AKI) is a syndrome (or more
accurately a group of syndromes)1 defined by an abrupt
decrease in glomerular filtration. AKI is a common
condition in all countries of the world, regardless of
economic status. The syndrome is associated with
considerable morbidity, mortality and high costs.
As an episode of AKI can lead to the development of
chronic kidney disease (CKD) or end-​stage renal dis-
ease (ESRD), and the incidence of AKI is increasing, the
impact of AKI on long-​term health and cost is far greater
than formerly acknowledged2,3.
Importantly, an episode of AKI is not only associated
with short-​term adverse outcomes, such as fluid over-
load, electrolyte or acid–base derangement, immune
dysfunction and bleeding complications, but also has
a long-​term adverse effect on survival. Even mild AKI
(Kidney Disease: Improving Global Outcomes (KDIGO)
stage 1) is associated with a reduction in survival, which
remains detectable for 10 years or more4. Some of the
adverse consequences of AKI are certainly related to
non-​recovery of kidney function. An analysis of recovery
patterns after AKI showed that 41.2% of patients with
AKI did not recover their renal function before hospital
discharge. In these patients, 1-year age-​adjusted mortal-
ity was nearly 60%, which is more than three times that
in patients who did recover fully. Furthermore, 1-year
mortality was lowest (10%) in the group of patients
(26.6% of the cohort) whose AKI reversed within 7 days
and remained stable until discharge5. The continuation
of pathogenic processes and adverse events following an
episode of AKI led to the introduction of the term acute
kidney disease (AKD) to describe an AKI episode that
persists beyond 7 days (up to 90 days) after the start of
the initial AKI episode6 (Fig. 1). Although nephrologists
increasingly appreciate the adverse consequences of AKI
and its sequelae for long-​term health, efforts to improve
the prevention and early treatment of AKI require an
understanding of the epidemiology and aetiology of AKI
and of how these vary in different populations.
In this Review, we provide an overview of the global
epidemiology of AKI and discuss the underlying reasons
for variation in the incidence and outcomes of this dis-
ease in different regions of the world. Throughout this
article, countries’ economies are categorized according
to the World Bank’s classification scheme, which is based
on gross national income per capita: low-to-middle-​
income countries (LMICs) include the low (<US$1,005)
and lower-​middle (US$1,006–3,955) ranges, whereas
high-​income countries includes the upper-middle
(US$3,956–12,235) and high (>US$12,236) ranges7.

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Reviews
Key points
• Acute kidney injury (AKI) is a syndrome encompassing a wide variety of aetiologies
and pathophysiologic processes leading to decreased kidney function.
• The Kidney Disease: Improving Global Outcomes classification stages AKI into three
levels of severity on the basis of increases in serum creatinine level, decreased urine
output or need for renal replacement therapies.
• In high-​resource settings, AKI occurs in one in five hospitalized adult patients, which
is approximately half of adult patients receiving intensive care, and in one in four
paediatric patients receiving intensive care.
• Each episode of AKI is associated with considerable mortality and long-​term adverse
outcomes, including cardiovascular complications, chronic kidney disease and
end-stage renal disease.
• In low-​resource settings, AKI is often caused by environmental factors such as
contaminated water and endemic infections; public health interventions are essential
to decrease its incidence and complications.
• In low-​resource settings, AKI recognition, diagnosis and treatment initiation are often
delayed or inadequate, leading to avoidable increases in mortality, severe
complications and cost.
Definitions and diagnosis
Loss of kidney function is classically defined by increases
in serum creatinine level; however, in community
settings and circumstances in which a patient’s volume
status is closely monitored — for example, in the inten-
sive care unit (ICU) — oliguria or anuria might be the
only recognizable sign of AKI8. Accordingly, in the
KDIGO guideline, AKI severity is classified into three
stages on the basis of either the increase in serum cre-
atinine level or the duration and extent of oliguria9–11
(Table 1). However, as noted in the KDIGO guideline,
these criteria inform but are not a substitute for clinical
judgement. Additional tests, such as examinations of uri-
nary sediment, blood tests and kidney ultrasonography
can be used to determine the cause of AKI.
AKI can be challenging to diagnose, as clinical signs
might be unobserved or absent entirely. A checklist that
includes the clinical context, alternative diagnoses, con-
firmatory data such as urine sediment and the pattern
of changes in serum creatinine levels can be helpful12.
The clinical context is especially important because AKI
does not cause pain. Patients with increased susceptibil-
ity to AKI (those aged >65 years and those with diabe-
tes mellitus, CKD, heart failure or anaemia) and those
who have been exposed to predisposing factors (such
as sepsis, major surgery or nephrotoxins) have a greatly
Author addresses
1
Intensive Care Unit, Ghent University Hospital, Ghent University, Ghent, Belgium.
2
Center for Critical Care Nephrology, Pittsburgh, PA, USA.
3
Centre for Kidney Research and Innovation, Division of Medical Sciences and Graduate
Entry Medicine, School of Medicine, University of Nottingham, Royal Derby Hospital
Campus, Nottingham, UK.
4
University of Münster, Department of Anesthesiology, Intensive Care and Pain Medicine,
Münster, Germany.
5
VA Pittsburgh Healthcare System, University of Pittsburgh, Pittsburgh, PA, USA.
6
Department of Critical Care Medicine, Faculty of Medicine and Dentistry, University of
Alberta, Edmonton, Alberta, Canada.
7
Division of Nephrology and Hypertension, The Heart Institute, Cincinnati Children’s
Hospital Medical Center, Cincinnati, OH, USA.
8
Division of Nephrology and Hypertension, Albany Medical College, Albany, NY, USA.
9
VA Medical Center, Department of Medicine, Washington, DC, USA.
© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
increased risk of developing AKI. In some patients,
high levels of urinary biomarkers, such as neutrophil
gelatinase-​associated lipocalin (NGAL), tissue inhibi-
tor of metalloproteinases 2 (TIMP2), insulin-​like growth
factor-​binding protein 7 (IGFBP7) and chitinase 3-like
protein 1, indicate renal impairment in the absence of
any other evidence of AKI13–15. Whether such findings
indicate nonspecific biomarker elevation (that is, a false
positive result) or subclinical AKI is not known. We do
know, however, that raised serum creatinine levels are an
insensitive marker of kidney dysfunction, particularly
in patients without underlying CKD, because a normal
kidney has considerable excess filtration capacity (renal
reserve)16. Even a large loss of renal mass might not sub-
stantially increase serum creatinine levels. For example,
healthy kidney donors (who lose half their renal tissue,
by definition) might demonstrate only a minimal change
in serum creatinine concentration. An interesting con-
sequence is that increased levels of biomarkers such as
TIMP2 and IGFBP7 in a patient with an underlying kid-
ney disease that compromises renal reserve are strongly
predictive of concurrent AKI17. The reason is that a
biomarker-​detected episode of AKI will often be followed
by an increase in serum creatinine concentration in a
patient with an underlying kidney disease, whereas in
a healthy individual, such episodes often remain sub-
clinical — that is, without an accompanying detectable
increase in serum creatinine concentration. Essentially,
subclinical AKI exists because our current clinical tools
to recognize AKI are limited.
These challenges in AKI diagnosis and the lack of a
‘gold standard’ for its identification mean that estimates
of AKI incidence are likely to be flawed. In some series,
AKI incidence might be overestimated because unrec-
ognized CKD has been labelled AKI. In most studies,
however, AKI rates are probably underestimated owing
to the inclusion of patients with subclinical disease or the
failure to recognize patients with detectable but subtle
clinical features.
AKI in high-​income countries
In high-​income countries, the typical patient with AKI
is aged ≥65 years and has comorbidities such as CKD,
diabetes mellitus or cardiovascular disease. After a hos-
pital admission for that disease or a related procedure,
such individuals develop AKI as a complication of either
the disease or the procedure used to diagnose or treat it
(such as radiocontrast administration for a computed
tomography (CT) scan or coronary angiography, use of
nephrotoxic antibiotics or major surgery). Critically ill
young adults and children treated in the ICU are also at
risk of developing AKI (Table 2).
Hospitalized patients
Epidemiology and risk factors. The widespread adop-
tion of standardized criteria to define the presence and
severity of AKI has facilitated comparisons of the epide-
miology and outcomes of AKI across hospital settings18.
However, this standardization should not imply that AKI
is a single entity. Rather, AKI is a syndrome that encom­
passes a multitude of clinical scenarios, underlying aetio­
logies, comorbidities, drug exposures and severities of
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Fig. 1 | The spectrum of kidney disease. Acute kidney injury (AKI) stages map directly to
the new proposed acute kidney disease (AKD) stages. In addition, patients with AKD
might progress to chronic kidney disease (CKD). Stage 0 AKD represents partial recovery
from AKI. Stage 0C includes patients for whom serum creatinine (SCr) levels are higher
than baseline but within 1.5 times baseline levels. Stage 0B includes patients whose SCr
has returned to baseline levels but who still have evidence of ongoing kidney damage,
injury or loss of renal reserve. Stage 0A includes patients who have had an episode of AKI
and retain a risk of long-​term events without structural or damage markers for AKD.
Patients whose SCr levels have not returned to baseline and who have ongoing evidence
of kidney damage and/or injury are termed stage 0B/C. KDIGO, Kidney Disease:
Improving Global Outcomes; RRT, renal replacement therapy. Figure reproduced from
ref.6, Springer Nature Limited, CC BY 4.0.
renal dysfunction. AKI also involves several different
pathophysiological processes; in experimental models,
gene expression in the kidney in response to intrinsic
renal tubular injury differs from that seen in homeo-
static responses to volume contraction, even when each
mechanism results in similar changes in serum creati-
nine concentration19. These factors are important to
consider when evaluating studies describing the epide-
miology of AKI in hospitalized patients (or indeed, in
any group of patients), especially given that most epi-
demiologic studies use serum creatinine criteria alone
to define AKI and generally do not report the aetiology
of AKI or the characteristics of the hospitals studied20
(Box 1). We should not be surprised, therefore, that the
reported incidence of AKI among hospitalized patients
shows some variation. For example, two multicentre
studies from China, which were both conducted using
data from the same year (2013) and employing KDIGO
criteria, reported notably different proportions of hospi-
talized patients who sustained AKI: 3.02%21 and 11.6%22.
Several possibilities might underlie this disparity; for
example, differing applications of the AKI diagnostic cri-
teria could influence sensitivity (in one study, inclusion
was based on a mix of biochemical and coded diagnoses,
whereas in the other, inclusion was based on biochemi-
cal screening with nephrologist adjudication of the diag-
nosis). Differences in case mix could also influence the
findings (one study included patients in main regional
hospitals only, whereas the other included patients in
both academic centres and smaller rural hospitals).
Some between-​study differences in AKI epidemiology
might also result from variation in the way that relevant
terms (such as baseline creatinine)23 are defined, as well
as in the use of Risk, Injury, Failure, Loss, and End-​Stage
Kidney Disease (RIFLE), Acute Kidney Injury Network
(AKIN) or KDIGO criteria24. Across all studies that
used current criteria to define AKI, the proportion of
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hospitalized adult patients who developed AKI ranged
from 3.0% to 18.3%20. Yet, even for values at the low end
of this range, it is abundantly clear that AKI affects a
and that in most health-​care systems the majority of
these patients are cared for outside specialist clinics.
Only a minority (<5%) of patients with AKI require
renal replacement therapy (RRT)25.
Hospitalized patients often have a high frequency
of risk factors for AKI, for example, older age, male
sex and comorbidities such as diabetes, heart failure
and hypoalbuminaemia26–30. Older age also correlates
positively and directly with the number of AKI risk
factors26–30. Pre-​existing CKD and/or proteinuria seem
to be particularly strong risk factors26. Use of combina-
tions of nephrotoxic medications can also increase the
risk of AKI: for example, nonsteroidal anti-​inflammatory
drugs (NSAIDs) combined with angiotensin-​converting
enzyme inhibitors and diuretics31 or even proton pump
inhibitors32. However, as with all cohort studies, a degree
of caution should be exercised in interpreting these
associations owing to a potential risk of confounding
by indication (as patients at an increased risk of AKI
also have an increased likelihood of being prescribed
these medications). Finally, particular situations also
contribute to an increased risk of AKI, including sepsis,
hypotension, hypovolaemia and exposure to iodinated
contrast media33. This long list of risk factors for AKI in
the gene­ral ward presents a challenge for clinicians
in gauging the level of risk of an individual patient. Risk
scores that could be used at the bedside and prediction
tools involving complex computational models based on
machine learning are being developed34,35. However, their
present use is limited, as most have only moderate
discrimination, and none has been externally validated.
Of course, the ultimate goal is to prevent AKI.
Although effective quality improvement practices have
been developed for specific settings, including a com-
plex intervention to reduce the use of contrast-​induced
AKI in non-​emergency coronary angiography36 and a
pharmacy-​led screening and decision support process
for use in paediatric populations on high-​risk medica-
tions37, no strategies are proven to prevent AKI in gene­
ral populations of hospitalized adults. As two-thirds
of AKI episodes are already present at the time of hos-
pital admission, AKI prevention must also consider
pre-hospital factors25.
Outcomes. AKI is associated with poor outcomes; even
in non-​ICU hospitalized patients with AKI, mortality is
typically 10–20%25,38,39. A strong and graded relationship
between AKI severity and increased mortality is also
clearly evident39. The inclusion of numerically small
increases in serum creatinine levels in current diag-
nostic criteria reflects the strong association of these
changes with adverse outcomes, which persists even after
adjustment for important confounders such as age and
comorbidity38,40. Both the presence and severity of AKI
are associated with increased durations of hospital stay,
increased rates of unplanned critical care admissions,
requirement for RRT (although <10% of patients in this
setting receive RRT) and an increased risk of subsequent
Reviews

Table 1 | Diagnosis and staging of AKI Economic impact. Several studies have estimated
the economic impact of AKI in hospitalized patients.
Stagea Serum creatinine level Urine output In a United States analysis that compared the costs of
Diagnosis • Increase of ≥0.3 mg/dl (26.5 µmol/l) • <0.5 ml/kg/h for 6 h hospital admission in patients with and without AKI,
within 48 h, or which was adjusted to account for costs attributable
• Increase of ≥1.5-fold above baseline,
known or assumed to have occurred
to excess comorbidity, AKI was associated with an
within 7 days increase in costs of US$1,795 per admission (95% CI
$1,692–1,899)53. In the minority (<5%) of patients who
1 • ≥1.5–1.9 times baseline, or • <0.5 ml/kg/h for 6–12 h
• >0.3 mg/dl (26.5 µmol/l) increase required dialysis, AKI was associated with a cost increase
from baseline of $42,077 (ref.53). Interestingly, the unadjusted addi-
tional costs of AKI were similar to those in a previous
2 • ≥2.0–2.9 times baseline • <0.5 ml/kg/h for ≥12 h
United States analysis from >10 years ago40. Both studies
3 • ≥3.0 times baseline, or • <0.3 ml/kg/h for ≥24 h or used diagnostic coding to identify patients with AKI,
• Increase of serum creatinine to ≥4.0 mg/dl • Anuria for ≥12 h
(353.6 µmol/l), or which could have skewed the cohorts towards severe
• RRT or presentations of AKI. In another study that used a
• In patients aged <18 years, a decrease similar approach, the additional costs associated with
in eGFR to <35 ml/min/1.73 m2 AKI were US$7,100 per admission24. In an economic
eGFR , estimated glomerular filtration rate; RRT, renal replacement therapy. aIn the Kidney analysis of health-​care costs attributable to AKI in
Disease: Improving Global Outcomes (KDIGO) classification, diagnosis of acute kidney injury England, the incidence of AKI was extrapolated from
(AKI) requires either an increase in serum creatinine level or an episode of oliguria; AKI
severity is staged by the worst of either serum creatinine changes or oliguria. a single centre to derive national rates and combined
with national reimbursement tariffs and estimated
CKD. Indeed, in one study, CKD occurred in 24.6% of a increases in length of stay54. All costs associated with
general hospitalized population after 3 years of follow-​ AKI (including those from critical care) were combined
up41,42. In 9–23% of hospitalized patients AKI progresses, to generate an estimated annual inpatient expenditure
and this group has an increased chance of adverse out- of £1.02 billion, most of which (an estimated £750 mil-
comes43,44. Despite the high mortality observed in hos- lion) was attributed to an increased duration of stay in
pitalized patients with AKI, reported causes of death non-critical care. An additional estimated £179 million
reflect coexisting conditions rather than kidney injury45. was related to long-​term costs of AKI after discharge54. A
This finding suggests that further descriptions of the epi- different approach was adopted in another study, which
demiology of AKI in discrete clinical cohorts would be isolated the treatment costs attributed to the portion of
valuable and would build on current data showing that a patient’s stay in which an episode of AKI occurred55.
mortality from AKI differs in different settings: exacerba- Attributed costs ranged from £3,205 to £4,287 depend-
tions of bronchiectasis owing to infection (33%)46, heart ing on AKI stage, with the highest costs associated with
failure (11–13%)47, urological conditions (7.8%)48, liver AKI stage 3 (ref.55).
disease (36%)49 and pneumonia (36.2%)50,51. In summary, AKI in hospitalized patients involves
In some populations of hospitalized patients, the a spectrum of differing aetiologies, severity of kidney
association between AKI stage and mortality is attenu­ injury and clinical scenarios, but its presence almost
ated. Patients with very low baseline serum creatinine universally increases resource utilization and the risk
values can show percentage changes in creatinine levels of adverse outcomes. Along with the large number of
that meet AKI criteria and might represent either a true patients affected, these circumstances make a strong case
change in excretory function or biological or laboratory for improved prevention, recognition and treatment of
variation. In one study, 80% of patients with a baseline AKI in the general hospital population.
creatinine level <0.6 mg/dl (53 µmol/l) who met the
KDIGO criteria for AKI had a percentage increase in Critically ill patients
serum creatinine level that was less than the 0.3 mg/dl Epidemiology and risk factors. In the majority of criti-
(26.5 µmol/l) absolute increase24. Moreover, in this cally ill patients, AKI is a complication of severe illness.
study, mortality in patients with a baseline creatinine In only a small minority of patients is AKI caused by
level <0.4 mg/dl (35.4 µmol/l) was the same regardless a specific kidney disease such as vasculitis, glomerulo­
of whether or not they had AKI24.Treatment is another nephritis or interstitial nephritis (Box 1). AKI as defined
confounding variable. Serum creatinine levels might fall by the sensitive RIFLE, AKIN or KDIGO criteria9–11
soon after admission owing to fluid resuscitation only to occurs in one-​third to two-​thirds of patients in the
increase back to baseline later on. Such an increase that ICU56–58. These variations in the incidence of AKI in crit-
crosses the threshold of 0.3 mg/dl (26.5 µmol/l) within ically ill patients can (as for their counterparts in general
48 h technically meets the KDIGO criteria. Pre-​existing wards) be explained by differences in baseline charac-
CKD also affects the performance of AKI criteria. The teristics of the cohort studied, the length of the observa-
combination of AKI and CKD increases the absolute risk tion period and in the way that definitions of AKI (such
of adverse outcomes, but the effect of AKI on in-​hospital as use of serum creatinine criteria only) were applied57,59
mortality is strongest in patients with a baseline estimated (Table 2). RRT was used in approximately 10–15% of
glomerular filtration rate (eGFR) >60 ml/min/1.73 m2. critically ill patients with AKI in the large multicentre
In other words, differences in mortality between FINNAKI and AKI-EPI studies56,58. Both the incidence
lower and higher AKI stages are attenuated in patients of AKI and the use of RRT in ICU patients are increas-
with CKD52. ing over time. Analyses of administrative databases

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Table 2 | epidemiology and outcomes of AKI across cohorts
population Age
Non-​ICU hospitalized patients Adult
Critically ill patients Adult
Paediatric
Patients undergoing cardiac Adult
surgery
Paediatric
Patients with sepsis Adult
ICU, intensive care unit; NR , not reported; RRT, renal replacement therapy.
that used International Statistical Classification of
Diseases and Related Health Problems coding showed
a marked increase in the incidence of AKI60–62. In the
United Kingdom, the use of RRT in patients with AKI
increased from 15.9 per million patients in 1998–1999 to
208.7 per million patients in 2012–2013 (ref.63). Simi­
larly, RRT use increased fourfold between 1996 and
2010 in Canada64. These increases in the incidence of
AKI and in the use of RRT can be explained by changes
in the spectrum of patients treated in ICUs. Today’s
ICU patients are older and have more comorbidities
(such as diabetes, hypertension and CKD) than ICU
patients in the past65. Changes in attitudes towards ini-
tiation of RRT and improved medical record-keeping
in administrative databases have also contributed to
this observation.
Outcomes. AKI in critically ill patients is, in the major-
ity of individuals, a complication of severe illness,
trauma or major surgery. The condition leading to AKI
is, therefore, an important determinant of the patient’s
outcome, although whether AKI itself also contributes
to outcome is difficult to evaluate. Multiple large studies
that used multivariate analysis to evaluate the contri-
bution of AKI to patient outcomes in different settings
found that after correction for potential confounders,
AKI was independently associated with increasing
morbidity and mortality. Specifically, in the AKI-​EPI
study, moderate and severe (stages 2 and 3) AKI were
associated with increased in-​hospital mortality (AKI
stage 2 adjusted OR 2.9 and AKI stage 3 adjusted OR
6.9)58. AKI has the least adverse effect on outcomes in
the most severely ill patients66. Advanced age not only
incurs an increased risk of developing AKI but also
strongly and adversely influences outcomes, by increas-
ing both mortality and the incidence of ESRD67–69. The
exact mechanisms underpinning how AKI leads to
worse outcomes in critically ill patients are less well
established. Apart from the direct consequences of
decreased kidney function, such as volume overload
and electrolyte and acid–base abnormalities, AKI
could also lead to functional impairment of virtually
all other organ systems by inducing an inflammatory
response70.
Patients with AKI who receive RRT are among
the most severely ill individuals in the ICU. Despite
advances in treatment, mortality for this group has
remained more or less constant over time at ~50%71.
This observation can be explained by the increasing
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Incidence (range) rrT requirement (%) Mortality (%)
<1 in 5 patients <10 10–20
1 in 3 to 2 in 3 patients 5–11 NR
1 in 4 patients (10–82%) 1–2 11
1 in 5 patients (2–50%) <5 10
1 in 3 to 1 in 2 patients NR 6
1 in 20 to 1 in 2 patients 15 30–60
severity of the underlying diseases and comorbid-
ities over time. Although patients with severe AKI
and anuria will inevitably die without RRT, the exact
effects of several aspects of RRT — specifically, the
choice of modality and timing of treatment — on
outcomes remain unclear72. RRT modalities used in
patients with AKI in the ICU setting might be simi­lar
to those used in patients with CKD (namely, short-
duration RRT, lasting <4 h), but continuous RRT or
intermediate-​duration RRT (lasting 6–12 h daily;
termed hybrid therapy) are also used. Randomized
studies could not demonstrate a benefit on relevant
outcomes of one modality over the other11,73. However,
intermittent therapies can be haemodynamically more
challenging for the patient, especially when large vol-
umes of fluid need to be removed within a short time
frame. On the other hand, continuous RRT can inter-
fere with mobilization of the patient and with diag-
nostic or therapeutic procedures (such as CT scans or
surgery) that need to be performed outside the ICU.
All RRT modalities present a challenge for the correct
dosing of antibiotic therapy. Several large studies sug-
gest that continuous RRT is associated with improved
renal recovery; however, these findings are based on
observational data and might be subject to bias74. Other
studies suggest that early initiation of RRT is associ-
ated with improved outcomes 75–77. The small pilot
STARRT-​AKI study75 (in 101 patients) and the larger
AKIKI study76 (in 620 patients) could not show a bene­
fit for initiation of RRT soon after onset of AKI stage 3
compared with a ‘wait and see’ approach in a general
population of patients in the ICU. Importantly, these
two studies excluded patients with urgent indications
for RRT, such as uraemia, acidosis or fluid overload. By
contrast, the ELAIN study77 of 231 patients admitted
to a single ICU after surgery showed a reduction in
mortality when RRT was initiated at AKI stage 2 rather
than waiting until onset of AKI stage 3. However, the
limited number of patients included in these three
studies and the hetero­geneity in their design, the defi-
nition of early initiation used and patient populations
included preclude firm conclusions from being drawn
on the optimal timing of initiation of RRT in patients
with AKI.
At least two additional multicentre studies are ongo-
ing and are expected to contribute to this topic. The
IDEAL-​ICU study78 in 500 patients with septic shock
has finished recruiting, and results are expected shortly.
The definitive STARRT-​AKI study79 in 2,866 general
Reviews
Box 1 | epidemiological variability in AKI
Several variables explain the disparate findings of epidemiological studies of acute
kidney injury (AKI).
patient-​related factors
• Baseline characteristics: age, sex and ethnicity
• Comorbid conditions: diabetes mellitus, cardiovascular disease and chronic use of contrast media, major surgery and nephrotox-
kidney disease
• Chronic exposure to medication: nonsteroidal anti-​inflammatory drugs,
angiotensin-converting enzyme inhibitors and diuretics
Factors associated with acute disease
• Type and severity of underlying conditions leading to AKI: septic shock and
cardiogenic shock
• Exposure to nephrotoxic drugs and substances: aminoglycosides, diuretics and
parenterally administered iodinated radiocontrast media
• Associated organ dysfunction
Factors associated with diagnostic criteria usage
• Use of variants of the Kidney Disease: Improving Global Outcomes (KDIGO)
consensus definition of AKI (namely, Risk, Injury, Failure, Loss, and End-​Stage Kidney
Disease (RIFLE) or Acute Kidney Injury Network (AKIN))
• Use of serum creatinine criteria only
• Use of variant urine output criteria
• Baseline serum creatinine absent and/or incorrectly used
ICU patients is currently recruiting and is expected to
be completed in 2019.
Sepsis
Sepsis was redefined in 2016 as “a life-​threatening organ
dysfunction caused by a dysregulated host response to
infection”80. Although sepsis is a major public health issue
and a leading cause of morbidity and mortality world-
wide, few studies to date have utilized this new definition.
Sepsis and AKI both remain hampered by imperfect con-
sensus definitions11,80. The concurrent manifestation of
sepsis and AKI is termed septic AKI11,80,81.
As in other situations, the diagnosis of AKI in patients
with sepsis relies predominantly on relative changes in
serum creatinine level and urine output. Conventional
diagnostic tests of urine biochemistry and microscopy
have shown questionable value for discriminating septic
from non-​septic AKI82,83. Selected novel biomarkers of
kidney damage, such as plasma or urine levels of NGAL
and a biomarker panel including urine levels of TIMP2 and
IGFBP7, have shown promise for the prediction of AKI
in at-​risk patients with sepsis84,85. Studies in a pig model of
sepsis have shown that different kidney gene expression
profiles are associated with septic AKI and with sepsis
that is not complicated by AKI86. The septic AKI gene
expression profile showed increased upregulation of
several genes related to inflammation, metabolism and
apoptosis, including TLR4 (encoding Toll-​like receptor 4),
PTGS2 (encoding prostaglandin G/H synthase 2, also
known as cyclooxygenase 2), AGTR2 (encoding type 2
angiotensin II receptor), CASP3 (encoding caspase 3)
and PPARG (encoding peroxisome proliferator-​activated
receptor-​γ), compared with the profile associated with
AKI without sepsis86. These observations could lead to
further insights into disease susceptibility patterns and
protective biologi­cal mechanisms and the identification
of potential intervention targets87.
© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
Epidemiology and risk factors. In epidemiological stud-
ies, sepsis is consistently identified as the most common
contributor to AKI in critically ill patients; ~50% of
all patients with AKI in ICU settings have sepsis58,88,89.
Patients with sepsis are also exposed to numerous addi-
tional potential renal insults, including hypotension,
ins, which can confound their prognosis as well as our
understanding of the aetiology of their AKI.
The risk of AKI rises incrementally with worsening
sepsis severity90–92. In a single-​centre cohort of 315 crit-
ically ill patients, the incidence of AKI increased from
4.2% in patients with sepsis to 22.7% in patients with
severe sepsis and 52.8% in patients with septic shock92.
Both patients with septic shock and those with AKI
were likely to experience delays before receiving effec-
tive antimicrobial therapy, and each successive 1 h delay
was associated with a 14% increase in the likelihood of
developing AKI93.
Risk factors for AKI in patients with sepsis include
advanced age, increased acuity of illness and a high bur-
den of comorbidities, specifically CKD, diabetes melli-
tus, heart failure, cancer and liver disease90,93–96. Specific
sources of sepsis — particularly bloodstream infection,
infective endocarditis and abdominal or genitouri-
nary sources — are also associated with increased risk
of AKI90,93,95,96.
Outcomes. Patients with septic AKI generally have a
higher disease acuity and burden of organ dysfunction
than patients who have non-​septic AKI95. Septic AKI is
also associated with increased aberrations in inflam-
matory markers and biochemical profiles, and these
patients are more likely to receive mechanical venti-
lation, haemodynamic support with vasoactive ther-
apy and large fluid volumes for resuscitation58,93–95,97.
Notably, two randomized trials failed to show any
reduction in the incidence of AKI associated with
vasopressin98 or any improvement in kidney function
with levosimendan99, which suggests that these treat-
ments are of no benefit for preventing AKI in patients
with sepsis. In a prospective pilot study, a conserva-
tive fluid management strategy was associated with
a reduction in the proportion of patients who expe-
rienced worsening of AKI compared with standard
resuscitation (37% versus 54%; P = 0.03) in patients
with septic shock100. Similarly, protocol-​based resus-
citation (which delivered more fluid than standard
resuscitation) was not associated with either a reduc-
tion in the incidence of AKI or an improvement in
recovery in patients with septic shock101. These find-
ings suggest that fluid overload, which can be caused
by current standard resuscitation strategies, plays an
important part in the pathogenesis of AKI102. These
preliminary findings from underpowered and retro­
s­pective studies need to be explored further in large
prospective studies.
AKI also increases the short-​term and long-​term
risk of incident sepsis103,104. In a secondary analysis
of data from 618 critically ill patients with AKI, 40% of
patients developed sepsis, which occurred a median of
5 days after AKI onset104. Moreover, mortality and rates
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of RRT utilization were significantly increased in the
patients who developed sepsis after onset of AKI. In a
population-​based cohort study, the risk of severe sepsis
following hospitalization for severe AKI treated with
RRT was examined in patients who survived for 90 days
after hospital discharge compared with control patients
without AKI who were matched for age, sex and concur-
rent diabetes103. The adjusted relative risk of developing
severe sepsis requiring re­admission to the hospital was
approximately twofold higher in patients who had severe
AKI than in those without AKI103.
The prognostic implications of septic AKI might
differ from those of other AKI aetiologies. In a secon­
dary analysis of data from the BEST Kidney Study95,
in-​hospital mortality was significantly higher for sep-
tic AKI than for non-​septic AKI (70.2% versus 51.8%).
After adjustment for potential confounders, septic AKI
remained associated with a significantly increased
risk of death (OR 1.48, 95% CI 1.17–1.89; P = 0.001)95.
Similar increments in the risk of death for septic as com-
pared with non-​septic AKI have been found in other
studies89,94,96. Mortality is also increased in patients with
septic AKI compared with patients with sepsis who do
not have AKI105. Moreover, 20% of patients with septic
AKI have at least two further episodes of recurrent AKI
following their initial recovery while still in the ICU106.
Recurrence of AKI in these patients was associated
with increases in the adjusted risk of death at all time
points. Septic AKI was also associa­ted with prolonged
durations of ICU and hospital stay compared with
non-​septic AKI94,95.
Kidney recovery following AKI, particularly severe
AKI treated with RRT, is an important patient-​centred
outcome, given that AKI is a recognized risk fac-
tor for incident CKD and/or accelerated progression
to ESRD. Among patients with AKI who survived to
hospital discharge, septic AKI was associated with
trends towards improved recovery of kidney function
and reduced rates of RRT dependence compared with
non-​septic AKI (9% versus 14%; P = 0.052)95. The like-
lihood of kidney recovery is probably influenced by
a fine balance between baseline susceptibilities, such
as older age, diabetes and CKD, and modifiable risk
factors, such as a positive fluid balance and the tim-
ing and modality of RRT. Furthermore, survivors
of septic shock who had recovered from AKI before
hospital discharge had 1-year survival comparable to
that of patients without AKI, whereas non-​recovery
from AKI at discharge was associated with a three-
fold increase in the risk of death at 1 year101. Patients
with septic shock, regardless of their diabetes mellitus
status, had similar rates of AKI and RRT utilization
while in the ICU; however, survivors with diabetes
were more likely than those without diabetes to be
RRT-​dependent at hospital discharge (10% versus 5%;
P = 0.02). At discharge, survivors with diabetes also had
higher serum creatinine values than survivors with-
out diabetes (1.5 mg/dl (134 µmol/l) versus 1.7 mg/dl
(103 µmol/l); P < 0.001), implying that the survi-
vors with diabetes were highly likely to develop
incident or worsening CKD 107. Additional factors
are also likely to modify a patient’s probability of
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Reviews
recovery from AKI, particularly additional kidney
insults (hypotension, fluid overload and nephrotox-
ins) and/or care-​related issues (diuretic use, timing of
RRT initiation, RRT modality and treatment-​related
complications)72,76,81,108–110.
Cardiac surgery
Epidemiology and risk factors. Approximately 2 million
cardiac surgical procedures are performed around the
world each year111. AKI is a common complication of
cardiac surgery and has been identified as one of the
strongest risk factors for death in patients undergoing
such procedures112. In two meta-​analyses published in
2016, the pooled incidence of AKI in patients undergo-
ing cardiac surgery was 22.3% (95% CI 19.8–25.1)113,114.
However, reported rates of cardiac-​surgery-associated
AKI vary widely114, mainly owing to differences in
the application of diagnostic criteria. Although most
studies have used standard definitions for AKI based
on RIFLE, AKIN and KDIGO criteria, modified defi-
nitions without the use of urine output criteria are
frequently employed113–117. These studies all show that
increases in morbidity and mortality are associated
with increasing stages of AKI severity113–117. However,
the incidence of AKI differs when serum creatinine
criteria rather than urine output criteria are used. In
one study, the incidence of AKI was 9.7% when serum
creatinine criteria were applied and 40.2% when urine
output criteria were applied118, illustrating the low sen-
sitivity of serum-​creatinine-based criteria and the low
specificity of urine-​output-based criteria. In addition,
serum-​creatinine-defined AKI is associated with higher
mortality at 1 year than is oliguria-​defined AKI118.
In addition, AKI prevalence and the influence of
AKI on patient outcomes vary across studies because
different exclusion and inclusion criteria are used
and different surgical procedures are included119. In a
retrospective analysis of data on 2,804 adult patients
after cardiac surgery, 42% of these patients met the
KDIGO diagnostic criteria for AKI115. In this study,
AKI stage 1 was an independent predictor of 30-day
postoperative mortality (HR 3.25, 95% CI 2.19–5.12),
verifying that small increases in serum creatinine lev-
els in patients after cardiac surgery are an independent
predictor of death115.
In contrast to many other situations that result in
AKI, cardiac surgery is a predictable insult, and most
patients at risk of postoperative AKI can be identified
by the presence of comorbidities, such as advanced
age, diabetes mellitus, congestive heart failure, CKD
and chronic obstructive pulmonary disease, before
surgery120,121. In a meta-​analysis published in 2016,
which included 51,934 patients from 14 case–control
studies, preoperative risk factors associated with
RIFLE-​defined AKI included age, preoperative serum
creatinine level, hypertension, diabetes mellitus, res-
piratory system disease, peripheral vascular disease,
cerebral vascular disease, cardiopulmonary bypass
time, aortic clamping time, use of an intra-​aortic bal-
loon pump, type of surgery, infection, need for a repeat
operation, need for emergency surgery and low cardiac
output122. A reliable way of assessing preoperative risk
Reviews

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Fig. 2 | Comparison of different risk scores for AKI following cardiac surgery. Important differences between these
scores include their prediction of either severe acute kidney injury (AKI) or the requirement for renal replacement
therapy. The Thakar and Mehta scores use non-​consensus definitions of AKI, whereas the Ng and Birnie scores use
current criteria for AKI and can predict all stages of AKI. In general, discrimination of all four scores is reasonably good
(area under the receiver operating characteristic curve (AUC) values 0.75–0.80), although discrimination differs between
discovery and validation cohorts and when scores are applied in distinct geographic regions223–227. Shading highlights the
close similarities between some of the parameters used in different risk scores. BMI, body mass index; CABG, coronary
artery bypass graft surgery ; COPD, chronic obstructive pulmonary disease; GFR , glomerular filtration rate; IABP,
intra-aortic balloon pump; NYHA , New York Heart Association; RBC, red blood cell.

of AKI in this setting is desirable and could eventually
lead to the development of AKI prevention strategies.
A number of risk scores have been developed to pre-
dict an individ­ual’s risk of postoperative AKI (Fig. 2).
However, these scores have not been universally adopted
into clinical practice, perhaps reflecting the current lack
of proven preventive strategies. Another appropriate use
of such scores might be to enrich study populations at
entry into clinical trials.
Outcomes. As in other settings, cardiac-surgery-
associated AKI is associated with increased mortality
and morbidity (both short-​term and long-​term)123,124.
In a study of patients who had elevated serum creat­inine
levels before undergoing coronary artery bypass graft
surgery, 76% of those who went on to develop stage 3
AKI received RRT, of whom 66% died within 30 days125.
As mentioned above, however, even patients with ‘mild’
AKI after cardiac surgery have higher in-​hospital mor-
tality and longer hospital stays than their counterparts
without AKI126. Long-​term mortality remains increased
for patients with postoperative AKI, with survival dif-
ferences of as much as 44% versus 63% for patients
with and without AKI at 10 years of follow-​up123,124,127.
This survival differe­nce is evident even in patients with
postoperative AKI who completely recover from AKI
by the time of hospital discharge4,123,128. The duration
of cardiac-surgery-associated AKI is another impor-
tant prognostic indicator. Persistent AKI is associated
with increased in-hospital mortality (15.3% for AKI
lasting ≥7 days versus 4.1% for AKI lasting 1–2 days)
and reduced 5-year survival (HR 3.40 for AKI lasting
≥7 days or longer versus 1.66 for AKI lasting 1–2 days)129.
Conversely, early recovery from AKI is associated with
improved long-term survival130.
Postoperative AKI is also associated with increased
morbidity. Patients with AKI had higher rates of post-
operative complications, including cerebrovascular
and cardiovascular events and infections, and a longer
duration of mechanical ventilation than did their AKI-​
free counterparts4,131–133. The 5-year risk of a composite
cardiovascular end point (stroke, myocardial infarction
or heart failure) was 24.9% for patients with postopera-
tive AKI compared with 12.1% for patients without AKI
after cardiac surgery131. The risk of developing CKD is
increased after episodes of postoperative AKI128,134,135.
Economic impact. Postoperative AKI substantially
increases hospital stay, health-​care costs and resource
utilization. The results of a study published in 2005
showed that an episode of hospital-​a cquired AKI
resulted in nearly US$7,500 of excess costs and that
hospital-​acquired AKI resulted in annual expenses
exceeding US$10 billion40. A study published in 2008

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showed similar results 126. Total postoperative costs
averaged US$18,463 in cardiac surgery patients with-
out AKI, whereas costs increased to $37,674 in patients
with cardiac surgery-​associated AKI. In addition to the
increased costs in patients with AKI, durations of ICU
and total hospital stay increased, which all increased
proportionally with worsening AKI stage126.
Contrast administration
Epidemiology and risk factors. AKI is associated with
the intravascular administration of iodinated contrast
media, either intravenously (as for contrast-​enhanced
CT) or by intra-​arterial injection (as required for coro-
nary or non-​coronary angiography). The incidence of
contrast-​associated AKI in epidemiological studies and
clinical trials is highly variable and depends on the specific
diagnostic criteria used as well as the characteristics of the
population studied. Most individuals have a low risk of
developing AKI after contrast exposure; however, patients
with pre-​existing kidney disease (particularly diabetic
nephropathy), heart failure, advanced liver disease, vol-
ume depletion or concomitant exposure to other nephro-
toxins (particularly NSAIDs) are at substantially increased
risk. The risk associated with contemporary low-​osmolal
and iso-​osmolal contrast agents is substantially lower than
that associated with high-​osmolal agents.
The criteria used to define contrast-​associated AKI
have varied and often deviate from the standard KDIGO
AKI definition11. For example, the European Society of
Urogenital Radiology defines contrast-​associated AKI
as either a relative increase (that is, from baseline)
of ≥25% in plasma creatinine level or an absolute
increase of ≥0.5 mg/dl (44.2 µmol/l) within 3 days after
administration of iodinated contrast media136. Other
definitions have used the same relative increase or abso-
lute increase values over time frames ranging from 48 h
to 5 days. In addition, attribution of an episode of AKI to
radiocontrast administration might be confounded by
comorbidities such as infections, hypotension or thor­
acoabdominal pathology that precipitated the need for
contrast-​enhanced imaging, or by concurrent adminis-
tration of other potentially nephrotoxic drugs. In patients
undergoing angiography, contrast-​associated AKI also
needs to be differentiated from atheroembolic disease
and other procedural complications. These caveats need
to be acknowledged when assessing epidemiological
studies of contrast-​associated AKI.
In a retrospective study of 4,622 patients, the overall
incidence of hospital-​acquired AKI was 7.2%; the third
most common aetiology of AKI was contrast adminis-
tration, which accounted for 11.3% of AKI episodes137.
AKI occurred after 2.8% of coronary catheterization
procedures and 1.7% of contrast-​enhanced CT scans137.
In an observational analysis of 20,479 patients under-
going percutaneous coronary intervention (PCI), the
overall incidence of contrast-​associated AKI was 2.0%138.
Major risk factors for contrast-​associated AKI included
decreased kidney function, diabetes mellitus, congestive
heart failure, peripheral vascular disease, hypertension,
use of an intra-​aortic balloon pump, the need for an
urgent or emergency procedure and use of large con-
trast volumes. Other factors that might contribute to
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the risk of contrast-​associated AKI include whether the
contrast media is administered intravenously or intra-​
arterially and whether repeated exposures occur over a
short duration. In the lowest risk group (>60.0% of the
cohort), the risk of contrast-​associated AKI was 0.3%,
whereas in the highest risk group (0.5% of the cohort),
the risk of contrast-​associated AKI was 35.0%138. A sep-
arate study of 8,357 patients undergoing PCI identified
similar AKI risk factors139. Contrast-​associated AKI
developed in 13.3% of these patients, with rates increas-
ing from <8.0% among patients in the lowest risk groups
to >55.0% among patients in the highest risk groups139.
The true risk of AKI in patients undergoing contrast-​
enhanced CT is unclear, as some evidence suggests that
intravenous contrast administration is not causally
related to the subsequent development of AKI140–143. For
example, in a study that used 1:1 propensity matching
of patients who underwent contrast-​enhanced versus
non-​contrast-enhanced CT imaging, the overall inci-
dence of post-​CT AKI was ~5%, and the risk of AKI
did not differ between the two groups (OR 0.94, 95%
CI 0.83–1.07)141. When the patients were stratified into
subgroups on the basis of their baseline eGFR value, the
risk of AKI increased with decreasing kidney function
but remained independent of contrast exposure143. In
contradistinction, another study using 1:1 propensity
matching reported a trend towards an increased risk of
AKI with contrast exposure among patients with eGFR
30–44 ml/min/1.73 m2 (OR 1.40, 95% CI 1.00–1.94)
and an increased risk of AKI among patients with eGFR
<30 ml/min/1.73 m2 (OR 2.96, 95% CI 1.22–7.17)142.
In an analysis of administrative data, similar rates of
AKI were observed in hospitalized patients who were and
were not exposed to radiocontrast media144. However,
contrast exposure was associated with a reduced risk of
AKI (compared with non-​exposure) among patients with
a low burden of comorbidities, whereas patients with the
highest burden of comorbidities had a 17% increase
in the risk of AKI (OR 1.17, 95% CI 1.12–1.23)144.
Although these data suggest that the risk of AKI follow-
ing intravenous contrast administration is lower than
previously estimated, their interpretation must be tem-
pered by the possibility of selection bias related to the use
of propensity matching and residual confounding in the
statistical adjustments for provider assessment of AKI
risk associated with the choice of contrast-​enhanced or
non-​enhanced imaging.
A variety of strategies have been evaluated to miti-
gate the risk of contrast-​associated AKI. Periprocedural
administration of intravenous isotonic crystalloid is the
main preventive strategy11,145–147, although its benefit has
been questioned148. Although some studies suggested
a benefit of intravenous bicarbonate as compared with
saline11,149–151, no benefit was observed in the nearly 5,000
high-​risk patients included in the PRESERVE trial152 (the
largest study to compare these interventions) with regard
to either contrast-associated AKI or a composite of death,
need for dialysis or a persistent decline in kidney function
assessed at 90 days after angiography. Similarly, various
pharmacologic agents have been investigated to assess
their capacity to reduce the risk of contrast-​associated
AKI. Furosemide153,154, mannitol153,154, dopamine11 and
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fenoldopam11,155 are not of benefit. Studies evaluating
N-​acetylcysteine have yielded conflicting results11,156–158,
although this agent was not effective at preventing contrast-​
associated AKI in the two largest trials conducted to date,
which included a total of >7,300 patients152,159. Similarly,
N-​acetylcysteine was not effective for preventing the com-
posite of death, need for dialysis or persistent decline in
kidney function assessed 90 days following angiography
in the PRESERVE trial152,159. The role of statins in preventing
contrast-​associated AKI remains uncertain151,160–162.
Outcomes. Contrast-​associated AKI is associated with
both renal and non-​renal adverse outcomes, including
the development and progression of CKD, the develop-
ment of dialysis-​dependent ESRD, cardiovascular com-
plications and death138,158,163–165. Patients who develop
contrast-​associated AKI after PCI have an increased risk
of stent re-​occlusion, myocardial infarction and hospi-
talization for heart failure138,164. However, the extent to
which these risks are attributable to the development of
AKI per se, versus being associated with the same risk
factors that predispose to the development of AKI164,
remains unknown.
Economic impact. A decade ago, the average in-​hospital
cost for an episode of contrast-​associated AKI in the
United States was estimated to be US$10,345, with an
overall 1-year cost of $11,812 per episode166. These costs
were largely driven by the prolonged hospital and ICU
stays associated with contrast-​associated AKI. In 2016,
an economic analysis of a French hospital discharge
database estimated that >32,000 hospitalizations per year
are complicated by contrast-​associated AKI and that the
incremental cost associated with an episode of contrast-​
associated AKI was €12,413 (ref.167). The overall annual
estimated cost of contrast-​associated AKI in France
was >€200 million167.
Critically ill paediatric patients
Importantly, this section discusses children who develop
AKI in the paediatric or cardiac ICU and will not include
a discussion of the neonatal ICU population.
Children in the paediatric intensive care unit. AKI in pae-
diatric ICU patients has been studied extensively over the
past decade. In some ways, the data from this population
mirror and in other ways contrast with that from adult
patients. Standardization of AKI diagnosis and severity
staging using the paediatric modified RIFLE (pRIFLE)168,
AKIN10 and KDIGO11 criteria (which harmonized pRI-
FLE and AKIN) has led to improved understanding of
the risk factors and outcomes of paediatric AKI.
Children in the cardiac intensive care unit. Epidemio­
logical studies of AKI in children admitted to the cardiac
ICU generally focus on patients who have undergone
cardiac surgery. This group is an important cohort
because the timing of the insult leading to AKI (namely,
cardio­pulmonary bypass) is known, and these patients
gene­rally lack other comorbidities. A multitude of
studies reveal that AKI occurs in 30–50% of children
after cardiac surgery. Given this very high incidence of
© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
AKI, some centres routinely place a peritoneal dialysis
catheter at the time of cardiac surgery169–171. Young ages
(<90 days) and long bypass times (usually >120 min)
are independently associated with the development
of AKI in this setting172–174. In a large single-​centre study of
430 infants aged <90 days undergoing cardiac surgery,
AKIN-​defined AKI developed in 52% of the patients,
and 21% of the patients developed AKIN stage 2 or stage
3 AKI175. In-​ICU mortality was 7% and was higher in
patients with AKI (11.6%) than in those without AKI
(2.9%). AKIN stage 2 (OR 5.1) and stage 3 (OR 9.5)
AKI were associated with increased mortality after con-
trolling for single ventricle status and use of circulatory
support175. Similarly, AKIN stage 2 and stage 3 AKI
were associated with increased durations of mechanical
ventilation and increased inotrope use175.
Epidemiology and risk factors. The newly developed
paediatric AKI definitions were initially used in small,
single-​centre prospective studies including a few hun-
dred children176 or larger retrospective studies including
≤8,000 children177–180. These studies reported a widely
ranging prevalence of AKI (10–82%) in paediatric
patients in the ICU, but all revealed that creatinine-​based
KDIGO stage 2 or stage 3 AKI (or its equivalent in studies
using pRIFLE or AKIN definitions) was independently
associated with mortality177–180. Three well-​designed epi-
demiological studies involving very large sample sizes
and/or use of clinical records instead of administrative
data to diagnose and stage AKI have been published since
2015 (refs181–183). Review of a large national administrative
database comprising over 2.6 million paediatric hospital-
izations revealed 3.9 patients with AKI per 1,000 admis-
sions181. Among children admitted to intensive care,
in-hospital mortality was higher in those with AKI than in
those without (32.9% versus 9.4%)181. Another retro-
spective study used the serum-​creatinine-based compo-
nents of three different AKI criteria, pRIFLE, AKIN and
KDIGO, to assess the incidence of AKI in a single-​centre
cohort of 1,759 children admitted to the ICU182. For all
three AKI definitions, in-​ICU mortality was higher in
patients with AKI (range 13.4–16.0%) than in those with-
out AKI (range 1.8–2.3%). In addition, increasing stages
of AKI severity were associated with progressively higher
mortality. Stage 3 AKI was associated with the highest
mortality (range 30.4–35.9%) and longest duration of
ICU stay (median 28–35 days)182.
The largest prospective study of AKI epidemiology
and outcomes to date was published in 2017. The AWARE
study183 is a prospective observational study of 4,683 pae-
diatric patients admitted to the ICU from 32 centres in
9 countries. Both serum-​creatinine-based and urine-​
output-based KDIGO criteria were used to diagnose AKI.
AKI developed in 26.9% of the overall cohort, whereas
severe (that is, stage 2 or stage 3) AKI occurred in 11.6%
of patients. Children with severe AKI had increased
28-day mortality compared with the rest of the cohort
(11.0% versus 2.5%). Children with severe AKI also had
increased 28-day mortality compared with children
without AKI after controlling for 16 covariates in a mul-
tivariable model (OR 1.77) or one of three locally used
illness-severity scoring systems (OR 2.41–5.12 across all
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 Reviews

scores)183. AWARE was the first paediatric study to use systems and barriers to the publication of LMIC data
both serum-​creatinine-based and urine-​output-based in well-​regarded scientific journals. Nonetheless, two
AKI criteria. The results revealed that children with successive meta-​analyses of the global epidemiology of
KDIGO oliguria-​based stage 3 AKI had the highest mor- AKI have shown improvements in AKI ascertainment
tality — significantly higher than that of patients with and the utilization of KDIGO criteria in LMICs3,20.
KDIGO creatinine-​based stage 3 AKI (32% versus 18%). However, data from high-​income countries remain dis-
Furthermore, two-​thirds of the children who had severe proportionately represented. In the 2013 meta-​analysis20
AKI according to oliguria-​based criteria did not have (which included 49,147,878 patients with AKI), nearly
severe AKI according to serum-​creatinine-based criteria. half of the included studies were from North America,
Additionally, the duration of ICU stay demonstrated a which is home to only 5% of the world population; only
stepwise increase with increasing AKI severity183. Taken two studies were from Africa, which is home to 15% of
together, the findings of these three large studies of AKI in
the world population. Most studies (84%) originated
critically ill children confirm that AKI is associated withfrom high-​income countries, and 94% of the included
increased morbidity and mortality and suggest that urine countries spent >5% of their gross domestic product
output as well as serum creatinine levels should be meas- (GDP) in total health expenditure. The remainder of the
ured to avoid missing patients who develop AKI owing included studies were from LMICs, but the proportion
to oliguria. They also validate the KDIGO criteria as an of GDP spent by these countries on total health expend-
epidemiological outcome measure. iture was not reported. The 2015 meta-​analysis3 (which
included 77,393,454 patients with AKI) showed increas-
Long-​term outcomes. Long-​term outcomes in survivors ing use of KDIGO or KDIGO-​equivalent definitions of
of paediatric AKI have received increased attention in AKI in LMICs, making their data comparable to those
the past 5 years. High rates of CKD stage 1–2 (38.1%) from other regions of the world. Additionally, the pooled
and microalbuminuria (9.5%) were reported in 126 incidence of AKI in LMICs is increasingly approaching
children assessed 1–3 years after an episode of AKIN-​ that in high-​income countries, in contrast to findings
defined AKI184. In data from a Canadian provincial in previous reports. For example, in the 266 studies that
database, 2-year mortality was increased among children used the KDIGO definition of AKI (which included a
who developed AKIN stage 3 AKI after cardiac surgery total of 4,502,158 patients), AKI affected 21% of hos-
compared with their counterparts who did not develop pital admissions in LMICs, a figure that is broadly in
post-​surgical AKI (21.4% versus 4.3%)172. Another study agreement with the worldwide incidence of AKI (Fig. 3).
of children 5–7 years after cardiac surgery found no dif- The overall proportion of patients with AKI requiring
ferences in eGFR, hypertension or microalbuminuria RRT in LMICs was lower than in high-​income countries
but did find persistently elevated biomarkers of kid- (2% of patients admitted to the hospital and 11% of all
ney damage in children with AKI versus those without patients with AKI). Overall, 12% of patients admitted
AKI185. Finally, in a Danish National Health Service to the hospital in LMICs (80% of all patients with AKI)
Registry study, which included clinical laboratory data, had KDIGO stage 1 AKI. This figure is difficult to
children who had KDIGO-​defined AKI had an increased compare meaningfully with data from high-​income
risk of developing stage 2–5 CKD ≥1 year after the AKI countries owing to considerable inter-​study variation.
episode (adjusted HR 6.5)186. Importantly, whereas in the 2013 meta-​analysis none
Stage 2 and stage 3 AKI in critically ill children are of the included studies obtained data from Africa or
therefore unquestionably associated with increased southeast Asia, the 2015 analysis included multiple
in-​hospital morbidity and mortality, as well as an reports from each of these regions, in which AKI had
increased risk of CKD. As these children do not have been defined by KDIGO criteria.
the comorbidities that are common in adults (cirrhosis,
heart failure, diabetes mellitus and underlying CKD), Mortality
the paediatric AKI literature supports the concept Initial efforts to characterize AKI around the world
that AKI itself might be integral in mediating these were based on an exhaustive review of the published
adverse short-​term and long-​term outcomes. This literature between 2004 and 2012, which suggested that
concept is of particular interest given that children mortality from AKI was lower in LMICs than in high-​
will have a longer lifespan in which they could develop income countries189. The factors underpinning this
these long-​term issues. Therefore, interventional tri- finding included the young age of the AKI population
als should be designed to prevent AKI in children and in LMICs and the cause of AKI being more frequently
to assess the long-​term development of CKD in AKI a single disease. By contrast, multiple organ failure
survivors187,188. causes a high proportion of AKI episodes in (mostly
aged) individuals from high-​income countries. The low
AKI in low-​to-middle-​income settings overall pooled mortality of 21% in LMICs was attrib-
Epidemiology uted to the predominance of patients with KDIGO
The epidemiology of AKI in LMICs has been reviewed stage 1 AKI3. However, patients with KDIGO stage 3
in depth elsewhere3,20,189–191. Despite the high burden AKI or patients requiring RRT had much higher over-
of AKI in LMICs2,3,20,191,192, reliable information on the all pooled mortality (42% and 46%, respectively, and
incidence of AKI in LMICs has been slow to accrue owing unadjusted ORs for death of 12.5 and 19.7, respec-
to limitations in the quantity and availability of local tively)3, in agreement with values reported in other
and regional data, the use of outdated AKI classification studies. Further efforts to ascertain the consequences

Nature Reviews | Nephrology

© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
Reviews
0QTVJGTP
'WTQRG

9GUVGTP
'WTQRG
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Fig. 3 | global variation in the incidence of AKI. Published estimates of the incidence of acute kidney
injury (AKI) as defined using Kidney Disease: Improving Global Outcomes (KDIGO) criteria vary widely across
countries and regions. The percentages shown represent the proportion of the hospitalized population with
AKI. Data from refS3,20.
of AKI in LMICs have consistently shown that mor-
tality from AKI in LMICs is equal to or higher than
in high-​i ncome countries 20,191. Specifically, AKI-​
associated mortality declined significantly (P = 0.02)
over the 8-year study period20 and was inversely related
to the percentage of country GDP spent on total health
expenditure (P < 0.001) and country gross national
per-​capita income (P < 0.001).
Data from the International Society of Nephrology 0
by 25 Global Snapshot, a multinational cross-​sectional
study191, show that mortality at 7 days was higher in
LMICs than in the high-​income and upper-​middle-
income countries combined 191. These preliminary
findings also highlight particularly large disparities in
children with AKI in LMICs, among whom adjusted
mortality seems to be several orders of magnitude
higher than that of children with AKI in high-​income
countries. Such high estimates are consistent with the
findings of a 2017 systematic review193. Our current
interpretation of the AKI mortality data from LMICs
highlights severe barriers to care (discussed below).
Conversely, kidney recovery after AKI might be bet-
ter in LMICs than in other regions191. We provision-
ally interpret the latter finding as associated with the
young age and lack of comorbidities in patients with
AKI in LMICs, as well as the reduced prevalence of
CKD in this population. These data require confir-
mation in further studies. The International Society of
Nephrology is currently working towards incorporating
AKI into the Global Burden of Disease project, a sys-
tematic effort to quantify leading global causes of poor
health and disability194. The 0 by 25 initiative aims to
© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
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establish longitudinal data on the contribution of AKI
to morbidity and mortality for 188 countries around
the world. This process, which is ongoing, will require the
relationship between disorders that cause AKI and their
resultant effects on health outcomes to be established.
Once completed, this initiative is expected to establish
the leading causes of AKI and the most susceptible pop-
ulations across the world, which would greatly facili-
tate the design of interventions and measurement of
outcomes.
Aetiology and risk factors
The aetiology of AKI in LMICs is often different from
that in high-​income countries and also differs between
urban and rural environments. Thus, in LMICs, rural
community-​acquired AKI is associated with severe
gastroenteritis, acute glomerulonephritis, envenoma-
tion, intoxication from traditional remedies and com-
plications of endemic infections (including malaria,
HIV/AIDS, leptospirosis and dengue). Conversely,
aetiologies of AKI in large urban centres resemble
those in high-​income countries3,20,189–191,195,196 (Table 3).
The two most common causes of AKI in the 0 by 25
Global Snapshot191 were hypotension, occurring in
1,615 (40%) of patients, and dehydration, occurring
in 1,536 (38%) of patients. In this study, several risk
factors such as infection, sepsis and use of nephrotoxic
drugs were common to all countries, which suggests
that a standardized approach to the early recognition
and treatment of AKI is possible. However, generaliza-
bility of the results of this study remains limited owing
to under-​representation of LMICs.
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Table 3 | The contrasting characteristics of AKI around the world
Characteristic high-​income countriesa
Pattern of Occurs predominantly in ICUs
occurrence
Disease patterns Associated with multiple organ
failure
Mortality High mortality
Demographics A disease of elderly populations
Incidence Increasing
Reporting Adequately reported
Prevention Difficult to prevent
Cost Very expensive to treat
Main exposures • Sepsis and septic shock
• Trauma
• Complex surgery (cardiac
surgery or major non-​cardiac
surgery)
• Nephrotoxic drugs and agents
• Burns
ICU, intensive care unit. aIncludes World Bank upper-​middle income (US$3,956–12,235) and high-​income (>US$12,236) categories.
b
Includes World Bank low-​income (<US$1,005) and lower-​middle income (US$1,006–3,955) categories7.
Some important AKI risk factors present in LMICs
are modifiable, including those induced by acute
events such as nephrotoxin exposure, whereas others
are non-​modifiable, such as comorbidities and demo-
graphic factors (Box 2). Some important environmental
and infrastructural risk factors for AKI in LMICs are
also potentially modifiable, but the substantial invest-
ment required (for example, to improve sanitation and
the availability of clean water) is often not afforda-
ble. Nonetheless, the high incidence of community-​
acquired AKI caused by modifiable factors creates
an opportunity to effectively combat the problem at an
early stage and thereby avoid disease progression190,197.
Several current public health programmes (such as the
President’s Malaria Initiative) are not only reducing
the incidence of severe diseases but also influencing
their complications and consequences, including AKI.
Given the limited investment in health care of LMICs,
which severely hampers the availability of RRT and
intensive care, and given the severity of disease that
dialysis-​requiring AKI entails, the main focus in LMICs
is the reduction of AKI incidence and morbidity by
targeting modifiable exposures and promoting mater-
nal health, which are both of enormous importance
in reducing AKI incidence, severity and costs.
Diagnosis
AKI is potentially treatable and reversible, and treatment
is often specific to the underlying condition. However,
failure to recognize early AKI is associated with disease
progression requiring unaffordable thera­pies, delayed or
impaired recovery and high mor­tality195,198,199. Limited
education about renal disease and inadequate access to
basic health care in LMICs hamper the early recognition
of AKI and delay intervention2,196. As a result, patients
Nature Reviews | Nephrology
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Reviews
low-​to-middle income countriesb
Occurs in rural health centres and hospitals as well as in large
urban hospitals
Often caused by a single disease; multiple organ failure is
uncommon
Mortality similar to or even higher than in high-​income
countries
A disease of otherwise healthy children and young persons
Increasingly recognized as high
Severely under-​reported
Preventable, generally with public health initiatives
Very inexpensive to treat at early stages; unaffordable at
severe stages
• Diarrhoea and endemic infections: malaria, leptospirosis,
dengue fever, cholera, yellow fever, tetanus, hantavirus and
HIV/AIDS
• Obstetric complications (including septic abortion)
• Animal venoms (snakes, bees and wasps, Loxosceles spp.
spiders and Lonomia spp. caterpillars)
• Natural and traditional remedies and natural dyes
• Prolonged physically demanding work in an unhealthy
environment
often spend days with worsening and untreated AKI197.
By the time they reach the hospital, these patients are
severely sick and at high risk of death. Further delays
usually occur in the hospital, where the erratic availa­
bility of dialysis and lack of funds impair timely care
and initiation of RRT, again causing high mortality and
impairing recovery197. Diagnostic and treatment delays
are especially severe in children with AKI193. In sub-​
Saharan Africa, delays of up to 3 weeks between onset
of symptoms and presentation to the hospital were
described in adults with AKI197, wher­eas delays in pres-
entation to the hospital (mean 6 days) and treatment ini-
tiation were present in 50–80% of children with AKI197.
The problem of AKI under-​ascertainment (Fig. 3) has
also been investigated in the 0 by 25 Global Snapshot191.
In LMICs, patients are rarely or never seen by a
nephrologist and are rarely seen by a physician; rather,
their first contact with the health-​care system occurs
in the community dispensary, where nurses (or other,
less-​well-educated health-​care providers) are the only
available resources191. Given those constraints, efforts
to educate individuals about AKI in LMICs must be
focused on the most basic levels of the health-care
system200. In LMICs, diagnosis of AKI is influenced
by the patient’s clinical presentation and by the con-
text of their initial encounter with the health-​c are
system196,201. Improved awareness that the presenting
symptoms and signs might correspond to AKI is the
first step towards timely recognition, but missed diag-
nosis of AKI remains common197. Practical and easily
accessible educational strategies focused on primary
providers are indispensable to achieve early recog-
nition of AKI and should highlight the importance
of clinical contexts such as seasonal variations in the
incidence of endemic diseases, including malaria and
Reviews
Box 2 | risk factors for AKI in lMICsa
Modifiable
• Dehydration
• Intravascular volume depletion
• Hypotension
• Anaemia
• Hypoxia
• Use of nephrotoxic drugs and agents
Non-​modifiable
• Comorbid medical disorders
-- Chronic kidney disease
-- Diabetes
-- Cancer
-- Chronic heart disease
-- Chronic lung disease
-- Chronic gastrointestinal disease
• Demographic factors: sex and older age
• Environmental and infrastructural factors
-- Inadequate sanitation
-- Insufficient clean water
-- Inadequate control of parasites
-- Inadequate control of infection-​carrying vectors
-- Poor transportation
-- Inadequate health budget
-- Insufficient health-​care human resources
-- Insufficient health services and hospitals
a
Low to middle income countries, as defined by the World
Bank classification (low and lower-​middle income groups
combined). AKI, acute kidney injury.
gastroenteritis. AKI as a maternal or neonatal complication
of childbirth deserves special consideration in the
LMIC environment.
Acute Dialysis Quality Initiative (ADQI) XVIII
recommendations for diagnosis and staging of com-
munity-​acquired AKI in LMICs195 include estimation
of urine output (a valid diagnostic trigger in the com-
munity), measurement of serum creatinine levels by
point of care tests and thorough urinalysis. Given the
invaluable information that can be obtained by basic
urine microscopy, training in this procedure should be
promoted as a key, low-​resource test for AKI detection
in LMICs. The value of the application of such diag-
nostic measures has been convincingly demonstrated191.
However, detection of an elevated serum creatinine level
at the patient’s initial presentation might indicate CKD
rather than AKI, and misdiagnosis could unnecessar-
ily delay the initiation of urgent therapeutic measures.
Therefore, another ADQI XVIII recommendation is
that patients with apparently acute, severe kidney dys-
function should receive emergency treatment as though
they had AKI until proved otherwise195. This course of
action is necessary because in LMICs information on
changes in serum creatinine levels over time is generally
not available by the time that patients reach the regional
dispensary, and its absence should not interfere with the
delivery of timely care.
Although increases in serum creatinine level remain
central to the diagnosis of AKI in LMICs, differences in
individual body composition and dietary composition
across populations can result in differences in creatinine
© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
production and distribution volume. These factors have
largely been ignored in studies from LMICs, even though
they might impair the accuracy of current estimates of
AKI incidence originating in the developed world202.
The current KDIGO definition of AKI (an abrupt
decrease in kidney function occurring during a period
of ≤7 days) was derived predominantly from ICU
patients in high-​income countries, in whom the princi-
pal causes of AKI are ischaemia, toxins and severe sepsis.
In LMICs, by contrast, the most common causes of AKI
are severe glomerulonephritis, thrombotic microangi-
opathy, haemolytic uraemic syndrome and interstitial
nephritis. Therefore, additional testing is recommended
for hospitalized patients with AKI in LMIC settings,
including renal imaging and (when indicated) kidney
biopsies. Currently, kidney biopsies are more commonly
performed in patients with AKI (and hence their value
is more highly appreciated) in LMICs than in high-​
income countries. Although results from biopsy series
are subject to confounding by indication bias, as biop-
sies are more likely to be performed in patients with rare
causes of AKI such as systemic diseases, the available
studies (reviewed elsewhere195) suggest that renal biopsy
should be considered, when appropriate and feasible, in
the diagnosis and management of patients with AKI of
unclear aetiology to both identify the underlying patho­
logy and direct the management of these individuals.
Such an approach is supported by emerging evidence of
a lack of correlation between AKI as defined by KDIGO
criteria11 or AKD as defined by ADQI criteria6 and histo-
pathological findings203. These observations suggest that
histopathology studies should be performed in LMIC
settings to understand the AKI process in these patients.
Basic training of local patholo­gists in recognition of
potential pathologies underpinning AKI could provide
valuable information for guiding the management of
these patients. Conversely, given their high cost and as
yet unproved efficacy, the use of biomarkers of structural
injury (such as NGAL, TIMP2 and IGFBP7) cannot yet
be recommended in LMIC settings195.
Treatment
Wide variations are present in the use of RRT for AKI
around the world (reviewed elsewhere3), and striking
differences in RRT access, availability and procedures
are evident when comparing high-​income countries,
middle-​income countries and LMICs. Access to RRT
is strongly dependent on socio-​e conomic develop-
ment and health-​system organization. Availability of
RRT can also vary widely within a country’s urban and
rural regions. Such differences greatly impede compar-
isons within and between countries. In general, RRT is
un­available to patients in LMICs except for a select elite
of the population, which is a source of severe inequality.
When RRT is available, peritoneal dialysis is used more
commonly than intermittent haemodialysis, and these
two techniques demonstrate equivalent outcomes204–206.
The Saving Young Lives initiative207–209 has shown that
providing assistance with and promoting the devel-
opment of local resources can help to generate local
RRT programmes in LMICs. However, given the lack
of investment and resource constraints of LMICs, the
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 Reviews

prospects for enabling the delivery of affordable RRT to (stage 0C); partial recovery of kidney function with
all patients with AKI in LMICs remain limited208,210. other evidence of ongoing injury such as proteinuria or
loss of renal functional reserve (stage 0B); or full recov-
Barriers to care ery (stage 0A)6. Permanent non-​recovery requiring
In addition to delayed diagnosis and a lack of access to RRT and full recovery of renal function are both equally
appropriately trained health-​care professionals, indi- uncommon; consequently, many patients are at risk of
viduals with AKI in LMICs also experience barriers in AKI sequelae (which are broadly classified into renal,
access to appropriate care owing to pervasive economic cardiovascular and other effects). The well-​documented
and sex inequalities, which especially limit the treat- long-​term kidney-​specific sequelae are increased risk
ment of AKI in women and girls and can even result in of ESRD and advanced CKD (reviewed elsewhere215).
denial of care (including denial of RRT). Such discrim- The risk of progressive renal deterioration persists for up
ination, together with an unacceptably high incidence to 10 years after an episode of AKI, even after apparent
of pregnancy-​related AKI191, causes a disproportionate full renal recovery, so these patients should be monitored
burden of disease in women and babies. As described in carefully and durably216. In addition, new findings sug-
the United Nation’s Millennium Goals and Sustainable gest that how and over what time span a patient with AKI
Growth Initiatives, actions to address such problems and recovers their renal function is also important. Patients
sources of inequality should be a key priority211–214. with AKI who show rapid recovery, stuttering recov-
Focusing on preventive public health measures will ery or prolonged recovery show progressively worsen-
help to limit the incidence and decrease the severity of ing outcomes compared with patients without AKI5.
AKI. The empirical observation that AKI-​associated Thus, interventions that shorten or modify the recovery
mortality is inversely associated with both national period might offer important therapeutic benefits.
health expenditure and per-​c apita gross national The increased cardiovascular risk observed in
income20,191 needs to be investigated further to develop patients after AKI relates to major adverse cardiovascu-
specific suggestions for improving health investment lar events, including stroke163,217,218. Not surprisingly, the
in the areas most likely to deliver the greatest benefit in most common major adverse cardiovascular event seen
each specific region. Efforts to work with local, regional after an episode of AKI is congestive heart failure, but an
and national governments, driven by a detailed under- increased risk of myocardial infarction has also been reli-
standing of the epidemiology and magnitude of the bur- ably shown in multiple cohorts163,217,218. The mechanism
den of AKI, will be essential to improve the recognition underlying the increased risk of myocardial infarction
and care of AKI in LMICs around the world. Improved is not well understood but might be linked to the pres-
education at all levels of the health-​care system, from ence of subclinical CKD and increased levels of protein-​
physicians and nurses to other health-​care workers with bound uraemic toxins coupled with loss of Klotho219,220.
limited training, will make these providers more likely Increased risks of an assortment of other diseases have
to think of AKI and to implement early diagnostic meas- been linked to AKI, including gastrointestinal bleed-
ures, such as point of care measurements of creatinine ing, organ fibrosis and liver injury221,222. In summary,
levels and diuresis196. the development of AKI heralds a strong likelihood of
Coordinated initiatives involving governments, non-​ increased morbidity, and these adverse outcomes are
governmental organizations and international grassroots not limited to kidney-​centric effects. Given the cur-
movements (such as UN-​Water, UNAIDS and anti-​ rent absence of therapeutics for AKI, efforts to prevent
malaria campaigners Nothing But Nets) will reduce the and rapidly diagnose AKI, and thereby to attenuate its
exposure of individuals to the factors that cause many severity and duration, are key clinical priorities.
cases of AKI in LMICs and will most likely have the larg-
est sustainable effect on reducing the incidence of AKI Conclusions
in these countries. AKI is a frequently occurring syndrome of heteroge-
neous aetiology that often occurs as a complication
Long-​term outcomes of other conditions. AKI is associated with increased
The notion that AKI survivors have an increased risk of morbidity and mortality and adverse long-​term patient
developing CKD or ESRD is now widely accepted but and kidney outcomes related to the retention of waste
not well appreciated outside the nephrology specialty215. products, a generalized inflammatory response and
Given the adverse prognosis of many patients after an incomplete recovery of kidney function. The incidence
episode of AKI and the public health ramifications of of AKI is similar across countries regardless of resource
progression to late-​stage CKD, efforts to identify clinical levels, although RRT is less widely used in LMICs than
risk factors for progression in patients with and without in high-​income countries. Specific considerations in
pre-​existing CKD who have survived an episode of AKI LMICs are that AKI is often the consequence of mod-
are urgently needed. ifiable risk factors and that diagnosis is often delayed.
A consensus guideline published by ADQI catego- However, the recognition and management of AKI
rizes patients who have experienced an episode of AKI also require improvement in high-​income countries,
or AKD into five groups: non-​recovery of kidney func- in which unmet needs include modalities for improv-
tion with ongoing need for RRT; incomplete recovery ing diagnosis of AKI and strategies to improve the care
of kidney function resulting in CKD stages 1–3; par- of affected patients.
tial recovery of kidney function with serum creatinine
concentration between baseline and 1.5 times baseline Published online xx xx xxxx

Nature Reviews | Nephrology

© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
Reviews
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Author contributions
All authors researched data for the article, wrote the manu-
script, contributed substantially to discussions of the article
content and participated in review and/or editing of the
manuscript before submission.
Competing interests
E.A.J.H. declares that he has received speaker’s fees from
Alexion and research grants from the University of Ghent for
biomarker research. S.M.B. declares that he has received
consulting fees from Baxter Healthcare and is the Canada
Reviews
Research Chair in Critical Care Nephrology. All other authors
declare no competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.
Reviewer information
Nature Reviews Nephrology thanks M. Joannidis,
M. Ostermann and the other anonymous reviewer(s) for their
contribution to the peer review of this work.
Related links
The world Bank: How we classify countries: http://www.
worldbank.org/
international society of Nephrology 0 by 25 Global
snapshot: http://www.0by25.org/
UN-water: http://www.un.org/sustainabledevelopment/
water-​and-sanitation
UNAiDs: http://www.unaids.org
President’s Malaria initiative: https://www.pmi.gov/home
Nothing But Nets: https://www.nothingbutnets.net