Acute Kidney Injury 2019

Seminar
Acute kidney injury

Claudio Ronco, Rinaldo Bellomo, John A Kellum
Acute kidney injury (AKI) is defined by a rapid increase in serum creatinine, decrease in urine output, or both. AKI Lancet 2019; 394: 1949–64
occurs in approximately 10–15% of patients admitted to hospital, while its incidence in intensive care has been reported Department of Medicine,
in more than 50% of patients. Kidney dysfunction or damage can occur over a longer period or follow AKI in a continuum University of Padova, Padova,
Italy (C Ronco MD);
with acute and chronic kidney disease. Biomarkers of kidney injury or stress are new tools for risk assessment and could
International Renal Research
possibly guide therapy. AKI is not a single disease but rather a loose collection of syndromes as diverse as sepsis, Institute of Vicenza, Vicenza,
cardiorenal syndrome, and urinary tract obstruction. The approach to a patient with AKI depends on the clinical context Italy (C Ronco); Department of
and can also vary by resource availability. Although the effectiveness of several widely applied treatments is still Nephrology, San Bortolo
Hospital, Vicenza, Italy
controversial, evidence for several interventions, especially when used together, has increased over the past decade. (C Ronco); Critical Care
Department, Austin Hospital,
Introduction conclusions on the epidemiology of this syndrome. Melbourne, VIC, Australia
Acute kidney injury (AKI) is a syndrome. It is an important International consensus criteria were first introduced by (R Bellomo MD); and Center for
Critical Care Nephrology,
complication in patients admitted to hospital (10–15% of the Acute Dialysis Quality Initiative,4 and subsequently Department of Critical Care
all hospitalisations)1 and in patients in the intensive modified by the AKI Network,5 and finally by Kidney Medicine, University of
care unit (ICU) where its prevalence can sometimes Disease Improving Global Outcomes (KDIGO)6 as Pittsburgh, Pittsburgh, PA,
exceed 50%.2 Despite its complexity, AKI is traditionally shown in table 1 and panel 2. Through use of standard USA (J A Kellum MD)
seen as a single disease or classified according to semi- criteria, estimates of incidence and prevalence of AKI, Correspondence to:
Dr Claudio Ronco, Department of
anatomical categories (ie, pre-renal, intrinsic, and post- and comparisons of outcomes across centres are now Nephrology, San Bortolo
renal AKI) in reference to the kidney (panel 1). possible. Rates of AKI have been described to be as low Hospital, Vicenza 36100, Italy
This simplistic taxonomy is now giving way to more as 2% in community hospitals, whereas in large academic [email protected]
specific syndromic descriptions including among others institutions, rates can reach more than 20% of all
hepatorenal,8 cardiorenal,9 nephrotoxic,10 and sepsis-asso hospitalisations.19,20
ciated AKI.11 This increased specificity is because of Furthermore, if specific hospital units are studied such as
increasing evidence that these syndromes have a unique ICU, cardiac surgery, oncology, and transplant centres,
pathophysiology and treatment. rates of AKI can be 50% or more.2,12 Other aspects have
Another major challenge to AKI diagnosis and treat been recently analysed in a global snapshot done in
ment is that specific syndromes often coexist as conjunction with the 0by25 initiative.13,21 AKI rates and
illustrated by the overlaps shown in figure 1. Because causes were highly variable in different countries with spe
AKI often arises as part of other syndromes (ie, heart cific refer
ence to the local resources and health-care
failure, liver failure, and sepsis), which themselves cause systems. The epidemiology of AKI is schematically
substantial morbidity and mortality, it is easy to overlook described in figure 2.21–23 Finally, it is important to place
the significance of AKI as both a marker of disease
severity and a determinant of short-term and long-term
outcomes. Search strategy and selection criteria
In patients with septic shock, 60-day mortality is three We searched PubMed and MEDLINE for original research
to five times greater in those who develop AKI.15 Although papers, reviews and systematic reviews, meta-analyses,
this mortality could be a function of greater sepsis severity editorials, and commentaries published between Jan 1, 2014,
in patients with severe AKI, the syndrome itself might and June 30, 2019, using the following search terms: “acute
independently increase mortality by leading to electrolyte kidney injury”, “acute renal failure”, “continuous
and acid-base disorders, fluid accumulation, and meta hemofiltration”, “continuous renal replacement therapy”,
bolic dysfunction, impairing neutro phil function and and “haemodialysis”. We combined the terms “continuous
reducing the patient’s ability to clear infection.16 hemofiltration”, “continuous renal replacement therapy”,
Thus, the early and rapid diagnosis and treatment of and “haemodialysis” with “acute kidney injury” and “acute
AKI is an important part of the overall management of renal failure”. We identified 8679 potentially relevant titles.
patients with the various syndromes that cause or are All titles were scanned. We gave preference to citations from
associated with AKI. By contrast, management of the the past 5 years but included selected papers from older
original disorder, in some cases, might help to resolve literature when more recent studies were not available or
the secondary AKI syndrome. Although some aspects when citing the historical basis for clinical practice.
might not be modifiable, there is evidence that some 494 relevant articles were selected. For all articles, abstracts
causes of AKI can be mitigated in some settings.17,18 were reviewed and the full reference list developed.
Additional references were selected from relevant articles
Consensus definitions and epidemiology and chapters of recent textbooks in the field. Only English
Different terms and different criteria for AKI have been language manuscripts were included.
used previously making it impossible to reach accurate
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Seminar
Second, a patient might present with abnormal kidney

Panel 1: The history of acute kidney injury function of unknown duration and the clinician has to
In the first part of the 20th century, the diagnosis of acute renal failure, as it was known, then decide if the condition is AKI, CKD, or both. This
was based on abrupt oliguria and rapid development of uraemic symptoms. Patients scenario can pose a substantial clinical dilemma part
typically died from the clinical consequences of severe impairment of renal function such as icularly if the patient’s medical history, including baseline
gastrointestinal bleeding, pulmonary oedema, or cardiac dysrhythmias. The main causes renal function, is not well documented.27 Indeed, baseline
of acute renal failure were dehydration, haemorrhagic shock, glomerulonephritis, and acute renal function often has to be inferred using various
intoxication. With the introduction of laboratory medicine and the measurement of sources of information including the medical history,
glomerular filtration rate with exogenous or endogenous markers such as creatinine, kidney size using imaging, presence or absence of
diagnosis became easier and more accurate. Autopsy findings late in the course of acute albuminuria, and the history of serum measurements of
renal failure often showed patchy necrosis of the tubular cells and the term acute tubular serum creatinine over time. A decrease in serum creatinine
necrosis was suggested and gradually became synonymous with acute renal failure. after hospital admission might indicate that AKI had
However, even as these results were reported, other studies were done with kidney biopsy occurred before admission.
and in some conditions, such as sepsis and shock, tubular necrosis was almost absent despite Conversely, small decreases in creatinine can reflect the
profound kidney dysfunction. Thus, the term, acute tubular necrosis, although still combined effects of changes in volume status, fasting,
commonly used, can be misleading in many cases.3 and bedrest typical of the first few days of hospitalisation.
Thus, decreases in serum creatinine, although they do
A similar problem was recognised with the term acute renal failure. Evidence accumulated
not define AKI, should prompt clinicians to suspect
indicating that even mild alterations in renal function contributed to morbidity and
resolving AKI and might be especially useful when
mortality in patients who are critically ill, and thus the term failure seemed inappropriate.
baseline function is unknown.28
Furthermore, variation in the use of haemodialysis or haemofiltration, and the enormous
variation in the biochemical criteria used to define the syndrome meant that individual
Assessing kidney function
studies could not be compared or combined. In 2002, the Acute Dialysis Quality Initiative
Changes in serum creatinine or urinary output are
assembled an international, interdisciplinary group of experts in Vicenza, Italy, to standardise
neither sensitive nor specific for AKI, yet they are the
the definition of what became known as acute kidney injury (AKI).4 The new definition and
cornerstone of our current diagnostic approach. Although
classification system known as Risk, Injury, Failure, Loss and End-stage kidney disease
glomerular filtration rate (GFR) can be accurately
(RIFLE)5 was still based on serum creatinine and urine output, but by standardising the
measured in the research setting, the available technology
criteria, subsequent epidemiological studies, diagnostic tests, and even interventional trials
is cumbersome and time consuming. Thus, changes
would likewise be standardised and comparable with each other. In the next decade,
in kidney function are usually assessed clinically by
rates and outcomes for AKI in more than a million patients were reported in various studies.
monitoring solutes that are normally cleared by the
With time, RIFLE was refined,6 and ultimately adopted into the Kidney Disease Global
kidney (eg, creatinine, cystatin C), and by urine volume
Initiative AKI guideline.6 This guideline is the commonly accepted definition and
over time in the context of the patient’s overall volume
classification system for clinical trials and clinical practice. However, it will evolve further as
status (table 1). Changes in serum creatinine lack
more rapid diagnostics are used and as subtypes of AKI are better understood.7
sensitivity for AKI because in a healthy person, nearly
50% of GFR must be lost before a change in serum
AKI in the continuum of kidney disease from acute to creatinine is detectable.29,30
chronic. In this continuum, AKI is part of acute kidney Moreover, studies from 2014 confirmed that healthy
disease, which is defined as abnormalities in kidney individuals might have a sub stantial amount of renal
structure or function that have existed for fewer than functional reserve. This reserve can be lost progressively
90 days (the point at which chronic kidney disease [CKD] even in the presence of a constant baseline GFR.30,31
is defined).6,24 Changes in urine output might be more sensitive but
appear less specific. In some cases of AKI (eg, acute
Clinical presentation interstitial nephritis), polyuria can occur as the result of
Kidney disease is usually a silent condition. Except for defects in tubular urine concentration ability.
urinary tract obstruction, it does not cause pain or any Furthermore, urine output, and to a lesser extent, serum
specific signs or symptoms. Patients can therefore present creatinine, are exquisitely sensitive to overall volume status
in two ways. First, a patient might present with an acute such that hypovolaemia will trigger changes in urine
illness such as sepsis,25 or be exposed to a condition known output without the necessity for injury. Indeed, totally
to be associated with AKI such as major surgery.26 different genes are expressed by hypovolaemia versus
Importantly, such patients might not present to the ICU ischaemia induced changes in kidney function.32 Thus,
and it is therefore essential that clinicians working changes in function can also lack specificity because they
outside the ICU are aware of the clinical presentation can be initially triggered by hypovolaemia without direct
of kidney disease and specifically AKI. In ideal circum damage to the kidney or by direct damage from ischaemia.
stances, a premorbid assessment of kidney function
within the past 3 months might be available and changes Diagnostic criteria and clinical judgment
from this baseline state can be detected by measuring AKI is a clinical diagnosis. A clinician has to interpret
serum creatinine or urinary output. the changes in kidney function (or lack thereof) in the
1950 www.thelancet.com Vol 394 November 23, 2019

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context of the clinical picture. Patients who are critically Cardiac surgery Acute decompensated
ill and injured who are cared for in modern ICUs are heart failure
rapidly volume resuscitated making hypovolaemia per se
an improbable cause of persistent changes in kidney
function. However, some conditions (eg, heart failure)
and medications (eg, angiotensin-converting enzyme
inhibitors) can mimic hypovolaemia in some ways. Thus,
the astute clinician has to consider the various potential Shock
causes of altered kidney function and kidney tissue
damage (panel 3).33–48
The conditions described in panel 3 are not solely for Drugs
patients who are critically ill. Indeed, outside the ICU, Sepsis
infections like pneumonia are common causes of AKI25
and medications are also commonly implicated. In
the pre-hospital setting and especially in low-income
countries where gastrointestinal losses are a major cause
of AKI, hypovolaemia is a common problem.
Even in patients who are hospitalised, intravascular
hypovolaemia can occur secondary to excess fluid losses Thrombotic Pre-eclampsia
microangiopathy
from wounds and drains, from the gastrointestinal tract, AKI
redistribution of fluid into the extravascular space, Obstruction
decreased fluid intake, and from use of diuretics. Such Toxins
patients were often labelled as having pre-renal azotaemia Cancer
rather than AKI. The danger here is that AKI looks the Glomerulonephritis
same clinically, and without examining tissue or knowing
the long-term clinical consequences (including CKD), it
is nearly impossible to be sure that tissue or cell injury
has not occurred.3 End-stage kidney disease
Despite the above challenges and nuances, interna

tional consensus criteria have been developed,4 and later
refined,5,6 for the diagnosis and staging of AKI (table 1).
The purpose of these criteria is to standardise the way Figure 1: The clinical spectrum of AKI syndrome
AKI is reported in clinical trials and in epidemiological AKI syndrome can develop as a consequence of different pathological conditions that might or might not lead
studies and to serve as a basis for approaching the to AKI depending on the balance between patient susceptibility and intensity of the exposure. Different
pathological conditions can also interfere in a combined causality as described by the overlapping of the
diagnosis in individual patients. different circles. The dimension of the circles and the area in common with the AKI circle describe the size
There is evidence establishing the value of these of the problem and the frequency of AKI for each pathological condition (in rough approximation based on
criteria. First, in a large before and after study, including data compiled from various sources).2,12–14 AKI=acute kidney injury.
more than half a million patients, an electronic clinical
decision support system was used to help identity Tubular epithelial simplification, tubular epithelial
patients who were hospitalised with AKI.1 The support mitosis, and cell sloughing appear to correlate with clini
system analysed previous creatinine data and reported cally severe AKI (stage 2–3) and have been reported to
changes when they met KDIGO criteria.6 The imple achieve a sensitivity of 0·93 (95% CI 0·85–1·00), specificity
mentation of this clinical decision support system of 0·95 (0·83–1·00), and area under the receiver-operating
resulted in a small (0·8%), but sustained significant and characteristic curve of 0·98 (0·98–1·00).49 An important
clinically meaningful reduction in hospital mortality and limitation to such data, however, relates to possible
also a reduction in hospital duration by nearly a third of a selection bias, small sample size, and the single-centre
day.1 The clinical decision support system provided no nature. Large-scale studies of histopathology are not
clinical management advice, so the effect can be available for AKI. The reason for this is due to the high
attributed specifically to informing clinicians that these risk involved with the kidney biopsy procedure in critically
criteria were met. This reasoning is plausible because ill patients, often anticoagulated or carrying other risks or
subtle changes in renal function are easily missed. In contraindications. Because AKI mainly occurs in these
addition, we now have preliminary evidence that a path patients, the evidence provided by histopathological exams
ophysiological correlate might exist between AKI staging made from biopsies is very limited.
and histology from kidney biopsies.49 Although typical
findings of tubular necrosis appear relatively uncommon, Clinical course
more subtle changes in tubular epithelial cell architecture Nearly two-thirds of AKI cases resolve within 7 days.50
appear present. When a case does not resolve or relapse occurs with

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Timing Functional changes Structural damage*

Change Threshold
Acute kidney ≤7 days Creatinine ≥1·5 times baseline (or increase of Urine volume <0·5 mL/kg for ≥6 h Undefined
injury ≥0·3 mg/dL within any 48 h period)
Acute kidney >7 days, <90 days Creatinine ≥1·5 times baseline (or increase eGFR <90 mL per min (with damage marker) Kidney damage
disease ≥0·3 mg/dL within any 48 h period) eGFR mL per min per 1·73 m² <60 mL per min
Chronic kidney ≥90 days Not applicable eGFR <90 mL per min (with damage marker) Kidney damage
disease eGFR mL per min per 1·73 m² <60 mL per min
Comparisons are in terms of timing, functional changes, and structural damage. eGFR=estimated glomerular filtration rate. *Kidney damage can be assessed by pathology,
urine or blood markers, or imaging. Stuctural criteria are not included in the current definitions for acute kidney injury as none have yet been validated for this purpose.
Table 1: Comparison of acute kidney injury, acute kidney disease, and chronic kidney disease
diagnostic approach to and the treatment of AKI. Several

Panel 2: Staging of acute kidney injury according to current molecules have been identified as potential markers for
Kidney Disease Improving Global Outcomes definition early detection of kidney damage before serum creatinine
Stage 1 rises (table 2).53–62 However, limitations in specificity
Creatinine ≥1·5 times baseline or increase of ≥0·3 mg/dL (especially in patients with comorbid conditions) and in
within any 48 h period, or urine volume <0·5 mL/kg for some cases, sensitivity, have meant that damage markers
6–12 h are used mainly for research purposes.
A second generation of markers was developed mostly
Stage 2 in the past 5 years using modern definitions of AKI.
Creatinine ≥2·0 times baseline or urine volume <0·5 mL/kg Two markers of cell cycle arrest, tissue inhibitor of
for ≥12 h metalloproteinases 2 (TIMP-2) and insulin-like growth
Stage 3 factor binding protein 7 (IGFBP7) have been incorporated
Creatinine ≥3·0 times baseline or increase to ≥4·0 mg/dL or into the first diagnostic test for AKI approved by the US
acute dialysis, or urine volume <0·3 mL/kg for ≥24 h Food and Drug Administration—Nephrocheck (Astute
Medical, San Diego, CA, USA). This test is also available
in many countries around the world. Unlike damage
subsequent lack of resolution, substantially worse clinical markers, TIMP-2 and IGFBP7 can be released in response
outcomes are expected. Patients with stage 2–3 AKI who to non-injurious, noxious stimuli.53,63 The molecules are
resolve within 7 days and remain alive and free of renal preformed and do not require gene transcription to be
dysfunction by hospital discharge have a 1-year survival expressed.63,64 These characteristics have led us to refer to
of more than 90%. By contrast, patients who never them as kidney stress markers (figure 5).65,66
resolve, have a 47% hospital mortality and, among those Two single-centre studies have shown benefit associated
who are discharged alive, 1-year survival is only 77%.50 with use of urinary [TIMP-2 × IGFBP7] in patients after
Thus, it is important to ensure that patients who can surgery.18,67 In one study,18 biomarker-positive patients who
recover renal function do so and for those that do, to help were undergoing cardiac surgery were randomly assigned
insure that they do not have a clinical relapse.24 to receive a care bundle that included fluid management
Relapses might reflect additional injuries or recurrent and titrating vasoactive medication. AKI was significantly
exposures, which are regrettably common.51 They might reduced with the intervention compared with the controls
also result from renal compensation. Hyperfiltration can (55·1 vs 71·7%; absolute risk reduction 16·6%, 95% CI
result in apparent recovery from AKI, only to then lead to 5·5–27·9; p=0·004).
subsequent deterioration. Unfortunately, most patients In another study,67 a similar care bundle including
do not receive nephrology follow-up after AKI.52 These early optimisation of fluids and maintenance of
concepts have led to the conceptual framework depicted perfusion pressure was given to patients undergoing
in figure 3. From this conceptual framework, it emerges non-cardiac major surgery after testing positive for the
that different situations can occur with possible damage biomarker. Overall, AKI rates were not statistically
or dysfunction, or coexistence of the two in a frank AKI different between groups at 19 (32%) of 60 in the
syndrome. The framework of definitions is detailed in intervention group versus 29 (48%) of 61 in the standard
table 1 while the clinical and pathophysiological AKI care group (p=0·076). However, rates of moderate and
continuum is schematically depicted in figure 4. severe AKI, a secondary endpoint, were reduced with the
intervention (four [6·7%] of 60 vs 12 [19·7%] of 61;
Modern diagnostic methods p=0·04), as were lengths of ICU stay (median difference
Two advances from the past 10 years, the discovery of AKI 1 day; p=0·035) and hospital stay (median difference
biomarkers, and the application of computer decision 5 days; p=0·04). These results, although statistically
support, have the potential to substantially improve the significant, have limited robustness given the small

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15–32%
39 per 1000 15–20%
22–25%
18 per 1000
8–24%
13–24%
29–31%
17–26%
37 per 1000
Figure 2: AKI epidemiology per hospital admission and corresponding incidence by region
AKI incidence taken from various sources compiled by Susantitaphong and colleagues,22 Mehta and colleagues,13 and Hoste and colleagues.23 Hospitalisation rates for
the USA were obtained from the US Centers for Disease Control and Prevention and for other countries from the Organisation for Economic Co-operation and
Development. In Europe, hospitalisation rates per population vary from 8·5% in Portugal and 9·6% in the Netherlands, to 25·7% in Germany and 25·3% in Austria.
An average rate of 17% was therefore used. For other regions, information on hospitalisation rates is not available. Given that there is a two times variation in
population incidence despite similar rates per hospital admission, it seems probable that many AKI occurrences are not captured.21–23 AKI=acute kidney injury.
sample size. Furthermore, no significant differences involving 24 000 patients did find partial adoption and an
were observed in the use of renal replacement therapy effect on hospital duration.75 However, the effect size was
(RRT) or in-hospital mortality in either study. not much larger than that achieved by provision of the
As with any diagnostic test, it is important to use those alerts alone without care recommendations.1
such as urinary [TIMP-2 ×
IGFBP7] in the intended
population in which its test characteristics are favourable— The pathophysiology of AKI
in this case, patients who are critically ill. When used in AKI is a loose collection of syndromes. Thus, its patho
patients who are low risk, the false positive rate will physiology varies according to the myriad of conditions
increase. When used before an injurious exposure has associated with its development.76 In addition, the
occurred, the test will not forecast AKI. Similarly, the test pathophysiology of AKI secondary to uncommon imm
might not remain positive for a long time after injury, unological diseases of the kidney parenchyma (glom
particularly if the insult was not persistent. erulonephritis) or direct infection of the renal parenchyma
Besides biomarkers, other diagnostic tools are under (pyelonephritis) is complex.77,78 The same applies to acute
going technical and clinical evaluation to refine risk (but also uncommon) vascular events, which can cause
assessment and AKI diagnosis. Among these are real- parenchymal injury, and to obstructive disease of the
time GFR measurement, assessment of renal functional urinary tract.
reserve (glomerular stress test), and assessment of Drug-induced AKI is also relatively common both in
tubular reserve (furosemide stress test). Despite their patients who are hospitalised and in the community.
potential utility and clear rationale, these tests are still However, the pathophysiology and mechanisms of such
under evaluation and are thus research tools not yet used injury vary from drug to drug and are described in
in clinical medicine. dedicated articles and books.79,80 Finally, severe hypo
Finally, information technology is used in large centres volaemia, as can be seen in diarrhoeal diseases or other
to do both pragmatic trials and to establish algorithms forms of obvious volume losses, is typically addressed and
for electronic AKI alert procedures.68–75 Several lines of resolved by rehydration and does not usually raise complex
evidence suggest that electronic data collection and sub issues of pathophysiology. Thus, here we will focus on
sequent analysis by expert or machine learning systems AKI conditions such as sepsis, major surgery, cardiac
could provide support for accurate detection, early surgery, cardiorenal syndrome, and hepatorenal syndrome,
diagnosis, and prevention of AKI. which dominate in patients who are hospitalised2,14 and
However, evidence is inconclusive as to what specific remain poorly understood. General risk factors for AKI
interventions can be effective when driven by electronic include advanced age and underlying CKD.
alerts. A randomised trial involving 2300 patients
found that clinical adoption of the interventions recom Sepsis-associated AKI
mended by the alert system was poor and did not affect Sepsis is the most common trigger of severe AKI in
outcomes.74 Subsequently a larger step-wedge trial patients who are critically ill.2,14 Its pathophysiology,

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Panel 3: Causes and pathophysiological mechanisms of AKI

Renal hypoperfusion species or nitric oxide production can contribute to endothelial
Renal hypoperfusion due to several causes (hypovolaemia, damage, which leads to increased vascular permeability and
systemic vasodilatation, increased vascular resistance, among worsening interstitial oedema. Septic cardiomyopathy can
others) activates adaptive mechanisms (ie, autoregulation contribute to renal hypoperfusion.35,40,41
mechanisms, sympathetic nervous system, and RAAS) to Major surgery
maintain GFR. When the hypoperfusion is sustained or the The fluid depletion related to several causes (eg, blood losses,
adaptive response is inadequate, GFR is initially decreased increase in insensible losses, extravasation of fluid to the third
without parenchymal damage (ie, pre-renal AKI); then, if an space, among others) and the systemic effects of anaesthetic
adequate renal perfusion is not restored, organ damage can drugs (eg, peripheral vasodilation, myocardial depression,
occur (ie, ischaemic acute tubular necrosis). In this case, among others) are considered the main cause of AKI in patients
the sustained inadequate oxygen and nutrient delivery to the undergoing surgery. The increased level of circulating cytokines
nephrons and the ATP-depletion activates epithelial cellular and reactive oxygen species, respectively due to the endotoxin
injury and death via necrosis or apoptosis, or both, load from impaired visceral perfusion and ischaemic-
which ultimately leads to endothelial injury, activation of reperfusion-injury, contributes to renal damage.42,43
inflammatory processes, and renal damage and
dysfunction.32–34 Intra-abdominal hypertension
The increase of intra-abdominal pressure over certain values
Cardiorenal syndrome type 1 leads to a decrease in renal perfusion due to the reduction of
An acute worsening of cardiac function can lead to renal both arterial inflow and venous outflow and the increase of
hypoperfusion through a reduction in effective circulation fluid Bowman’s space hydrostatic pressure. The systemic
volume or an increase in central venous pressure. Other potential inflammation, due to the impaired visceral perfusion and the
mechanisms involved are sympathetic nervous system and RAAS production by the kidney of inflammatory mediators,
activation, chronic inflammation, and imbalance in reactive contributes to kidney damage.44,45
oxygen species, or nitric oxide production.9,35–37 Rapidly progressive glomerulonephritis
Nephrotoxin exposure (toxic acute tubular necrosis) In patients who are genetically predisposed, different agents
Nephrotoxic drugs (eg, antibiotics, contrast media, among activate an autoimmune response that results in glomerular
others) and endogenous toxins (eg, myoglobin, uric acid, inflammation and injury.46
among others) are filtered and concentrated (some of them also Acute interstitial nephritis
reabsorbed or secreted) by the nephrons and could reach toxic In patients who are genetically predisposed, drugs or infectious
levels for the tubular cells. Toxins can: (1) have a direct cytotoxic agents can activate an immune reaction. The interstitial
effect on renal tubular epithelial or (2) endothelial cells, inflammatory cellular infiltrates stimulate the expression of
(3) determine impaired intrarenal haemodynamics cytokines that contribute to the amplification of the process
(eg, mesangial cell constriction), and (4) cause precipitation of and the production of extracellular matrix. If the process is not
metabolites or crystals, among others.33,38 interrupted at the appropriate times, interstitial fibrosis can
Sepsis occur.47
The exact mechanism for sepsis is still under investigation. Post-renal AKI
Macrovascular and microvascular dysfunction, immunological Extrarenal (eg, prostate hypertrophy, retroperitoneal fibrosis,
and autonomic dysregulation, and abnormal cellular response among others) or intrarenal (eg, nephrolithiasis, blood clots,
to injury are proposed. An increase in the level of circulating among others) obstruction leads to an increase in intratubular
inflammatory cytokines and leucocyte activity can lead to the pressure, impaired renal blood flow, and inflammatory processes
formation of capillary microthrombi. These, along with that can result in severe complications, depending on previous
redistribution of intrarenal perfusion due to altered vascular kidney function, the severity of the obstruction, and the time of
tone and shunting, kidney inflammation, and oedema, can onset in AKI.48
decrease capillary blood flow and oxygen delivery and increase AKI=acute kidney injury. GFR=glomerular filtration rate. RAAS=renin–angiotensin–
aldosterone system.
venous output pressures. The imbalance in reactive oxygen
however, remains poorly understood. The overwhelming Two possible mechanisms for increased renal blood
majority of our pathophysiological theories are derived but decreased GFR have been proposed and can occur
from animal models and their relevance to human simultaneously: efferent arteriolar vasodilatation85,86 and
disease remains controversial.81 However, large animal intrarenal shunting.87–89 Such shunting can divert the
models of septic AKI show that in Gram-negative increased renal blood flow to the cortex and away from
bacteraemia renal blood flow increases above normal the medulla and contribute to decreased medullary
levels and renal histopathology in the first 48 h is oxygenation.90 These findings support the need for the
indistinguishable from normal.82–84 measurement of renal blood flow in humans. However,

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magnetic resonance-based techniques are difficult to Mitigation or Removal of toxic drugs

use and cannot provide continuous measurements.91 intervention Limitations of imaging procedures
Para-amino hippurate clearance is invasive, has only Control of inflammation
been used in a few patients with established septic Risk Stress Injury
shock, and showed a renal blood flow decrease of
approximately 20% compared with well patients post-
Risk
No acute kidney Damage Inflammation
cardiac surgery.92 There is also limited information on
Risk modifiers
injury Biomarkers Nephrotoxic drugs
tubular injury early in the course of sepsis. No signs or Urine abnormalities Contrast media
Mitigation or Mitochondrial
The experimental data available show that the degree intervention symptoms Imaging
Stress
No evidence dysfunction
Volume optimisation
of tubular injury is generally mild and that acute Haemodynamic
Hypoperfusion
Anaemia
tubular necrosis is uncommon.84 However, even mild stabilisation Congestion
tubular injury can contribute to loss of GFR via Correction of anaemia
Decreased GFR
Improved cardiac
activation of the tubuloglomerular feedback reflex.93 performance Dysfunction Acute
Sympathetic system activation94 and neurohormonal Control of Decreased GFR kidney injury
inflammation Decreased RFR Increased serum
responses unique to the kidney appear to be activated
Altered tubular creatinine
in the setting of AKI.95 They include activation of function Decreased UO
the renin– angiotensin–aldosterone system, activation
of the renal sympathetic system, and activation of
the tubuloglomerular feedback system.96 Such findings Risk modifiers
might reflect association rather than causation. Volume depletion

However, their activation has been reported in expe Haemodynamic alterations
Sepsis
rimental models of general anaesthesia, which also Diabetes
show markedly decreased renal blood flow by the Catabolic state
administration of anaesthetic agents, even in the Anaemia
absence of surgery.97 Figure 3: Conceptual framework of AKI syndrome based on functional and damage criteria
In the top left panel, no evidence of damage or dysfunction might identify a normal clinical condition; in the
Cardiorenal syndrome bottom left panel, a progressive decrease in GFR with increase in serum creatinine shows kidney dysfunction
alone. This dysfunction might occur with the use of an angiotensin-converting-enzyme inhibitor, which can
In the case of acute decompensated heart failure, the reduce GFR without damaging the kidney. In the top right panel, kidney damage is identified by specific
condition of cardiorenal syndrome type 1 (AKI due to biomarkers, but no dysfunction is present (normal serum creatinine). This condition has also been described as
cardiac disease) can develop because of a low cardiac subclinical AKI. In the bottom right panel, both damage and dysfunction are present. Red arrows show
output state, renal vein congestion, or both.98,99 Both progression, whereas green arrows show regression or recovery. Progression or regression can be affected by risk
modifiers or by specific interventions. AKI=acute kidney injury. GFR=glomerular filtration rate. RFR=renal
conditions can affect kidney perfusion pressure while functional reserve. UO=urine output.
compensatory mechanisms can become insufficient
to maintain blood flow autoregulation. Inflammation,
neurohormonal activation, and concomitant drug toxicity congestion, preoperative risk factors, predisposing
with the presence of pre-existing kidney CKD can conditions such as CKD, and diabetes (common in this
contribute to the development of the syndrome.37,38,98,100–102 population). Decreased perfusion and oxygen delivery
during car diopulmonary bypass are probably impor
Hepatorenal syndrome tant and can be visually shown with microvascular
The hepatorenal syndrome is perhaps the most extensively imaging.107,108 The effects of free haemoglobin together
studied of the AKI syndromes in terms of neurohormonal with systemic inflammation are likely to also be
changes.103,104 This syndrome is associated with high important.
amounts of activation of the renin–angiotensin–aldosterone
system, suggesting that neurohormonally driven vaso Distant organ effects of AKI
constriction leads to its development. In this regard, In many conditions, the presence of AKI can induce
decreased systemic blood pressure secondary to systemic dysfunction or damage of distant organs. This effect on
vasodilatation is considered a key event in triggering this distant organs can be the case in cardiorenal syndrome
response.105 type 3 (cardiac disease precipitated by or contributed to
by AKI), in which the heart is affected with myocardial
Cardiac surgery-associated AKI contractility defects and inflammatory infiltrates in the
Mortality associated with cardiac surgery is low cardiac tissue. Another example is represented by the
compared with that in the past, other major surgeries, multiple interactions with the lungs.109,110 The effect of
and other causes in hospital, but the occurrence of AKI acute or chronic uraemia on brain physiology and
is common.106 The pathophysiology of cardiac surgery- cognitive function has also been studied,111 as have the
associated AKI remains poorly understood and multi effects of AKI on the liver.111–113 There is a clear need to
factorial.106 Key factors are likely to include postoperative explore crosstalk and interactions between different
low cardiac output (including right-heart failure), organ organ systems in patients who are critically ill.102,114–117

Seminar
The literature on complex syndromes with multiorgan multiple organ dysfunction makes combined forms of
involvement emphasises the need for multidisci extracorporeal organ support highly recommended or
plinary management. In these conditions, the level of even mandatory.118,119
Normal kidney
Baseline GFR >90 mL per min
High susceptibility
CKD
Baseline GFR >60 mL per min
Figure 4: The continuum of
AKI
Different original conditions
are possible (normal, Acute Exposures
increased susceptibility, or or chronic
CKD). When exposure causes
injury or dysfunction or both, Full recovery AKI
different outcomes are (baseline GFR
possible depending on risk >90 mL per min and
modifiers and patient’s RFR >30 mL per min,
full nephron mass)
response. Normal kidney:
normal baseline GFR (>90 mL
per min) and intact RFR
(>30 mL per min); highly
susceptible kidney: baseline Stage 1 Stage 2 Stage 3
GFR >90 mL per min and RFR Stress Damage Dysfunction
<30 mL per min or previous
history of AKI. AKI=acute
kidney injury; syndrome Apparent full recovery
defined by the current Kidney (baseline GFR >90 mL per min
Disease Global Initiative and RFR <30 mL per min, Resolution Regression Progression
diagnostic criteria and partial nephron loss)
classified into three stages
depending on values of serum
creatinine and UO. Reversal is
within 7 days. AKD=acute Persistent
kidney disease; acute AKI and
condition of the kidney that AKD
can precede, coexist, or follow
Adaptive
an episode of AKI but not Kidney recovery repair
necessarily leads to or results (GFR >60 mL per min) Maladaptive
from AKI. The temporal Progressive scarring repair
window is 90 days. AKD can
reverse or progress to CKD.
CKD=chronic kidney disease;
a chronic condition of the Reversal
kidney that might precede,
coexist, or follow an episode Fibrosis–sclerosis
of AKI. CKD is a steady state Clinical patterns
condition defined by Kidney 1 Early sustained reversal CKD–end-stage kidney disease
Disease Global Initiative 2 Late relapse Chronic dialysis
criteria into five stages. 3 Relapsing AKI with recovery
4 Relapsing AKI without recovery
ESKD=end-stage kidney
5 Non-reversal
disease requiring dialysis
(corresponds to stage 5 CKD).
GFR=glomerular filtration
rate. RFR=renal functional
reserve. UO=urine output.

Seminar
Sample Class Appearance or peak after injury* Functional role in the kidney
type
Tissue inhibitor of metalloproteinase-2; Urine Stress Immediately after cardiopulmonary Cell-cycle arrest: can induce cell-cycle arrest—thought to be a protective mechanism8
insulin-like growth factor-binding protein 7 bypass;53 peaks at 6–24 h
Neutrophil gelatinase associated lipocalin Urine or Damage <4 h after cardiopulmonary Iron trafficking: binds to iron-siderophore complexes in renal tubular epithelial cells;
plasma bypass;54 peaks at 4–6 h tubular epithelial genesis: forms an iron-siderophore complex (holo-neutrophil
gelatinase associated lipocalin), which is secreted by the ureteric bud, and can induce the
genesis of tubular epithelium;55 anti-inflammatory and anti-apoptotic56
Kidney injury marker-1 Urine Damage 12–24 h; peaks at 2–3 days57 Renal recovery and tubular regeneration: clearance of apoptotic bodies58; anti-
inflammatory effect59
Liver-type fatty acid binding protein Urine Damage Unknown Fatty acid uptake and intracellular transport: mobilises lipid peroxides from cytoplasm
of tubular epithelial cells to tubular lumen; L-FABP gene expression is increased by
peroxisome proliferator activated receptor-α60 and hypoxaemia61
Cystatin C Serum or Function NA None, filtration marker; cystatin C is normally taken up by renal tubular epithelial cells;
urine as such its appearance in the urine indicates tubular dysfunction
Pro-enkephalin Serum Function NA None, filtration marker
NA=not applicable. *Available evidence for the time from injury to detection of the marker. Filtration markers have a variable relationship to injury so specific times are not possible to establish.
Table 2: Characteristics of acute kidney injury biomarkers
Prevention of AKI In a study of 3000 such patients, a restrictive intra-

The first principle of AKI prevention is to treat its cause venous fluid regimen, designed to provide a net zero
or trigger. The second principle is to ensure that further fluid balance, was associated with an 8·6% rate of AKI
insults are avoided. Systemic haemodynamics should compared with a 5·0% rate with standard fluid therapy
be optimised so that, irrespective of the trigger, further (p<0·001). By contrast, in patients with septic shock,
damage does not occur and adequate renal perfusion protocolised resuscitation resulted in more fluids admin
and perfusion pressure are maintained. If intravascular istered but no decrease in the rates of AKI observed or its
volume is compromised, it must be rapidly restored by duration or severity.12,122
administration of intravenous fluids. Fluid composition has also been the subject of substantial
The extent of fluid administration and whether a degree investigation. The use of hydroxyethyl starch has been
of fluid overload is permissible remains unknown and shown to result in increased rates of AKI especially in
is likely to be modulated by the clinical context. patients with sepsis,123,124 while saline has been shown to
Such administration, however, must be both rapid and increase the risk for the composite of death, dialysis, and
sufficient but also judicious (figure 6). In this setting, persistent renal dysfunction compared with fluids that are
although of unproven benefit, haemodynamic monitoring more similar to physiological ones such as Ringer’s lactate
is a standard of care. Such monitoring can be achieved by solution.125,127
means of physical examination (ie, assessment of capillary Avoidance of other nephrotoxic drugs is another
return, peripheral skin perfusion, neck vein inspection, important step in preventing AKI or shortening its
and measurement of blood pressure and heart rate). course.127 However, no specific drug-based intervention
However, in patients who are more severely ill, invasive has been consistently and reproducibly shown to be
haemodynamic monitoring (eg, central venous catheter, kidney protective. Thus, there is no established pharma
arterial cannula, and even cardiac output monitoring in cotherapy for AKI. Among patients undergoing cardiac
some cases) is a standard of care. Adequate oxygenation surgery, off-pump coronary artery bypass grafting has
and haemoglobin concentration (at least >70 g/L) must been shown to attenuate renal injury. However, the
be maintained or rapidly restored. In 2019, a large magnitude of effect is small and the inferior quality
randomised trial showed that such a restrictive approach of grafting is a major concern.128 AKI prevention and
does not increase the risk of AKI.120 protection measures from further insults have been
If patients remain hypotensive (eg, mean arterial implemented in the past 3 years using urinary biomarkers
pressure [MAP] <65 mm Hg) after adequate intravascular for risk assessment. Biomarker-driven application of
volume expansion, restoration of MAP will require the specific bundles derived from KDIGO recommendations,
addition of vasopressor drugs. If an adequate volume has or structured organisation of nephrology rapid response
been provided and MAP is also adequate, yet the patient teams has permitted reductions in the occurrence of
develops AKI, cardiac output might be inadequate and severe AKI cases and the requirement of RRT in a
needs to be measured. In this setting, correction of a low substantial number of cases.18,67
cardiac output state can require inotropic drugs or even Contrast-associated AKI is becoming less frequent
mechanical devices. The importance of adequate fluid because of reduced toxicity and lesser amounts of
therapy in patients undergoing major abdominal surgery contrast media used for imaging techniques. However,
has been highlighted by the recent RELIEF trial.121 prevention measures should still be considered for

Seminar
A 7 mmol/L or electrocardiographic signs of hyperkalaemia

appear, RRT should be rapidly implemented.
Metabolic acidosis is common but rarely requires
Exposures Stress biomarkers treatment if mild or moderate. A randomised controlled
trial of 389 patients in the ICU, however, has shown a
potential beneficial effect of bicarbonate therapy in severe
metabolic acidosis in association with AKI.134
B
Anaemia might require correction, and a target of more
than 70 g/L is considered appropriate. To avoid drug
Insult or injury Damage biomarkers toxicity or drug-induced complications, drug therapy must
be adjusted to account for the loss of renal function. Stress
ulcer prophylaxis has not been specifically studied in
C patients with AKI, but is considered advisable in patients
who are ventilated in the ICU.135 Great attention should
Persistent insult be paid to the prevention of infection. Loop diuretics
or injury Dysfunction biomarkers can help manage fluid balance in patients who are
polyuric. However, in patients who are oliguric or have
fluid overload, early RRT is advisable. Severe azotaemia
(urea >30–35 mmol/L or creatinine >300–400 µmol/L) is
Figure 5: Events in the development of acute kidney injury and relevant
biomarkers
best treated with RRT unless recovery is imminent or
(A) Cellular stress detected by cell-cycle arrest biomarkers (eg, tissue already under way.
inhibitor of metalloproteinase-2 and insulin-like growth factor-binding Cardiorenal syndrome type 1 can be reversed resolving
protein 7). The condition is potentially reversible and cell damage might or the condition of low cardiac output state or improving
might not occur. (B) Cellular damage characterised by alteration of cell
metabolism and expression of adhesion molecules. The process is detected by
renal function. However, the pharmacological and sup
damage biomarkers (molecules not appropriately handled at the tubular level portive treatment should be paralleled with removal of
like albumin and cystatin C, or constitutive or induced molecules at tubular level toxic drugs, restricting imaging procedures with contrast
like N-acetyl-β-D-glucosaminidase and kidney injury molecule-1, or molecules agents, and control of the inflammatory response.137
produced by infiltrating immune cells like neutrophil gelatinase associated
lipocalin and interleukin-18. (C) Exfoliation of viable cells into the tubular lumen
Hepatorenal syndrome is a form of AKI. Several
with obstruction, necrosis, and apoptosis of tubular cells. Kidney dysfunction studies and meta-analyses suggest that a long-acting
and decreased glomerular filtration rate detected by endogenous or exogenous vasopressin derivative (terlipressin) improves GFR and
filtration markers like cystatin C, creatinine, and dye. probably patient outcomes in this condition.137 However,
this effect could simply be related to an increase in MAP,
individual patients, especially in particular settings such which can also be achieved with other vasoactive drugs
as oncology or interventional cardiology.129–131 A pivotal and highlights the importance of perfusion pressure in
multicentre randomised controlled trial has shown this setting.138 In addition, randomised controlled trials
that N-acetylcysteine and bicarbonate do not provide suggest that the addition of albumin to terlipressin could
additional protection beyond hydration therapy.132 achieve further levels of renal protection.139
Acute management of established AKI RRT and extracorporeal support

Clinical and pharmacological management In some patients, AKI is severe enough to require
Once AKI is both advanced and established, the focus of RRT.133,140,141 No single set of criteria exists to justify such
management should remain on delivering the same intervention. However, clinicians must consider factors
interventions used to prevent its development.133 However, like potassium levels, fluid status, acid-base status,
an additional focus of medical management should creatinine and urea levels, urine output, the overall
be directed to the prevention or rapid treatment of course of the patient’s illness, and the presence of other
complications. Such management might vary in com complications.142
plexity from fluid restriction to the initiation of extra The best time to start RRT remains controversial. Three
corporeal RRT. Nutritional support is an accepted randomised trials from 2016–17 have attempted to address
standard of care. However, no level 1 studies exist to this issue. The first143 assigned 620 patients in the ICU
define what optimal nutritional therapy should be in with KDIGO AKI stage 3 to immediate RRT or delayed
patients with AKI. Calorie and protein intake, as for other RRT (in which RRT was started in response to severe
patients in the hospital or ICU, seems acceptable. The hyperkalaemia, severe metabolic acidosis, pulmonary
use of specific renal nutritional solutions is not sup oedema, 72 h of oliguria, or a blood urea concentration of
ported by evidence. There are no specific vitamins or >37 mmol/L). Such a delayed interventional strategy did
trace element requirements. Potassium levels should not affect mortality, but decreased the use of RRT, the
be monitored. Hyperkalaemia (>6 mmol/L) should be incidence of catheter-related bloodstream infection, and
promptly treated. If serum potassium is more than shortened the time to diuresis.

Seminar
This trial was criticised for comparing late with very late this issue. The small to medium sized studies done,
RRT and for using intermittent haemodialysis (instead of however, do not suggest a difference in patient survival.
continuous RRT) in a large proportion of patients, even Accordingly, on the basis of patient survival, intermittent
though the majority of patients were on vasopressor haemodialysis, slow extended dialysis, or continuous
therapy. The second trial144 assigned 231 patients with RRT all appear acceptable options for RRT.152 However,
KDIGO stage 2 AKI to early or delayed (within 12 h of a body of observational evidence and meta-analyses
stage 3 or not at all) RRT. It found that early RRT (all by suggest that, compared with continuous RRT, the use of
continuous RRT) reduced mortality from 54·7% to 39·3% intermittent haemodialysis might be associated with
and increased the chance of renal recovery. This study delayed renal recovery.153
was criticised for not being multicentric, including a After a seminal study of RRT intensity,154 two large multi
cohort of only surgical patients, and being dominated by centre randomised controlled studies (the ATN study155
post-cardiac surgery AKI.145 The third trial146 focused on and the RENAL study156) have defined the standard for
patients with sepsis and AKI in French ICUs and assigned
488 patients with septic shock with the equivalent of
stage 3 KDIGO AKI to either RRT within 12 h or a delay
of 48 h if renal recovery had not occurred. Lacrimation
The study found no significant differences in mortality Mucosa
or other patient-centred outcomes. It was, however, Neck veins Central venous pressure and saturation
criticised for using intermittent haemodialysis in a third Inferior vena cava
of patients despite the presence of shock, an uncommon
Heart sounds Echocardiography
approach in most ICUs in Australia, New Zealand, Rales
North America, and the UK. Furthermore, 9% of patients
died during the delay of 48 h and another 17% required
emergent RRT. In light of this continuing controversy,
a much larger trial involving 3000 patients was started
Arterial line
and is now close to completion.147
Once a decision is made to begin acute RRT, three Blood pressure pulse Pulse-pressure variation
forms of RRT are available: continuous RRT, intermittent
RRT either in the form of intermittent haemodialysis or
Capillary refill
slow extended dialysis, and peritoneal dialysis.148–150
Because of its clearance limitations, difficulty with fluid
removal, and complications, peritoneal dialysis is rarely
used in adults in high-resource countries150 but is
frequently used in many resource-limited countries.
In such countries, there has been increased interest in Oedema
its use as a logistically efficient method of dialysis. In

Straight leg raise
this context, several studies have reported satisfactory
performance and outcomes.150,151
There is much controversy as to whether intermittent
or continuous RRT should be used. No suitably powered
randomised controlled trials have been done to address
Illness severity
Figure 6: Risk for complications related to fluid balance in patients with Restrictive fluid protocols Liberal fluid protocols
normal and compromised heart function
In a non-critically ill patient (left) fluid status is assessed by history and physical Diseased heart
examination. In the proper context (eg, diarrhoeal illness) with consistent signs
and symptoms (eg, dry mucous membranes, increased thirst), physical Procedures
Risk of complications
Drugs
examination findings will often suffice. In more complex patients (eg, underlying Renal replacement therapy
Normal heart
congestive heart failure) or in those with critical illness (eg, septic shock), more
invasive methods will often be required (illustrated by the right side of the
figure). Little evidence exists that one form of functional haemodynamic
monitoring is superior to another but dynamic measures (eg, pulse-pressure Hypotension
variation) are superior to static measures (central venous pressure). Bottom Tachycardia Hypertension
panel: relationship between hydration status and complications in acute kidney Shock Peripheral oedema
injury is a u-shaped curve. In the case of fluid restrictive protocols, the patient Organ hypoperfusion Impaired pulmonary exchanges
might experience hypotension and organ hypoperfusion perpetuating the Oliguria Organ congestion
Renal dysfunction Optimal status Renal dysfunction
damage to the kidney. The same problem can occur in case of too liberal policies
where the congestive state might impair kidney function and cause severe
Dehydration Fluid balance Overhydration
clinical complications.

Seminar
solute removal intensity at a delivered dose of continuous management.179 Importantly, however, not all episodes of
RRT equivalent to 20–25 mL/kg per h of effluent AKI lead to death or to CKD, so studies evaluating the
generation. Importantly, in both studies, all patients with effects of short-term interventions to prevent AKI on
AKI on vasopressor support received continuous RRT, long-term outcomes will need much larger sample sizes.
implying that continuous RRT is considered the standard Two recent studies from 2017 and 2018 evaluating
of care in patients who are haemodynamically unstable.157 balanced crystalloids compared with saline have shown
Although these two pivotal trials defined the standard small effects.125,126 Both trials found small effects on rates
of solute clearance, no large multicentre randomised of death, dialysis, and persistent kidney dysfunction
controlled trials have yet addressed the issue of volume favouring balanced fluids, and each study required
control. Thus, even though there is concern about the enrolment of more than 10 000 patients.
impact of a positive fluid balance on renal and patient
outcomes,158 volume management remains guided by Post-AKI care
individual clinical judgment.159 Once RRT is started, Patients with AKI tend to have worse medium-term to
there is uncertainty about when it should be stopped. No long-term outcomes than other patients who did not de
randomised controlled trials have addressed this issue. velop AKI.180,181 This observation suggests the opportunity
Observational studies have suggested that a spontaneous to improve care by close follow-up of patients who have
urine output of more than 500 mL per day seems to have one or more episodes of AKI during hospital or ICU
sufficient discrimination to be used for the purpose of admissions.182 These patients seem particularly fragile
considering a trial of continuous RRT cessation.160 and might require specific medical interventions.183
In the appendix, we schematically summarise the sub Of course, this extension of care will require additional
sequent steps that should be considered and implemented resources and might be challenging to do in many
from the first patient observation to the development of communities. Risk prediction models that can identify
AKI and the prescription of RRT. Once the targets for patients at high risk for subsequent CKD following AKI
RRT have been identified, the right prescription in could be very helpful in targeting patients most likely to
terms of modality and operational parameters should be benefit from this care.184
made, ensuring continuous monitoring and a data-driven
feedback on therapy modification. In this process, Conclusion
technology can help to prescribe, deliver, and monitor the AKI is undergoing substantial evolution in terms of
treatment and to modify the various steps based on definition and classification, understanding of patho
personalised dynamic criteria.161–166 physiological mechanisms, and interaction with other
disciplines and organ systems. Epidemiology describes an
AKI as a risk factor for CKD increasing incidence partly due to a more thorough
Over the past decade, multiple studies have shown a clinical evaluation and detection. New biomarkers and
strong epidemiological link between AKI and the advanced diagnostic techniques represent an important
subsequent development of CKD.167–172 The additional advancement in the field, leading to implementation of
risk of end-stage kidney disease after AKI has been timely and effective preventive and protective measures.
estimated at an additional 0·4 extra cases per 100 person- The management of patients with AKI has improved
years, and the additional risk of CKD after AKI has been together with the improvements in hospital and intensive
estimated at ten extra cases per 100 person-years.171 If the care quality, supported in part by sophisticated technology
link between AKI and CKD is causal, the public health of extracorporeal organ support, a more personalised
consequences of AKI in terms of CKD and end-stage pharmacological therapy, and a standardised and proto
kidney disease epidemiology are substantial. colised management of physiological endpoints. This
Several mechanisms have been proposed, which once Seminar reports on the new concepts that have emerged
triggered by AKI, could contribute to the development in the past 5 years corroborated by the most recent contri
of CKD. These mechanisms can be activated by AKI butions to the literature. In many areas, controversies
independently of the cause or trigger173 and involve a still exist but consensus has been reached in several
process that has been termed maladaptive repair174 protocols and treatments so that true benchmarking and
(figure 4). In experimental models, this process appears quality control are possible.
to involve transformation of tubular cells into fibroblasts, Several regions are still left behind and preventable
inflammatory cells are recruited, which also contribute causes of AKI should be reduced or eliminated. Access to
to the secretion of pro-fibrotic cytokines, the transition new technologies might also be limited in several
of endothelial cells to mesenchymal cells, pericyte geographical areas and this limitation will represent a
transformation into myofibroblasts, and activation of challenge for the near future: a sustainable and effective
multiple processes that resemble those seen with renal approach to this deadly syndrome, which is affordable
senescence.175–178 and effective in large populations and communities
These observations suggest that optimisation of post- where death and complications still occur at unacceptable
AKI care might be an important novel aspect of AKI frequency.

Seminar
Contributors 19 Ronco C. Epidemiology of acute kidney injury in critical care.

All authors contributed equally to the manuscript, writing sections of In: Nephrology CC, ed. Elsevier. Philadelphia, PA, 2019: 65–75.
initial draft and then each revising other sections. 20 Malhotra R, Bouchard J, Mehta RL. Community- and
hospital-acquired acute kidney injury. In: Critical Care Nephrology
Declaration of interests (third edn) Elsevier: Philadelphia, PA; 2019: 75–80.
CR has received consultancy and speaking fees from ASAHI, Astute, 21 Mehta RL, Cerdá J, Burdmann EA, et al. International Society of
bioMerieux, B Braun, Baxter, FMC, Toray, GE, OCD, Jafron, and Nephrology’s 0by25 initiative for acute kidney injury (zero preventable
Medtronic. RB has received grants and consultancy and speaking deaths by 2025): a human rights case for nephrology. Lancet 2015;
fees from B Braun and Baxter. JAK has received grant support 385: 2616–43.
and consulting fees from AM Pharma, Astellas, Astute Medical, 22 Susantitaphong P, Cruz DN, Cerda J, et al. World incidence of AKI:
Atox Bio, Baxter, bioMerieux, Bioporto, Mitobridge, NxStage, and a meta-analysis. Clin J Am Soc Nephrol 2013; 8: 1482–93.
Potrero. 23 Hoste EAJ, Kellum JA, Selby NM, et al. Global epidemiology and
outcomes of acute kidney injury. Nat Rev Nephrol 2018; 14: 607–25.
Editorial note: The Lancet Group takes a neutral position with respect 24 Chawla LS, Bellomo R, Bihorac A, et al. Acute kidney disease and
to territorial claims in published maps and institutional affiliations. renal recovery: consensus report of the Acute Disease Quality
Initiative (ADQI) 16 Workgroup. Nat Rev Nephrol 2017; 13: 241–57.
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Seminar

Acute kidney injury

www.thelancet.com Vol 394 November 23, 2019 1949

Second, a patient might present with abnormal kidney

1950 www.thelancet.com Vol 394 November 23, 2019

Despite the above challenges and nuances, interna­

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Timing Functional changes Structural damage*

diagnostic approach to and the treatment of AKI. Several

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Panel 3: Causes and pathophysiological mechanisms of AKI

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magnetic resonance-based techniques are difficult to Mitigation or Removal of toxic drugs

might reflect association rather than causation. Volume depletion

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Table 2: Characteristics of acute kidney injury biomarkers

Prevention of AKI In a study of 3000 such patients, a restrictive intra-

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A 7 mmol/L or electrocardiographic signs of hyperkalaemia

Acute management of established AKI RRT and extracorporeal support

1958 www.thelancet.com Vol 394 November 23, 2019

its use as a logistically efficient method of dialysis. In

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1960 www.thelancet.com Vol 394 November 23, 2019

Contributors 19 Ronco C. Epidemiology of acute kidney injury in critical care.

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1964 www.thelancet.com Vol 394 November 23, 2019

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Despite the above challenges and nuances, interna