AKI

Acute Kidney Injury

 CONTENTS

WHAT IS ACUTE KIDNEY INJURY?

1 Definition and diagnostic criteria .........................................2
2 Clinical judgement ................................................................4
PREFACE 3 Baseline kidney function .......................................................6
4 Acute kidney disease ............................................................8
5 Etiology and pathophysiology ..............................................8
THE GLOBAL BURDEN OF AKI
I’m often asked, “is there a quick guide to acute kidney injury for the 1 Epidemiology ...................................................................... 14
non-expert?” My response is to steer the person asking to various review 2 Community- vs. hospital-acquired AKI................................ 15
articles that have been written over the last few years. While these are 3 Short and long-term outcomes .......................................... 15
useful, they tend to either assume a certain level of familiarity with the 4 Economic burden ................................................................18
subject matter or be overly focused on certain aspects (e.g. CLASSICAL AND NOVEL
epidemiology, biomarkers, renal replacement therapy) and may not BIOMARKERS OF AKI
provide a comprehensive overview of the field. 1 Acute kidney injury or impairment .....................................19
2 Kidney damage and dysfunction ....................................... 20
Textbooks, by contrast, provide comprehensive overviews but lack the 3 Alternative markers of kidney function .............................. 21
practicality and portability of a short reference guide. Of course, the 4 Markers of kidney damage .................................................22
portability problem can be solved by electronic media, but the desired 5 Second-generation AKI biomarkers ...................................24
6 Other markers .................................................................... 26
answer to a specific question can still be far from one’s fingertips. 7 Clinical application ..............................................................27

With these considerations in mind, I have sought to create a practical, PREVENTION OF AKI
accessible, brief yet comprehensive resource on acute kidney injury for 1 Terminology and AKI time course ...................................... 28
front-line clinicians. I’ve paid particular attention to address both the 2 Clinical risk stratification ................................................... 29
3 Role of biomarkers ............................................................. 30
basics and the controversial using tables and figures, as well as text. It’s
4 Prevention bundles ............................................................ 30
my hope that as brief as this resource is, it can provide a useful
foundation for trainees as well as a quick reference for the seasoned EVALUATION AND MANAGEMENT
clinician. 1 Clinical approach to a patient with abnormal
kidney function ....................................................................32
2 Evidence of kidney damage ............................................... 34
3 Identifying the cause of AKI ............................................... 34
4 Non-specific management of AKI ...................................... 43
RENAL REPLACEMENT THERAPY
1 Indications .......................................................................... 46
John A. Kellum, MD 2 Modalities ........................................................................... 49
Distinguished Professor of Critical Care Medicine, 3 Management considerations .............................................. 51
Endowed Chair, Critical Care Research Director,
Center for Critical Care Nephrology, FOLLOW-UP FOR PATIENTS WITH ACUTE
University of Pittsburgh, Pittsburgh PA, USA
KIDNEY INJURY
1 Post-AKI phenotypes .......................................................... 54
2 Post-discharge monitoring and management ................... 54

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 WHAT IS ACUTE KIDNEY INJURY?

Table 1. Confounding conditions for AKI diagnosis using serum

creatinine and urine output.

EFFECT/CAUSE EXAMPLES

WHAT IS ACUTE KIDNEY INJURY? Serum Creatinine

Falsely low (not increased)
Increased volume of
Fluid overload
distribution
Decreased creatinine
Bed rest, fasting
production
1 Definition and diagnostic criteria Subclinical AKIa Renal reserve

Acute kidney injury (AKI) is a condition resulting in an abrupt loss of kidney Increased not from AKI
function. Specifically, AKI is defined as any of the following:1 Various drugs: cimetidine, trimethoprim,
Decreased tubular secretion
pyrimethamine, salicylates
Muscle breakdown, corticosteroids and vitamin D
within 48 hours Increased creatinine release
metabolites
an increase in serum creatinine (SCr) Return of creatinine to Decreased creatinine (e.g. fluid resuscitation) which
by ≥0.3 mg/dL (≥26.5 µmol/L) baseline is now normalizing
48h
Chronic kidney disease Patient presenting with unknown medical history
within the prior
an increase in SCr to ≥1.5 times 7 days Decreased GFR without injuryb Severe dehydration, ACE inhibition
baseline, which is known or Urine Volume
presumed to have occurred
Falsely high (not decreased)

for 6 hours Non-oliguric renal failure Many forms of nephrotoxic AKI

Especially osmotic diuretics. Not typical of loop
a urine volume <0.5 mL/kg/h Diuretics
diuretics as they require intact tubular function
6h Oliguria not from AKI
Lower urinary track
Clogged or dislodged Foley catheter
obstruction
For practical purposes this means that when AKI develops under close medical Unilateral obstruction Contralateral disease or one kidney
observation (e.g. in the hospital) an increasing SCr or a decreasing urine
Oliguria without injury Severe dehydration
output should prompt the clinician to consider AKI. Importantly however,
neither SCr nor urine output (UO) are specific for AKI and neither criterion ACE: Angiotensin converting enzyme; GFR: Glomerular filtration rate.
a
Injury with reductions in GFR less than the threshold for creatinine to rise.
itself is sensitive (although sensitivity increases with both criteria together). b
When severe or prolonged usually denotes injury.

Table 1 lists potential confounders that reduce the sensitivity and specificity
of SCr and UO for AKI.

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 WHAT IS ACUTE KIDNEY INJURY?

2 Clinical judgement Table 2. A checklist for Acute Kidney Injury.2

Reprinted by permission from Springer Nature: Springer, Intensive Care Medicine, Does this patient have acute
As Table 1 indicates, there are a number of possible causes for changes in kidney injury? An AKI checklist, Kellum, et al., Copyright 2016.
serum creatinine and urine output apart from AKI. Therefore, the clinician AKI More AKI Less
must use medical history and physical examination along with his or her Likely Likely
clinical judgement to diagnose AKI. Clinical Context
Susceptible populations
A checklist has been proposed to help with this process (see Table 2).2 Despite Volume depletion, Female, Black, CKD,
the simplicity of the diagnostic criteria, AKI can be a challenging diagnosis. Chronic diseases (heart, lung, liver),
Even if we set aside the sensitivity and specificity concerns with serum Diabetes mellitus, Cancer, Anemia, Over age 65
No susceptibilities
creatinine and urine output for accessing kidney function (Table 1), the Exposures
diagnosis can still be difficult. The two main areas of difficulty concern the Sepsis, Critical illness, Circulatory shock, Burns,
acuity vs. chronicity of kidney dysfunction and the fact that damage to kidney Trauma, Cardiac surgery (especially with CPB),
and kidney function can be dissociated. Thus, the clinician should seek to Major noncardiac surgery, Nephrotoxic drugs,
Radiocontrast agents, Poisonous plants and animals
evaluate kidney function and to understand whether changes in function are No exposures
attributable to disease and if so, whether it is acute or chronic or both. Alternative Diagnosis
For oliguria
One hallmark of AKI is its instability. Kidney function is unstable during AKI,
Dehydration, obstruction, retention
getting better or getting worse but rarely staying the same. Once kidney For increased serum creatinine
function stabilizes, the process causing damage has likely ended. If the injury Endogenous chromogens (acetone, bilirubin)
is reversible, function will improve. If not, a new steady state will be reached Medications (e.g., trimethoprim and cimetidine)
reflecting the extent of intact nephrons available. AKI Criteria
Serum creatinine increase
Two caveats should be stated here. ≥ 0.3mg /48h
First, restoration of kidney function may take days to weeks, or even months 1.5x reference
in some cases. Urine output < 0.5ml/kg/h for ≥ 6h
Both serum creatinine and UO criteria
Second, reversal of kidney dysfunction is not a guarantee that recovery Confirmatory Data
has occurred. Kidney damage in many forms of AKI is patchy and while Active urine sediment
some nephrons may be irreversibly injured, others may be spared. Since Serum creatinine
individual functioning nephrons can increase filtration to compensate for changing (up or down)
stable
lost nephrons, function may improve without recovery. Unfortunately, Biomarkers
these hyper-filtering nephrons may be susceptible to glomerular sclerosis [TIMP-2]•[IGFBP7]
over time and the loss of renal reserve (ability to augment glomerular ≤ 0.3 (ng/ml)2/1000
filtration rate (GFR) further when needed) may predispose to development >2.0 (ng/ml)2/1000
of AKI with subsequent exposures.3 NGAL (serum or plasma)
Low
High
Multiple markers
Negative
Positive

Shading indicates the column that applies to each row. Check marks indicate conditions
applicable to the case discussed in the original article.
AKI acute kidney injury, CKD chronic kidney disease, CPB cardiopulmonary bypass. NGAL
neutrophil gelatinase-associated lipocalin, TIMP-2 tissue inhibitor of metalloproteinase 2,
IGFBP7 insulin-like growth factor binding protein 7.

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 WHAT IS ACUTE KIDNEY INJURY?

3 Baseline kidney function Table 3 lists reference values for serum creatinine based on age, sex and race.
Of note, the adjustments for race have recently been called into question.5
One of the most challenging aspects of diagnosing AKI can be determining Although from a population perspective, these adjustments are valid, variation
the patient’s baseline kidney function. Because most people do not have their among individuals is great. Particular concern has been raised when the eGFR
kidney function checked regularly, it will always be a matter of judgement as is determined to be higher among blacks, potentially disadvantaging them
to what GFR (and hence creatinine) can be used as their baseline should they for kidney transplant eligibility. From a baseline creatinine perspective, use
develop a condition that can cause AKI. A further consideration is that people of adjustments for black race will mean that the estimated baseline will be
have their kidney function evaluated when they are sick, so values obtained higher, and AKI could be underdiagnosed. In general, use of the adjustment
during prior hospitalizations may be misleading. Furthermore, all of the for black race should be reserved for patients with higher-than-average muscle
considerations pertaining to serum creatinine listed in Table 1 can also apply mass. Alternatively, both adjusted and unadjusted values can be considered,
to a potential baseline value. As with any measurement, accuracy improves and clinical judgement used to determine which is most appropriate in any
when multiple values are pooled, especially if outliers are omitted. The median given patient.
of several prior values is therefore the most reasonable estimate of the
baseline. However, older values are less likely to reflect current function
compared to more recent values. Table 3. Reference creatinine values based on age, race and sex.4
Reprinted by permission from Springer Nature: Springer, Critical Care, Acute renal failure - definition, outcome
The following approaches can therefore be used: measures, animal models, fluid therapy and information technology needs: the Second International Consensus
Conference of the Acute Dialysis Quality Initiative (ADQI) Group, Bellomo, et al., Copyright 2004.

I f three or more serum creatinine values are available in the prior six
Estimated baseline creatinine
months, take the median of these. If not look for values over the past 12
months, taking the median of these. Black males Other males Black females Other females
Age
mg/dL mg/dL mg/dL mg/dL
(years)
(μmol/L) (μmol/L) (μmol/L) (μmol/L)
I f the two most recent values in the past 12 months are within 20% of
each other (e.g. 1.0 and 1.2 mg/dL), use the mean (e.g. Table 3). If not use 20-24 1.5 (133) 1.3 (115) 1.2 (106) 1.0 (88)
the median of values as described above. 25-29 1.5 (133) 1.2 (106) 1.1 (97) 1.0 (88)
30-39 1.4 (124) 1.2 (106) 1.1 (97) 0.9 (80)
If only two values are available in the last 12 months, take the mean of
these; if only one value is available use it. 40-54 1.3 (115) 1.1 (97) 1.0 (88) 0.9 (80)

Importantly, a sizable number of patients will not have any serum creatinine 55-65 1.3 (115) 1.1 (97) 1.0 (88) 0.8 (71)
values available within the last year. Older values (if available) might be useful >65 1.2 (106) 1.0 (88) 0.9 (80) 0.8 (71)
if the patient’s health has been stable. For patients without any historical Estimated glomerular filtration rate=75 (mL/min per 1.73 m2)=186 x (serum creatinine [SCr]) – 1.154 x (age) – 0.203 x
(0.742 if female) x (1.210 if black)=exp(5.228 – 1.154 x In [SCr]) – 0.203 x In(age) – (0.299 if female) + (0.192 if black).
creatinine values, a baseline value can be estimated from their demographics
using an estimated GFR (eGFR) equation and back-calculating a baseline
creatinine using a “normal GFR” value. A value of 75 mL/min/1.73m2 has been
reproposed (see Table 3).4

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 WHAT IS ACUTE KIDNEY INJURY?

4 Acute kidney disease 5 Etiology and pathophysiology

Acute kidney disease (AKD) is a relatively new term. AKD is defined as alterations AKI (and AKD without AKI) may be due to a variety of conditions including
in kidney structure or function lasting up to 3 months, with implications for disease, injury, toxins, drugs or major surgery (especially cardiac). A list of
health. The criteria for defining various kidney diseases and disorders are common conditions leading to AKI are shown in Table 5 along with clinical
shown in Table 4. Importantly, in this framework, AKI is a specific subtype of characteristics and pathophysiology.
AKD but AKD can also exist without AKI. For example, a patient can develop Importantly, it is common for patients developing AKI to have multiple etiologies
alterations in kidney structure or function that do not meet the criteria for at once. In the past, it was common to classify patients according to presumed
AKI, but nevertheless have implications for health. In patients cared for in pathophysiology using pseudo-anatomic categories as pre-, post- and intra-
the hospital, AKD with AKI may be most common but outside the hospital, renal, and in some textbooks this is still the case. The post-renal category
AKD without AKI may be significantly more common.6 refers to urinary tract obstruction and is therefore anatomically correct, but
the others are essentially meaningless.
Table 4. Criteria for defining kidney diseases and disorders.7
Sepsis, for example has been variably classified as pre-renal, intra-renal or
Reprinted from American Journal of Kidney Diseases, 61(5), Andrew S Levey, Adeera Levin, John A Kellum,
Definition and classification of kidney diseases, 686-688, Copyright 2013, with permission from Elsevier. a combination of both. As the understanding of the pathophysiology of AKI
has advanced,8 it has become very clear that this simplistic categorization
Functional Criteria Structural Criteria is misleading.
AKI
Increase in SCr by 50% within 7 d, or increase
No criteria Sepsis is the most common cause of AKI for patients with critical illness,
in SCr by 0.3 mg/dL within 2 d, or oliguria
representing 50% or more in most series.9-11 For many years it was assumed
CKD GFR <60 mL/min for >3 mo Kidney damage for >3 mo that sepsis caused AKI through hemodynamic alteration. However, AKI may
AKI, or GFR <60 mL/min/1.73 m2 for <3 mo, or develop in the absence of renal hypoperfusion and clinical signs of
AKD decrease in GFR by ≥35% or increase in SCr by Kidney damage for <3 mo hemodynamical instability,12-14 and in the presence of normal or increased
>50% for <3 mo
global renal blood flow.12,15-21
NKD GFR ≥60 mL/min/1.73 m2, stable SCr No damage
A ‘unified theory’ of sepsis-associated AKI (S-AKI) has been proposed in an
Note: Criteria for AKI and CKD proposed by KDIGO guidelines, based on evidence and expert opinion. Criteria for AKD
and NKD proposed to harmonize the criteria for AKI and CKD. GFR may be assessed from measured or estimated GFR. attempt to place a variety of mechanisms into a coherent framework of
Estimated GFR does not reflect measured GFR in AKI as accurately as in CKD. Kidney damage assessed by pathology,
urine or blood markers, imaging, and—for CKD—presence of a kidney transplant. NKD indicates no functional or structural
synergic interaction.22 The inflammatory response is the host’s main defense
criteria according to the definitions for AKI, AKD, or CKD. Clinical judgment is required for individual patient decision mechanism from invading pathogens. However, a dysregulated inflammatory
making regarding the extent of evaluation that is necessary to assess kidney function and structure.
Abbreviations: AKD, acute kidney diseases and disorders; AKI, acute kidney injury or impairment; CKD, chronic kidney response may be responsible for organ dysfunction and poor outcome.
disease; GFR, glomerular filtration rate; NKD, no known kidney disease or disorders; SCr, serum creatinine.
During sepsis, various mediators including pathogen-associated molecular
patterns (PAMPs) and damage-associated molecular patterns (DAMPs) are
released in the intravascular compartment. These molecules bind membrane
bound pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs),
present on the surface of immune cells, initiating a downstream cascade of
signals that will result in the synthesis and release of proinflammatory
molecules. Renal tubular epithelial cells also express TLRs, especially TLR2
and TLR4. When exposed to DAMPs or PAMPs filtered through the glomerulus
or through neighboring peritubular capillaries, proximal tubular epithelial
cells exhibit an increase in oxidative stress, production of reactive oxygen
species (ROS) and mitochondrial injury.23-26

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 WHAT IS ACUTE KIDNEY INJURY?

Trauma and major surgery (especially cardiac and vascular) are also common
Etiology Clinical Characteristics Pathophysiology
causes of AKI in the critically ill. The pathophysiology of AKI associated with
cardiac and vascular surgery is complex and poorly understood.27 Medications
Cardiopulmonary bypass (CPB) itself is likely to be responsible for one third
to half of AKI in these patients. Hemodynamic disturbances at each level of Toxicity is dose dependent and
arterial blood supply, inflammatory, immunological, neuro-humoral and Direct tubular (proximal)
Aminoglycosides can be reduced with careful
toxicity.
mechanical factors are all significant contributors. therapeutic drug monitoring.

The pathophysiology associated with AKI from these and other causes is
summarized briefly in Table 5. Toxicity is dose dependent and
Direct tubular (proximal)
Vancomycin can be reduced with careful
toxicity.
therapeutic drug monitoring.
Table 5. Common conditions leading to AKI
Significant variation in
Acylation of target proteins,
Etiology Clinical Characteristics Pathophysiology risk among drug classes.
causing respiratory toxicity by
The penems and some
inactivation of mitochondrial
cephalosporins have greatest
Infection Beta-lactams anionic substrate carriers;
in vitro nephrotoxicity while
and lipid peroxidation. Allergic
piperacillin-tazobactam is
interstitial nephritis may be a
most commonly associated
Sepsis causes AKI through common cause as well.
Serious infections with AKI.
(e.g. pneumonia) are common a complex series of events.
causes of AKI and AKI due to Damage and pathogen
systemic infection is sepsis by associated molecular patterns In addition to AKI, disorders Accumulation in the kidney
Sepsis
definition. directly signal of electrolytes and acid base through active transporters.
tubular-epithelial cells (including Fanconi syndrome) Toxic metabolites generated
Oliguria is an almost universal causing inflammation Cisplatin
are frequent. Thrombotic which have cytotoxic effects
feature. and injury. microangiopathies have also through their interaction
been reported. with DNA.

In addition to the direct

Massive hemolysis leading to effects of hemoglobin on Allergic interstitial nephritis Apart from rare cases of AIN,
Malaria hemoglobinuria tubular cells, systemic (AIN) has been reported. direct nephrotoxicity does
“blackwater fever”. inflammation Loop diuretics Risk may be higher with sulfa not occur with loop diuretics.
contributes to AKI. allergy, but most patients are However, they may potentiate
not affected. toxicity from other causes.

Still under investigation but

COVID-19 May present with proteinuria.
similar to sepsis. Small increases in serum These agents reduce GFR
creatinine are generally but do not directly cause
ACE inhibitors,
expected and usually do not nephrotoxicity. There is
ARBs
indicate AKI. May potentiate controversy as to how much
AKI from other causes. change is acceptable.

Inhibition of the
Both dose dependent and calcineurin-NFAT signaling by
idiosyncratic nephrotoxicity induces COX-2 inhibition which
Calcineurin
may cause AKI but chronic leads to renal vasoconstriction
inhibitors
toxicity is more common and and reduces GFR. This effect is
difficult to manage. dose-dependent and is usually
reversible.

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 WHAT IS ACUTE KIDNEY INJURY?

Etiology Clinical Characteristics Pathophysiology Etiology Clinical Characteristics Pathophysiology

Major surgery Endothelial/Vascular

Multifactorial with Thrombotic
Multiple forms including TTP, Complement mediated injury,
Typically manifests within contributions from hemolysis, microangio-
HUS and aHUS. microvascular thrombosis.
Cardiac 72 hours of surgery. cardiac dysfunction, pathies
Is almost always oliguric. hemodynamics and
inflammation. Multiple forms including Mechanisms vary by subtype but
Acute
non-crescentic, postinfectious, involve acute inflammation and
Glomerulo-
Tissue injury leading to release lupus nephritis and infiltration of glomeruli leading to
nephritis
of damage-associated molecular mesangiocapillary. an abrupt decline in GFR.
Early and delayed patterns. Hemodynamics and
Non-cardiac manifestations appear to have inflammation. Cholesterol crystals
different risk factors. Seen with dislodgement of
Abdominal compartment Cholesterol embolize and lodge in the
atheroma mainly from surgery
syndrome. emboli microcirculation causing
or other procedures.
ischemic injury.
Tissue injury leading to release
of damage-associated molecular Sickle cell Typically seen as part of an Hemoglobin-induced tubular
Clinical presentation patterns. Hemodynamics and disease acute crisis. cytotoxicity.
Trauma varies by type of injury and inflammation.
complications. TTP: Thrombotic thrombocytopenic purpura; HUS: Hemolytic uremic syndrome; aHUS:
Rhabdomyolysis, especially
with crush injury. atypical Hemolytic uremic syndrome.

Kidney perfusion may be

compromised by both lower
forward flow as well as back Etiology Clinical Characteristics Pathophysiology
Cardiac May occur with both reduced
pressure from right heart
disease and preserved ejection fraction.
failure. Other mechanisms Toxins
including treatment have been
characterized. Heavy metals, organic
Various mechanisms depending
Chemicals chemicals (e.g. pesticides and
Intense renal vasoconstriction on the agent.
herbicides).
results from splanchnic
Multiple forms of AKI may occur
vasodilatation. Other causes Several plants including some
in patients with liver disease.
Liver disease including bile acid nephropathy edible or medicinal (e.g.
A “pure form” is hepatorenal
and intraabdominal aristolochic acid, henna) can
syndrome type 1. Plants/ Various mechanisms depending
hypertension may also cause both acute and chronic
contribute. animals kidney damage. on the agent.
Scorpions and various spiders
(Loxosceles).

Crystals cause acute

Various drugs (e.g.
necroinflammation, tubule
Crystal- methotrexate, acyclovir, vit C)
obstruction or crystal
induced and chemicals (e.g. ethylene
granuloma formation and
glycol).
chronic tissue remodeling.

Oxidative injury has been

Far less common with modern
documented but precise
Radiocontrast agents. Patients with underlying
mechanisms are not fully
CKD are at highest risk.
known.

Lower or bilateral upper urinary

Obstruction to flow will cause
Urinary tract tract obstruction (or proximal
hydronephrosis if not treated
obstruction obstruction in a patient with
promptly.
one kidney) can present as AKI.

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 THE GLOBAL BURDEN OF AKI

Figure 1. Global incidence and rates in hospital for acute kidney

injury.38
Reprinted from The Lancet, 394, Ronco C., Bellomo R., Kellum J. A., Acute kidney injury, 1949-64, Copyright 2019,
with permission from Elsevier.

THE GLOBAL BURDEN OF AKI

15–32%
39 per 1000 15–20%
22–25%
18 per 1000
8–24%
13–24%

1 Epidemiology 29–31%
17–26%
37 per 1000
A comprehensive analysis of the global incidence of AKI has not been performed.
Various estimates come mainly from hospitalized patients and largely from
high-resource countries.
Figure 1 illustrates AKI occurrence among hospitalized patients as reported Schematic representation of AKI epidemiology per hospital admission and corresponding
incidence by region. Hospitalization rates for the US were obtained from the US Centers
in several large studies and metanalyses.28-30 Although ranges are relatively for Disease Control (cdc.gov) and for other countries from the Organization for Economic
large, most regions report rates between 15-25% of hospitalized patients. Cooperation and Development (oecd.org). In Europe an average rate of 17% was used. For
other regions, information on hospitalization rates are not available. Given that there is
However, marked variation in rates of (non-maternity) hospitalization exist a 2-fold variation in population incidence despite similar rates per hospital admission, it
even among similar-resourced countries. seems likely that many AKI occurrences are not captured.

For example, in Europe, hospitalization 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. The US has even lower rates at about 7.9%. If we use these data to
determine the incidence of AKI in the population (ignoring patients not 2 Community- vs. hospital-acquired AKI
admitted to hospital), we see that nearly 24 million patients develop AKI
The majority of AKI cases begin before hospital admission. This is because
annually in the US, EU and Australia. Extrapolating these rates to the rest of
many of the most common etiologies (e.g. sepsis, acute decompensated
the world (where many estimates are even higher) and we find roughly 232
heart failure, toxins and drugs) arise in the community. A notable exception
million people will develop AKI on an annual basis. Even if this number is
is surgery-associated AKI. Of note, many forms of AKI can manifest in the
inflated two-fold, there are still more than 100 million new AKI events per
hospital even though the injury began prior to admission.
year on average around the globe.
Estimates of AKI incidence in North America are further supported by a large
community-based study from James et al.6 These investigators examined AKI
and AKD incidence in the province of Alberta, Canada using data from 2008
and found that AKI occurred in 18 per 1,000 population while AKD was even
more common, 44 per 1,000 population.
3 Short and long-term outcomes
AKI is responsible for numerous short and long-term adverse outcomes (see
Table 6). Importantly, there was once a prevailing view among many clinicians
that AKI was not a causal death in critically ill patients but rather a marker
of disease severity. The logic was based on the fact that renal replacement
therapy is available and that patients rarely die of proximate causes directly
attributable to the kidney. The expression “patients die with renal failure not
of acute renal failure” was the articulation of this sentiment. However, multiple
lines of evidence refute this view.
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 THE GLOBAL BURDEN OF AKI

First, experimentally-induced AKI directly causes neutrophil dysfunction and Figure 2. Survival following Acute Kidney Injury as a function of
therefore reduces bacterial clearance and shortens survival.31 recovery status.33
Second, the clinical correlate of these animal experiments can be found in
Reprinted with permission of the American Thoracic Society. Copyright © 2021 American Thoracic Society. All rights
randomized trials where a drug was found to be nephrotoxic and resulted in reserved. Kellum, J. A., Sileanu, F. E., Bihorac, A., Hoste, E. A. & Chawla, L. S, 2017, Recovery after Acute Kidney Injury,
Am J Respir Crit Care Med, 195, 784-791. The American Journal of Respiratory and Critical Care Medicine is an
reduced survival apparently through its effect on AKI. Such was the case in official journal of the American Thoracic Society.
the 6-S trial where patients with sepsis randomized to receive hydroxyethyl
1.0
starch had reduced survival.32 The apparent explanation for the reduced Early Sustained Reversal
survival was increased AKI, a direct result of the drug. 0.8 Late Sustained Reversal

Age Adjusted Survival Function

Relapse Recovery
0.6
Table 6. Selected short- and long-term consequences of Acute
Kidney Injury. Relapse No Recovery
0.4

Short-Term (90 days) Long-Term* Never Reversed

0.2
Death Reduced survival
Immune dysfunction 0.0
Chronic kidney disease
(increased infection risk) 0 50 100 150 200 250 300 365

Fluid overload Cardiovascular events (MI, Stroke) Days from ICU Admission to Death or RRT
Impaired excretion of multiple drugs Impaired excretion of multiple drugs No. at risk
Acid-base and electrolyte abnormalities Acid-base and electrolyte abnormalities Early Sustained Reversal 4,507 4,404 4,317 4,235 4,176 4,122 4,070 4,026
Late Sustained Reversal 1,642 1,529 1,424 1,357 1,310 1,272 1,242 1,203
Platelet dysfunction / increased
Renal cancer Relapse Recovery 3,823 3,535 3,245 3,061 2,910 2,818 2,719 2,625
bleeding risk
Relapse No Recovery 2,496 1,386 1,190 1,114 1,075 1,052 1,027 1,008
Encephalopathy
Never Reversed 4,496 2,127 1,922 1,826 1,757 1,709 1,678 1,648
Increased ICU and hospital duration
*Generally seen when there is residual renal dysfunction following AKI (i.e. non-recovery).

Age-adjusted survival by recovery pattern. Survival differences are highly significant

overall (p<0.001). All pairwise comparisons are also significant. Early sustained reversal
However, some increased risk for death and cardiovascular disease persists indicates return of kidney function to baseline (creatinine <150% times baseline) within
7 days and no relapse prior to discharge. Late sustained reversal is defined as return of
even in patients who appear to recover following AKI. Also, complications kidney function to baseline after 7 days and no relapse prior to discharge. Relapse recovery
listed on the left (short-term) can also occur in the long-term if chronic kidney indicates return of kidney function to baseline within 7 days but with relapse and then
recovery prior to discharge. Relapse no recovery is the same as relapse recovery except
disease is not well managed. that recovery does not occur prior to discharge and never reversed is no return to baseline
kidney function during the hospitalization.
Adverse drug events are particularly problematic for AKI because kidney ICU: intensive care unit; RRT: renal replacement therapy.
function is unstable. Drugs can easily be overdosed because of decreased
clearance but they may also be underdosed when kidney function improves.
However, survival is a crude measure of long-term consequences of AKI.
The former leads to toxicity while the latter may result in treatment failures.
Development or progression of chronic kidney disease including end-stage
Readmissions following AKI are common and drug dosing is a common
disease is also common. For example, in patients developing stage 3 AKI by
precipitating cause.
creatinine criteria in the setting of cardiac surgery, more than 10% were still
Long-term outcomes are tightly correlated with recovery of kidney function. dialysis-dependent by 90 days.34 Furthermore, even patients with isolated
For example, in patients surviving critical illness, survival to 1 year is >90% oliguria (no change in serum creatinine) had an increased risk of new chronic
for patients who recovery kidney function within 7 days and remain recovered kidney disease 8.1% (228/2827) compared with 5.2% (65/1248) in patients
(no relapses or second events) until hospital discharge. Conversely, patients without AKI (p=0.0001). Rates of long-term outcomes following AKI are
who never resolve AKI have a 1-year survival of only 40%.33 depicted in Figure 3.
16 17
 THE GLOBAL BURDEN OF AKI

Figure 3. Absolute risks of clinical events for patients in

high-income countries in the year after hospitalization with AKI.35
Reprinted by permission from Springer Nature: Nature, Nature Reviews Nephrology, Long-term outcomes of acute
kidney injury and strategies for improved care, James et al., Copyright 2020.

35 CLASSICAL AND NOVEL

30
BIOMARKERS OF AKI
25
Absolute risk (%)

20

15

1 Acute kidney injury or impairment

10

0
In the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guideline,
ar

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ise ron the term AKI was defined as “acute kidney injury or impairment”. This was an
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effort to acknowledge the reality that, at the time, the available clinical
A

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os
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kid

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indicators used for the diagnosis of AKI were measures of kidney function
AK

An

not damage. The implications of this fact are that:

Mortality Cardiovascular Hospital Kidney
events readmission outcomes
If kidney damage occurs that does not impact kidney function, it will not
be ascertained using markers of kidney function.

Absolute risks of the most common clinical outcomes following discharge from Not all changes in kidney function are due to kidney damage.
hospitalization with acute kidney injury (AKI). Absolute risks within 1 year of discharge are
illustrated for kidney outcomes, cardiovascular outcomes, all-cause and cause-specific Several points follow from these implications.
mortality, and hospital re-admission with AKI. The absolute risk of rehospitalization of any
cause refers to the risk of rehospitalization within 90 days of hospital discharge. First, absent kidney histology, there was no acceptable way to identify kidney
damage for the majority of patients. A very small minority of patients have
evidence of damage using markers of glomerular injury (e.g. albuminuria,
4 Economic burden hematuria) but most forms of AKI spare the glomeruli. Traditional indicators
Since accurate information on global AKI incidence is lacking, it is difficult to of tubular damage such as muddy brown casts lack sensitivity and also require
accuractely determine the full economic impact of AKI. Some determinants some skill to identify correctly, leading to interobserver variation.36
of cost can be estimated from available information. Second, because healthy human beings have excess kidney functional capacity
(referred to as renal functional reserve), a significant amount of damage can
* Since AKI doubles hospital duration (the main driver of cost) we can
occur before GFR is affected. This is the physiological principle that explains
estimate that overall hospital expenditures increase as a function of AKI.
why kidney donation is feasible - with the loss of 50% of functioning nephrons
n In the US, annual hospitalization costs are approximately 1.2 trillion USD. If 25% of most donors can maintain a normal GFR. Thus, damage to the kidney frequently
patients develop AKI and this doubles their costs, the expenditures attributable to AKI goes undetected using serum creatinine.
would be 240 billion USD! Even if AKI only affects 10% of patients and increases costs
by only 50%, the expenditures attributable to AKI would still be 57 billion USD. Third, alterations in kidney function may occur that are unrelated to kidney
n In Germany, hospitalization costs are estimated at 105 billion euros. If 25% of patient damage. For example, the loss of free water from the plasma will result in
develop AKI and this doubles their costs, the expenditures attributable to AKI would be hemo-concentration and ultrafiltrate made from concentrated plasma will
21 billion euros. also be concentrated. When this ultrafiltrate hits the distal tubule, tubular-
Of course, these estimates of economic impact do not take into account the glomerular feedback will turn down GFR. This adaptive impairment of solute
fact that patients developing AKI may just be more expensive to care for. excretion will result in azotemia (increased serum creatinine as well as urea)
Conversely the costs do not include outpatient care. Overall, these estimates such that criteria for AKI may be met. However, this impairment is not associated
serve to illustrate the enormity of the problem. with kidney damage. Drugs, most notably ACE inhibitors, have similar effects.
18 19
 CLASSICAL AND NOVEL BIOMARKERS OF AKI

Similarly, when both functional markers, serum creatinine and urine output,
2 Kidney damage and dysfunction are abnormal, prognosis is considerably worse than when either is affected
It follows logically from the previous section that kidney damage and dysfunction alone.39 However, as discussed in chapter 1, there are significant limitations
are not the same nor should they occur in equal measure. Figure 4 illustrates to serum creatinine and urine output. These limitations have prompted a
this relationship. Importantly, the damage/dysfunction paradigm is not only number of different alternatives for measuring kidney (glomerular) function.
significant for determining etiology of AKI but also for prognosis. Damage or
dysfunction by themselves have much better prognosis than both together.37
3 Alternative markers of kidney function
Figure 4. Conceptual framework for AKI based on functional and Alternative markers of kidney function can be divided into two main categories:
damage criteria.38 endogenous substances which are cleared from the plasma by the kidney,
Reprinted from The Lancet, 394, Ronco C., Bellomo R., Kellum J. A., Acute kidney injury, 1949-64, Copyright 2019, and techniques for measuring GFR directly. The first category theoretically
with permission from Elsevier.
includes numerous substances but, for practical purposes, only two require
Mitigation or Removal of toxic drugs
intervention Limitations of imaging procedures discussion - cystatin C and proenkephalin.
Control of inflammation

Risk Stress Injury

Cystatin C is a 13-kDalton (kDa) protein that is freely filtered at the glomerulus
and not reabsorbed or secreted in the tubules. Its production is extremely
Risk

Inflammation
No acute kidney Damage constant, though it can be increased by corticosteroids. Thus, when measured
Risk modifiers

injury Biomarkers Nephrotoxic drugs

Contrast media
Mitigation or No signs or
symptoms
Urine abnormalities
Imaging Mitochondrial in the plasma it can be used as a marker of GFR much the same as serum
intervention
Stress

dysfunction
Volume optimisation No evidence
Hypoperfusion creatinine - only more accurately.40 It has already been used for many years
Haemodynamic Anaemia
stabilisation Congestion in patients with CKD and is unaffected by loss of muscle mass, making it a
Correction of anaemia
Improved cardiac more useful marker in patients recovering from critical illness.41
Decreased GFR

performance Dysfunction Acute

Control of Decreased GFR kidney injury
inflammation Decreased RFR Increased serum Proenkephalin is an endogenous opioid polypeptide hormone which has
Altered tubular creatinine
function Decreased UO been studied as a potential marker of GFR. Proenkephalin is freely filtrated
at the glomerulus and thus plasma concentrations correlate with GFR.42
Risk modifiers However, as a hormone, production rates are not stable and are subject to
Volume depletion various regulatory pathways. Little is known about the performance of the
Haemodynamic alterations
Sepsis marker in different patient groups but existing evidence supports its utility
Diabetes
Catabolic state in comparison to other filtration markers (creatinine, cystatin C).
Anaemia

The second category of filtration markers involve direct measurement of GFR.

Timed urine collections allow for creatinine clearance measures and various
In the top left panel, no evidence of damage or dysfunction might identify a normal clinical approaches can be used including collection times as short as two hours.
condition; in the 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 While these approaches may be superior to serum creatinine, they generally
an angiotensin-converting-enzyme inhibitor, which can reduce GFR without damaging suffer from all of the same limitations. Other approaches involve exogenous
the kidney. In the top right panel, kidney damage is identified by specific biomarkers,
but no dysfunction is present (normal serum creatinine). This condition has also been substances (e.g. inulin, iohexol), but these are impractical for critically ill
described as subclinical AKI. In the bottom right panel, both damage and dysfunction are patients. Recent advances in technology to measure fluorescent compounds
present. Red arrows show progression, whereas green arrows show regression or recovery.
Progression or regression can be affected by risk modifiers or by specific interventions. through the skin have opened the door for real-time monitoring of GFR. Using
AKI: acute kidney injury; GFR: glomerular filtration rate; RFR: renal functional reserve; UO: transdermal sensors, the plasma disappearance rate of an exogenous fluorescent
urine output.
compound eliminates the delay inherent in using an endogenous marker of
filtration and permits continuous monitoring of GFR.43 One or more technologies
using this approach should soon be available for clinical use.

20 21
 CLASSICAL AND NOVEL BIOMARKERS OF AKI

4 Markers of kidney damage NGAL is expressed in a severity-dependent fashion in AKI and is activated at
the time of patient presentation, for example in the setting of post contrast
There are numerous molecules that are expressed differently in patients with exposure, post cardiac surgery, and kidney transplantation. It is also clear
kidney damage compared to healthy persons. Some are specific to certain that dehydration alone does not trigger NGAL expression whereas kidney
parts of the nephron and a few can differentiate AKI from CKD. Table 7 lists damage does. However, NGAL expression lacks specificity for AKI and the
several such markers and their origins within the kidney and elsewhere.44 diversity of test kits on the market means that cut-offs are not standardized.

Table 7. The origin of biomarkers based on biological properties.44 * Liver-type Fatty Acid Binding Protein (L-FABP)

Adapted from Srisawat, et al. Crit Care Clin. 2020;36(1):125-140. This biomarker has a molecular weight of 14 kDa and is a member of a
superfamily of lipid-binding proteins, consisting of nine members named for
Biology Biomarkers the organ in which they were first identified, i.e. liver (L), intestine (I), muscle
and heart (H), adipocyte (A), epidermal (E), ileum (IL), brain (B), testis (T),
Albumin, Cystatin C, Beta 2
Filtered (impaired tubular reabsorption)
microglobulin, L-FABP
and myelin (MY).

Up-regulation NGAL, KIM-1, Clusterin, IL-18, Netrin-1 L-FABP is critical for fatty acid uptake and facilitates the transfer of fatty acids
between extracellular and intracellular membranes. L-FABP is not only found
Down-regulation Trefoil factor 3 (TFF3) in the liver, but also in many organs, such as the intestine, stomach, lung, and
Preformed (released)
ALP, GGT, GST, NAG, L-FABP, TIMP-2, kidney. L-FABP can be detected in urine and recently, urinary L-FABP has been
IGFBP-7 approved as an AKI biomarker in Japan.
L-FABP: liver type fatty acid binding protein; NGAL: neutrophil gelatinase associated lipocalin; KIM-1: kidney injury
molecule-1; ALP: alkaline phosphatase; GGT: gamma glutaryl transferase; GST: glutathione S-transferase; NAG: N- Ho J et al, analyzed the role of L-FABP to predict AKI after cardiac surgery by
acetyl-beta-D-glucosaminidase; TIMP-2: tissue inhibitor of metalloproteinase-2; IGFBP-7: insulin-like growth factor-
binding protein7.
including 6 major studies and showed AUCs between 0.52 and 0.85 with a
composite AUC of 0.72.48 In critically ill patients, L-FABP was superior to other
biomarkers including NGAL, interleukin-18, N-acetyl-beta-D-glucosaminidase
The following biomarkers have been extensively studied and widely used as
(NAG), and albumin, for predicting AKI with an AUC 0.75.50 Few studies have
diagnostic tests of AKI.
explored the role of L-FABP in predicting short or long-term renal outcomes
* Neutrophil Gelatinase Associated Lipocalin (NGAL) or mortality.
NGAL is the most studied AKI biomarker. This 25 kDa protein was first discovered * Kidney Injury Molecule-1 (KIM-1)
in the granules of neutrophils and later found in many organs, such as the
KIM-1 is a 38.7 kDa protein that is markedly upregulated in proximal tubular
kidney (proximal/distal tubular epithelial cells), lung, liver and large intestine.
epithelia after various exposures (e.g. ischemic/reperfusion, nephrotoxins).
The thick ascending limb and the intercalated cells of the collecting duct are
In response to injury, the extracellular component of KIM-1 is shed from the
the main intrarenal production sites, and NGAL can also be detected at the
cell membrane into the tubular lumen in a matrix metalloproteinase
proximal tubular epithelium because of the failure of filtered NGAL reabsorption
(MMP)-dependent manner.51 In clinical studies, KIM-1 has rather modest
in a megalin-dependent manner.45
performance as a biomarker of AKI with AUCs of 0.70-75.52,53 However, KIM-1
An important caveat is that age, gender (female), urinary tract infection and is very sensitive to injury and is approved for preclinical nephrotoxicity studies
impaired renal function (chronic kidney disease) may increase levels of urine by the US FDA.
NGAL.46 Two recent meta-analyses found the AUC for urine NGAL to predict
AKI was 0.82 and 0.72, respectively.47,48 Recently, a meta-analysis by Klein et
al, included 41 studies and showed the pooled AUCs for urine and plasma
NGAL were 0.72 (95% CI 0.638-0.803) and 0.755 (0.706-0.803), respectively.49

22 23
 CLASSICAL AND NOVEL BIOMARKERS OF AKI

5 Second-generation AKI biomarkers Importantly, both clinical59 and laboratory60 studies have shown that
[TIMP-2•IGFBP-7] increases with sub-lethal stimuli such that (particularly
Unlike the damage biomarkers discussed above, newer biomarkers have been at low levels) the test is marker of kidney “stress” rather than damage per se
discovered by studying multiple cohorts of patients with diverse exposures (see Figure 5).61 Indeed, clinical experience with the test indicates that early
that are known to cause AKI (e.g. sepsis, trauma, surgery) rather than starting treatment (e.g. discontinuation of a nephrotoxin) can result in rapid reversal
from a model system. These markers have undergone qualification and of the stress response and avoidance of AKI, as has been seen by others.62,63
verification using KDIGO criteria for AKI (Stage 2-3) which were not available Whereas, very high levels or persistently positive results are indicative of
when the first-generation biomarkers were discovered. irreversible AKI.

* Insulin-like growth factor-binding protein 7 (IGFBP-7) and tissue

Figure 5. Relation between kidney stress, damage and dysfunction.
inhibitor of metalloproteinases-2 (TIMP-2)
The first report of TIMP-2 and IGFBP-7 as markers of AKI came from Kashani
et al.52 This study included adult patients in ICUs in 35 centers across North
America and Europe. The primary endpoint was moderate-severe AKI (KDIGO Damage
Damage
stage 2-3) within 12 hours of sample collection which occurred in 14% of Stress Stress

subjects. Urinary [TIMP-2•IGFBP-7] demonstrated an AUC of 0.80 and was

significantly superior to all existing markers of AKI (p<0.002), none of which
achieved an AUC >0.72. In sensitivity analyses, [TIMP-2•IGFBP-7] remained Function Function
significant and superior to all other markers regardless of changes in reference
creatinine method. Time Time

Numerous subsequent studies have confirmed the initial results in various

cohorts - however, cardiac surgery remains the most common.54 In this area
a total of 10 studies have enrolled 747 patients. Pooled sensitivity and specificity
Depicted is the relationship between acute kidney stress, damage and dysfunction. The
were found to be 0.77 (95% CI: 0.70-0.83) and 0.76 (95% CI: 0.72-0.79), right panel shows a reversible injury. Stress begins soon after an insult and rises quickly.
respectively. Pooled positive likelihood ratio (LR), negative LR, and diagnostic Stress may abate as the insult is removed even as damage continues be incurred. Once a
sufficient number of cells are damaged, function will begin to fall. However, such damage
odds ratio were 3.26 (95% CI: 2.51-4.23), 0.32 (95% CI: 0.24-0.41), and 10.08 might be reversible (right panel) and as damage reverses, function can improve. Note,
(95% CI: 6.85-14.84), respectively. The AUC estimated by summary receiver that function may also improve in the absence of reversal of damage by hyper-filtration in
remaining nephrons.
operating characteristics was 0.83. There was no heterogeneity amongst the The left panel shows an irreversible injury. Stress increases as in the right panel and
10 studies from both threshold and non-threshold effects. As such, the first falls as the insult is removed. However, the damage is not reversed and function does not
recover. This irreversible damage results from cell death and dead cells are not replaced by
study implementing a care bundle for AKI using urinary [TIMP-2•IGFBP-7] normally functioning cell.
as an enrollment criterion was in cardiac surgery (discussed above).41
Since its release into the market, [TIMP-2•IGFBP-7] has been shown to perform
well in sepsis (AUC 0.85)55, in surgery patients (AUC 0.84),56 and in patients
with underlying chronic conditions including CHF (AUC 0.89) and CKD (AUC
0.91).57 The test has been shown to increase rapidly (within 4 hours) after
various exposures, and has very distinctive response kinetics after exposure
to various nephrotoxins - well before creatinine elevations.58

24 25
 CLASSICAL AND NOVEL BIOMARKERS OF AKI

6 Other markers 7 Clinical application

Numerous other molecules have been studied as potential second-generation The challenge for new biomarkers is that effective treatments will need to be
biomarkers for AKI including netrin-1, clusterin, calbindin, osteopontin,64 paired with the test in order to show benefit. For AKI, two single-center studies
fibroblast growth factor 23 and alpha Klotho.65 have shown benefit associated with use of [TIMP-2•IGFBP-7] in patients after
surgery.62,63
Furthermore, a third generation of biomarkers is emerging that can detect
persistence of AKI.66 As these markers become available for clinical use we In the first study,62 biomarker-positive patients were randomized to receive
will have a much better idea how they can be used. a care bundle which included a hemodynamic management algorithm based
on mean arterial pressure and stroke volume variation. AKI was significantly
Figure 6. Biomarkers for Acute Kidney Injury.64 reduced with the intervention compared to controls (55.1 vs. 71.7%; ARR
16.6% (95% CI 5.5–27.9%); p=0.004).
Reproduced from Luft FC. Acta Physiologica. 2021;231:e13479, under Creative Commons License BY-NC.
In the second study,63 a similar care bundle including early optimization of
fluids and maintenance of perfusion pressure, was applied to non-cardiac
major surgery patients after testing positive for the biomarker. Overall, AKI
Glomerulus Distal tubule
rates were not statistically different between groups (19/60 (31.7%) in the
Cystatin C Osteopontin
β2 microglobulin Clusterin intervention group vs. 29/61 (47.5%) in the standard care group, p=0.076).
α1 microglobulin GST- µ/π However, rates of moderate and severe AKI, a secondary endpoint, were
Albumin NGAL
Creatinine H-FABP reduced with the intervention (4/60 (6.7%) vs. 12/61 (19.7%), p=0.04), as
Urea Calbindin D28 were lengths of ICU stay (median difference 1 day, p=0.035, and hospital stay
Collecting median difference 5 days, p=0.04).
Proximal duct
tubule Recently, a multicenter, multinational, RCT tested a KDIGO bundle consisting
Calbindin D28
KIM-1
of optimization of volume status and hemodynamics, functional
Clusterin hemodynamic monitoring, avoidance of nephrotoxic drugs, and prevention
NAG
NGAL Henle’s loop of hyperglycemia in 278 high-risk patients identified by the urinary
TIMP-2 Osteopontin [TIMP-2•IGFBP-7] after cardiac surgery. Although overall AKI rates were
IGFBP-7
GST- α
NHE-3 not statistically different between groups, the occurrence of moderate and
Netrin-1 severe AKI was significantly lower in the intervention group as compared to
RBP
IL-18
the control group (14.0% vs 23.9%; ARR 10.0% [95% CI, 0.9-19.1]; p=0.034).67
HGF
PENK
CCL2
CCL12
Conclusions
L-FABP
Albumin Although the field of AKI has lagged behind other areas in the development
of biomarkers, there are now multiple tests available in various parts of the
world.
Shown is a nephron along which putative «biomarkers» are approximately located. It Both tests for [TIMP-2•IGFBP-7] and KIM-1 undergone regulatory review by the
is hoped that these products arrive in the urine before clinical evidence of decreased
glomerular filtration rate (increase in serum creatinine) is apparent. All are US FDA, the former for clinical use as an in vitro diagnostic and the latter in drug
dependent upon urine production. Thus, oliguria is a strong confounder. development. The recent studies showing clinical application are still few in
CCL: C-C motif chemokine ligand; GST: glutathione-S-transferase; HGF: hepatocyte
growth factor; IGFBP: insulin-like growth factor binding protein; L-FABP: liver-type
number but will likely be starting points for larger trials. In addition, new questions
fatty acid binding protein; NAG: N-acetyl-beta-D-glucosaminidase; NGAL: neutrophil concerning the evaluation of AKI etiology, prediction of outcomes including
gelatinase associated lipocalin; PENK: proenkephalin; RBP: retinol binding protein;
TIMP-2: tissue inhibitor of metalloproteinases-2.
recovery and need for RRT are being asked and new biomarkers are being
evaluated. The future will likely bring us many more tests.
26 27
 PREVENTION OF AKI

This figure also illustrates the terminology used for AKI interventions. The
term Prevention, or Prophylaxis, is often used for both pre-insult interventions,
as well as for interventions provided after the insult but before the clinical
manifestation of AKI using KDIGO criteria. The term Treatment, by contrast,
is reserved for interventions provided after the diagnosis of AKI is made (again
PREVENTION OF AKI using KDIGO criteria). This terminology will likely evolve as diagnostics for
AKI are further refined.

2 Clinical risk stratification

An ounce of prevention is worth a pound of cure.
Benjamin Franklin
The concept of risk includes both susceptibilities and exposures. Susceptibility
refers to what the patient brings to the risk equation. Typical susceptibility
variables include age and comorbid medical conditions; whereas exposures
1 Terminology and AKI time course include various clinical scenarios where AKI may occur, sepsis, major surgery,
drugs etc.1 Table 8 lists several susceptibilities and exposures for AKI.
Obviously, it is better to prevent an episode of AKI than to try and treat it but
all interventions, at least those that are effective, come with a price. Interventions Table 8. Common susceptibilities and exposures for Acute Kidney
have unintended effects and most also cost resources—whether monetary, Injury.1
non-monetary or both. Thus, all prevention strategies first consider who is Source: KDIGO. Kidney Inter., Suppl. 2012; 2: 1–138.
at risk and when they are at risk. Figure 7 illustrates the time course for AKI.
Exposures Susceptibilities
Figure 7. Time course for Acute Kidney Injury events.
Sepsis Dehydration or volume depletion

Insult(s) Critical illness Advanced age

Circulatory shock Female gender
Burns Black race
Relative Stress Time Trauma CKD
proportions Damage Function
of patients Cardiac surgery (especially with CPB) Chronic diseases (heart, lung, liver)
Major noncardiac surgery Diabetes mellitus
Detection thresholds Nephrotoxic drugs Cancer
Radiocontrast agents Anemia
Prophylaxis Post-Insult “Prevention” Treatment
Poisonous plants and animals
CKD: chronic kidney disease; CPB: cardiopulmonary bypass.

Risk stratification can be performed either before an insult (prophylaxis

Most acute kidney injury is due to multiple insults (either repeated similar insults such phase) or after the insult (post-insult prevention phase). If before the insult,
a nephrotoxic drug, or variable insults). Therefore, injury is rarely from a discrete event.
Kidney stress increases prior to damage and damage prior to change in function when only susceptibilities may be considered, whereas after the insult, exposures
the change in function is being caused by damage. Note, function may decline early in the can be included as well. Clinical risk stratification works best when applied
time course as some insults produce changes in function before damage (e.g. ischemia).
Note also that detection thresholds for various measures of stress, damage and function to very specific populations and therefore when the variables are also very
do not begin immediately and require some accumulation of signal —see chapter 3 for specific. For example, the type of cardiac surgery (i.e. valve replacement vs.
details. The relative proportions of patients exhibiting stress, damage and dysfunction are
illustrated by the vertical dimensions of each box. coronary artery grafting) is an important exposure criterion but it only applies
to cardiac surgery.
28 29
 PREVENTION OF AKI

3 Role of biomarkers 4 Prevention bundles

Even when specific to a given population and when including exposure variables, Given the complexities in risk stratification discussed above, prevention
clinical risk prediction can be quite limited. While certain exceptions exist strategies for AKI can be challenging to develop and deploy. Some basic
where results appear to validate across patient cohorts,68 most risk prediction interventions like providing adequate hydration and avoiding certain
models have limited generalizability across institutions. Another concern is medications can be applied in the prophylactic phase (Table 9 lists some
that in the context of a clinical study, ascertainment of a given variable may options for such interventions).
be much better than it is in the “real world”.
Biomarkers can address many of the limitations of clinical risk prediction. Table 9. Selected interventions for Acute Kidney Injury prevention.
However, as discussed in chapter 3, the only markers that can be used in the
prophylaxis phase are markers that help clarify underlying chronic disease — Action
Prophy- Post-
Comments
especially CKD (e.g. baseline serum creatinine, urinary albumin). Emerging laxis Insult
markers like urinary dickkopf-3 (DKK3) may have a role in identifying risk in Hydration refers to water—volume status
this phase primarily because they can detect CKD before it meets the definition.69 refers to total circulating blood volume.
Ensure proper
x x Although these two parameters are
hydration
associated with each other they can be
Another approach is to stress the system with a protein load and see if the discordant.
response is appropriate. Investigators have shown that failure to increase
Common examples include non-steroidal
GFR in response to a protein load by at least 15 mL/1.73 m2 resulted in an Avoid unnecessary
anti-inflammatory drugs, various
11.8 times greater likelihood to experience AKI (95% CI 4.62 to 29.89 times, nephrotoxins and
x x antibiotics such as vancomycin and
drugs that reduce
p<0.001) with subsequent cardiac surgery.3 piperacillin, angiotensin converting
kidney function
enzyme inhibitors.
Once the insult has occurred however, markers of kidney stress (e.g. TIMP-2, Obtain/assess baseline
x x
IGFBP-7) and damage (e.g. KIM-1, NGAL) can be used to identify patients kidney function
before they manifest AKI by KDIGO criteria. However, as Figure 7 illustrates, Use functional
This can be initiated in certain settings
not all patients that develop kidney stress will develop damage and not all hemodynamic
x just prior to the insult (e.g. surgical
monitoring to guide
those with damage will manifest a decline in function that is needed to meet procedures).
fluid management
the (currently accepted) criteria for AKI diagnosis. Importantly, markers of
Can be tailored to the patient population
kidney damage are inherently less useful compared to markers of kidney Subspecialist
x but may involve nephrology, intensive care,
involvement
stress because damage may rapidly become irreversible. Nevertheless, early cardiology, hematology and hepatology.
identification of damage is still much better than only identifying it when it
begins to impair function. Two single-center62,63 and one multicenter study67 have shown benefit
associated with the use of a KDIGO-based bundle in patients testing positive
for [TIMP-2•IGFBP-7] after surgery.

30 31
 EVALUATION AND MANAGEMENT

Table 10. Classification of kidney diseases and disorders.

Type of Kidney Meets

Disease/ Criteria criteria for Examples
Disorder AKI?
EVALUATION AND MANAGEMENT GFR <60 mL/kg/1.73m2
Diabetic nephropathy,
CKD No hypertensive kidney
for 90 days or more.
disease.

GFR <60 mL/kg/1.73m2 Cardiac surgery

Evaluation and management of AKI go together because often it is the response CKD with AKD
for 90 days or more with Yes associated AKI in a
to treatment that helps determine the nature of the disorder. For example, a (AKI)
superimposed AKI. patient with CKD.
patient with oliguria and fluid overload who improves with interventions that
improve cardiac function (e.g. an inotrope) has a high probability of cardio-renal GFR <60 mL/kg/1.73m2 Drug associated
for 90 days or more with AKD in a patient
syndrome. Similarly, a patient whose renal function improves with CKD with AKD a decrease in GFR of 35% with underlying
No
discontinuation of a nephrotoxic drug is very likely to have a drug-induced (no AKI) or greater within 90 days CKD—drugs may
AKI. Although some specific tests are available to help determine the cause but does not meet AKI accumulate as kidney
criteria. function declines.
of AKI, the response to treatment is a helpful clue.

1 Clinical approach to a patient with abnormal Increase in serum

Sepsis is the leading
creatinine 50% or more
cause, followed by
kidney function AKI
within 1 week OR increase
by 0.3 mg/dL or more Yes
drugs, cardiorenal
syndrome and
Patients with reduced kidney function may be identified on routine laboratory within 48h OR urine
surgery associated
output <0.5 mL/kg/hr for
testing or in the setting of an acute illness. Reduced kidney function in the 6 hours or longer.
AKI.
context of acute illness, especially if it is an illness known to be associated
with AKI (e.g. sepsis, trauma, heart failure) makes AKI more likely. However, GFR <60 mL/kg/1.73m2
various types of kidney disease and disorders may occur and often, they can for <90 days or increase
Drugs, glomerular
be challenging to differentiate. Table 10 lists the various conditions in which AKD (no AKI) in serum creatinine 50% No
disease.
or more over greater than
reduced kidney function may present. 1 week but <90 days.
The most important piece of information to obtain in the evaluation of patients
with reduced kidney function is the level of kidney function they have had
previously. A search for prior serum creatinine testing should be exhaustive. Chronicity can also be supported by kidney size (small kidneys are characteristic
Establishing a patient’s baseline kidney function will go a long way to of CKD) and by elevated parathyroid hormone. Bone loss may also be evident
determining what type of kidney dysfunction they have and will help guide on X-ray. Conversely, acuity is supported by oliguria, active urine sediment
the differential diagnosis (see Table 10). Baseline kidney function will also (granular casts, red and white blood cells) and presence of stress or damage
help establish the severity of AKI/AKD if present. For example, a patient with biomarkers (see Table 2).2
a GFR 50 has taken a much larger insult if their baseline GFR was 100 compared
to 60. Determining the baseline is therefore critical in the evaluation of kidney
disease.

32 33
 EVALUATION AND MANAGEMENT

2 Evidence of kidney damage Figure 8. Assessing risk for fluid imbalance.38

Reprinted from The Lancet, 394, Ronco C., Bellomo R., Kellum J. A., Acute kidney injury, 1949-64, Copyright 2019,
Evidence of kidney damage should always be sought in patients with decreased with permission from Elsevier.

kidney function (see Figure 4). However, kidney damage may also occur in
Lacrimation
the absence of change in kidney function and should therefore be considered
if the clinical context is appropriate—generally when an exposure has occurred Mucosa Central venous
in the acute setting (e.g. sepsis, chemotherapy) or when underlying disease Neck veins pressure and saturation
makes kidney damage likely in the chronic setting (diabetes, hypertension). Inferior vena cava

Typical markers of kidney damage in the chronic setting include albuminuria Heart sounds Echocardiography
and hematuria. Markers of damage in the acute setting include granular casts
Rales
and various urinary biomarkers (see Chapter 3). The presence or absence of
kidney damage can also help elucidate the causes of changes in kidney function.
Arterial line

Pulse-pressure
Blood pressure pulse variation
3 Identifying the cause of AKI
Capillary refill
Once AKI is suspected or diagnosed, the next step is to determine the cause or
causes. The most common conditions leading to AKI are listed in Table 5. While
this broad differential should always be kept in mind, the diagnostic approach
is not to address each one as being equally likely in every case. A “general workup”
is usually appropriate to quickly narrow the differential diagnosis. Oedema

This workup should focus on six broad areas: Straight leg raise
i. Fluid status; ii. Hemodynamics; iii. Infections; iv. Medications and other toxins;
v. Urinalysis; vi. Imaging.70

* Assessing fluid status

Perhaps one of the most over-diagnosed and misunderstood conditions Illness severity
responsible for kidney impairment is dehydration. Clinicians often assume
that any increase in serum creatinine is due to volume depletion and treat
all cases with fluids first. While volume depletion will result in retained
solute, its rarely the sole cause of AKI in hospitalized patients. Typically, In a non-critically ill patient (left) fluid status is assessed by history and physical
patients in the ICU are in positive fluid balance, not negative, and profound examination. In the proper context (e.g. diarrheal illness) with consistent signs and
symptoms (e.g. dry mucous membranes, increased thirst), physical examination findings
and sustained dehydration in a hospitalized patient is tantamount to will often suffice. In more complex patients (e.g. underlying congestive heart failure)
mismanagement. or in those with critical illness (e.g. septic shock), more invasive methods will often be
required (illustrated by the right side of the figure). Little evidence exists that one form of
However, patients will often present to medical attention with dehydration functional hemodynamic monitoring is superior to another but dynamic measures (e.g.
pulse-pressure variation) are superior to static measures (central venous pressure).
and this state contributes to a decrease in kidney function in many patients.
Furthermore, impaired kidney function due to dehydration may signal
life-threatening hypovolemia or it may simply mean that the patient
requires oral rehydration. Assessment of this condition therefore requires
a graded approach.38 Figure 8 illustrates some of the clinical features
that should be considered in the assessment of fluid status.

34 35
 EVALUATION AND MANAGEMENT

It is important to recognize that the relationship between fluid balance

and AKI complications is a “U-shaped” curve (Figure 9). When fluid balance
* Hemodynamic monitoring
In addition to fluid status, “hemodynamics” includes cardiac performance
is too negative, hypotension and organ hypoperfusion perpetuating the
and vascular tone. In patients where these variables are likely to be
damage to the kidney may occur. A complementary problem can occur
impacted (e.g. sepsis, cardiac surgery, heart failure), it is important to
when fluid balance is too positive—venous congestion might impair kidney
monitor them. Functional hemodynamics aims at increasing cardiac
function and cause severe clinical complications.
output, and variability of stroke volume or pulse pressure is measured in
response to various challenges. These variables have become common
Figure 9. Relationship between hemodynamic status and Acute place in modern ICUs. Typical challenges include positive pressure
Kidney Injury.38 ventilation, straight leg raise or fluid bolus infusion. These maneuvers
Reprinted from The Lancet, 394, Ronco C., Bellomo R., Kellum J. A., Acute kidney injury, 1949-64, Copyright 2019, alter central vascular blood volume, if only transiently, and can be used
with permission from Elsevier.
to gauge cardiac output response. For example, a pulse pressure variation
Restrictive fluid protocols Liberal fluid protocols >13% is usually predictive of an increase in cardiac output with fluids.
Diseased Management of impaired cardiac function is critical to the management
heart of AKI in such patients and treatment of vasomotor paralysis (e.g. septic
Procedures shock, post-cardiac surgery etc.) with vasopressors is similarly critical.
Risk of complications

Drugs
Normal Renal replacement therapy Norepinephrine is usually first-line therapy but vasopressin, epinephrine
heart
and angiotensin II are used as second-line therapy with variation in practice
Hypotension around the world and no clear advantage for AKI across the various drugs.
Tachycardia Hypertension
Shock Peripheral oedema
Organ hypoperfusion Impaired pulmonary exchanges
Oliguria
Renal dysfunction Optimal status
Organ congestion
Renal dysfunction
* Infections
Dehydration Fluid balance Overhydration
Sepsis is the most common cause of AKI in critically ill patients and is
common even outside the ICU - one third of community-acquired pneumonia
patients develop AKI.71 Similar rates have been reported with COVID-19.72
Furthermore, many large multicenter studies over more than 15 years
The relationship between hemodynamics and AKI complications is a U-shaped curve.
have shown that sepsis is a cause of AKI in 40-50% of patients.9,10,73 Thus,
In the case of fluid restrictive protocols, the patient might experience hypotension and sepsis should always be considered in patients presenting with or developing
organ hypoperfusion perpetuating the damage to the kidney. The same problem can occur AKI. This is particularly important when AKI occurs in a setting where it
in case of too liberal policies where the congestive state might impair kidney function and
cause severe clinical complications. is common but with a presentation which is uncommon. For example,
patients undergoing cardiac surgery typically develop AKI within 72 hours
of surgery; those developing AKI later in their course are more likely to
have a different etiology such as infection.
Finally, the presence of AKI in the setting of infection is a common way
to define sepsis (infection plus organ failure). Unfortunately, this relationship
is often missed.74 This may be due to lack of appreciation for the impact
of AKI on mortality in patients with sepsis. Even in patients with septic
shock, patients developing AKI were four times as likely to die within 60
days compared to patients without AKI in a large multicenter clinical
trial.75

36 37
 EVALUATION AND MANAGEMENT

* Medications and other toxins Table 12. Drugs with a high risk for adverse events when kidney
Medications are perhaps the most important factors in the development function is impaired.
of AKI and/or its consequences for patients. This is because many drugs ACE Inhibitors and ARBs Anti-tuberculosis drugs
can injure the kidney in many different ways and also most drugs are
Allopurinol
excreted by the kidney so that AKI can result in accumulation of drugs Antivirals
leading to adverse events. Of course, some drugs are on both lists. Table 11 Antibiotics
• Nucleoside analogues (e.g. acyclovir)
lists several of the most common nephrotoxic drugs and Table 12 lists • Aminoglycosides
• Most HIV and hepatitis drugs
drugs that are cleared by the kidney and are common causes of adverse • Aztreonam
drug events due to changes in kidney function. • Carbapenems Calcineurin inhibitors
• Cephalosporins* Chemotherapy agents
Table 11. Common potentially nephrotoxic drugs.76
• Colistin Colchicine
Reproduced with permission from Journal Pediatrics, Vol. 132, Pages e756-67, Copyright © 2013 by the AAP.
• Daptomycin Hydralazine
Acyclovir Enalaprilat Mesalamine • Penicillins Lithium
Ambisomea Foscarnet Methotrexate • Quinolones Methotrexate
Gadopentetate • Sulfamethoxazole-Trimethoprim Methylprednisolone
Amikacin Nafcillin
dimegluminea
Amphotericin B Gadoxetate disodiuma Piperacillin/tazobactam • Tetracycline Meperidine

Captopril Ganciclovir Piperacillin • Vancomycin Metformin

Carboplatin Gentamicin Sirolimus Antifungals NSAIDs

Cefotaxime Ibuprofen Sulfasalazine • Amphotericin-B Proton pump inhibitors

Ceftazidime Ifosfamide Tacrolimus • Azoles

Statins
Cefuroxime Iodixanol a
Ticarcillin/clavulanic acid • Flucytosine

Cidofovira Iohexola Tobramycin

*Renally cleared cephalosporins include Cefazolin, Cefepime, Cefotaxime, Cefotetan,
Cisplatin Iopamidol a
Topiramate Cefoxitin, Ceftazidime, and Cefuroxime.
Colistimethate Ioversola Valacyclovir ACE: angiotensin-converting enzyme; ARBs: angiotensin receptor blockers;
NSAIDs: nonsteroidal anti-inflammatory drugs.
Cyclosporine Ketorolac Valganciclovir
Dapsone Lisinopril Vancomycin
Enalapril Lithium Zonisamide
a
Medications counted for 7 days after administration toward exposure.

38 39
 EVALUATION AND MANAGEMENT

* Urinalysis Figure 10. Casts seen in spun urine.

Urine can provide multiple clues on the cause of kidney disease. Urine Reproduction of granular and red cell casts seen in spun urine.

chemistries, cells, casts and crystals can all help point to the type and
chronicity of kidney disease. Urinalysis can also help identify infection.
Table 13 describes the interpretation of findings on urinalysis. Granular A
casts (Figure 10) are suggestive of tubular injury, while red cell casts are
highly specific for glomerular disease. Granular casts (also called muddy
brown casts) have limited sensitivity for tubular injury and can easily be
missed, especially in dilute urine. Their identification requires experience
and so interobserver variation exists.36

Table 13. Interpretation of findings on urinalysis.

B
Results Interpretation

May be normal if urine is concentrated.

Large amounts of albumin indicate glomerular
Albumin without hematuria
disease (e.g. diabetic nephropathy, FSGS,
membranous glomerulopathy, amyloidosis).

Albumin with hematuria Concerning for glomerulonephritis.

Dysmorphic red cells/red A. Granular casts (also known as muddy brown casts) are strongly suggestive of acute
VERY concerning for glomerulonephritis.
cell casts tubular injury.
B. Red blood cell casts are seen with glomerulonephritis.
Tubular injury; free tubular epithelial cells may also
Granular casts
be seen.
Urine sodium has been used for centuries to test renal tubular function.
In isolation can be seen with infection or When plasma volume is reduced, the kidney becomes sodium avid and
White cells
tubulointerstitial disease. Together with granular urine sodium falls. To account for differences in urine concentration, the
casts, increases likelihood of tubulointerstitial
nephritis.
fractional excretion of sodium (FENa) has been used. In the setting of
oliguria, a FENa of less than 1% indicates that tubular function is intact
Calcium phosphate, uric acid, cystine, may be whereas a value of greater than 1% generally suggests a loss of tubular
indicative of renal calculi. function and AKI. However, use of diuretics, agents interfering with renin-
Calcium oxalate in the setting of AKI should raise angiotensin-adosterone system or osmotic agents such as mannitol
Crystals
concern for ethylene glycol toxicity.
Heavy uric acid crystals and AKI can be seen in tumor interfere with sodium excretion and FENa.
lysis syndrome.

Normal; can also be seen obstruction, hypertensive urinary sodium X plasma creatinine
Normal
nephrosclerosis, hepatorenal and cardiorenal disease. FENa = X 100
urinary creatinine X plasma sodium
FSGS: Focal segmental glomerulosclerosis

40 41
 EVALUATION AND MANAGEMENT

In patients who have received diuretics, fractional excretion of urea 4 Non-specific management of AKI
(FEUrea) may be useful. A low FEUrea (≤35%) is a more sensitive and
specific index than FENa in identifying intact tubular function especially Most cases of AKI have multi-factorial causes and even for cases due to a
if diuretics have been administered.77 single inciting event, it is important to avoid further injury. Thus, management
of AKI is predicated on three principles:
i. avoid further insults;
urinary urea nitrogen X plasma creatinine ii. monitor for recovery/progression;
FEUrea = X 100 iii. identify and manage/prevent complications.
urinary creatinine X blood urea nitrogen
The 2012 KDIGO guideline on AKI is an excellent resource for the application
of these principles (see Figure 11).
Urinary indices have not been validated in critically ill patients and have
shown disparate results in patients with septic AKI. Systemic inflammation Figure 11. Stage-based management of AKI.1
secondary to sepsis has been shown to cause conformational changes Source: KDIGO. Acute Kidney Injury Work Group. Kidney Inter Suppl 2012, 2(1):1–138.
in the Na/H, chloride and urea channels, thereby independently affecting
their excretion. Recent studies have consistently demonstrated the limited
diagnostic and prognostic utility of urine biochemistry in AKI78 and the Acute Kidney Injury Stage
routine use of these indices in patients with oliguria is not recommended.
High Risk Stage 1 Stage 2 Stage 3

* Imaging and histology Discontinue all nephrotoxic agents when possible

Kidney ultrasonography is widely used for evaluation of kidney disease. Ensure volume status and perfusion pressure
Kidney size (small kidneys are seen in CKD, although it may take years
for this to develop) and echogenicity can provide clues to the chronicity Consider functional hemodynamic monitoring
of disease. Obstruction will result in hydronephrosis - though caution is
Monitor serum creatinine and urine output
needed here as obstruction can be missed early on. Renal vascular disease
can also be identified, although angiography may be required to confirm. Avoid hyperglycemia
CT scans can also be useful in evaluating kidney disease and can help
identify other conditions, such as retroperitoneal fibrosis. Kidney histology Consider alternatives to radiocontrast procedures
obtained by biopsy is often used in AKI when the diagnosis is uncertain
Non-invasive diagnostic workup
or when glomerular disease is suspected.
Consider invasive diagnostic workup

Check for changes in drug dosing

Consider renal remplacement therapy

Consider ICU admission

Avoid subclavian catheters if possible

Shading of boxes indicates priority of action; solid shading indicates actions that are
equally appropriate at all stages whereas graded shading indicates increasing priority as
intensity increases.
AKI: acute kidney injury; ICU: intensive care unit.

42 43
 EVALUATION AND MANAGEMENT

Avoidance of further insults usually takes the form of careful attention on the topic (see Kellum JA, Cerda J. Renal and Metabolic Disorders;
to medications and avoiding radiocontrast when possible. It is also Oxford University Press, 2012 ISBN-13: 978-0199751600).
important to avoid both fluid overload and underfilling as discussed above. As depicted in Figure 11, management of AKI begins with “high-risk”.
Common complications from AKI are listed in Table 6 and include fluid Determining which patients are at high risk can be challenging and it is
overload, adverse drug events, acid-base and electrolytes abnormalities, the main rationale for the development of AKI biomarkers. Figure 12
increased bleeding, infection risks and encephalopathy. Detailed provides an approach to AKI management based on biomarkers.
recommendations for management of these complications are beyond
the scope of this monograph but the reader is referred to other reviews

Figure 12. Biomarker-guided management of patients at risk for AKI.70

Reproduced from Guzzi, et al., Critical Care. 2019;23 p.225 under Creative Commons License BY-NC.

Potential AKI Risk Patients Nephroprotective Bundle AKI Risk lncrease:

• Discontinue all nonessential Kidney Stress Origin
• Cardiovascular/respiratory
nephrotoxins (e.g., NSAIDs) What is causing increased kidney
compromise <24 h (≥21 y) • Avoid vancomycin or dose-adjust stress?
• Shock • Goal-directed fluid/diuretic • Additional patient evaluation
• Sepsis management* • Consider existing or additional
(suspicion/confirmation) • Discontinue all ACEs and/or ARBs treatments/consults
• Post-operative • Maintain close UO monitoring
>0.3 • Review meds with clinical
major/cardiac surgery Moderate/Severe pharmacist
• Trauma with AKI Risk • Retain invasive hemodynamic
cardiac/respiratory monitoring
compromise • Avoid saline
• Other • Consult Nephrology
0.3 • Repeat [TIMP-2]•[IGFBP7]
test in 12-24h
• Consult Intensive Care

Standard of Care
AKI Risk Score

AKI Prevented:
≤0.3 • Standard of care or fast-track
Standard of Care
Low AKI Risk • Repeat [TIMP-2]•[IGFBP7] test if
additional exposures occur Triage/Fast-Track/Step-Down
• Consider diuretics to maintain • Continue monitoring
fluid balance

Golden Hours of AKI Prevention† 4 12 24 48

* lncludes bedside ultrasound and functional hemodynamic monitoring.

[TIMP-2]•[IGFBP7] Testing
Consider additional testing with any significant change in patient condition or insult. 6-12 h post ICU admission or deemed critically ill

Protocol early management of AKI based on [TIMP-2•IGFBP-7] testing.

ACEs: angiotensin-converting enzymes;
AKI: acute kidney injury;
ARBs: angiotensin-receptor blockers;
ICU: intensive care unit;
NSAIDs: nonsteroidal anti-inflammatory drugs;
UO: urinary output.

44 45
 RENAL REPLACEMENT THERAPY

Table 14. Emergent Criteria for RRT in the setting of Stage 3 AKI.

Parameter STARRT-AKI81 AKIKI80

BUN NA >112 mg/dL (>40 mmol/L)
>6 mmol/L (>5.5 mmol/L
RENAL REPLACEMENT THERAPY K ≥6 mmol/L
despite treatment)
pH ≤7.20 (or serum pH <7.15 in the setting of
Acidosis
bicarbonate ≤12 mmol/L) metabolic acidosis
Ratio of partial pressure
of arterial oxygen to the Requiring >5L/min or 50% O2 to
Extracorporeal kidney support, otherwise known as renal replacement Pulmonary edema
fraction of inspired oxygen maintain O2 saturation >95%
therapy (RRT), in the form of dialysis or hemofiltration (or both) is provided of ≤200
to a minority of patients with AKI. In the worldwide AKI-EPI study, 23.5% of Persistent AKI Stage 2-3 AKI ≥72 hours
Stage 3 AKI with oliguria >72
hours
patients with AKI underwent RRT.10 A somewhat lower rate of 15% was seen in
the Southeast Asia AKI study.11 However, both of these studies focused on Criteria used for emergent RRT in recent larger clinical trials.80,81

patients with AKI being cared for in the ICU. In a recent multicenter study in
the US, about 5% of patients hospitalized with AKI (not limited to the ICU) In the chronic setting, dialysis is usually started to manage retention of solutes
received RRT.79 (e.g. urea, beta-2 microglobulin) that lead to variety of pathologic disturbances
(e.g. platelet dysfunction, arthralgia, loss of appetite) and metabolic acidosis
which leads to bone demineralization.
1 Indications In the acute setting, concerns are more focused on the effects of kidney failure
Traditionally, indications for RRT for AKI have been grouped into ‘emergent’ on fluid balance, platelet and neutrophil dysfunction and the contribution of
and ‘non-emergent’ indications. Emergent indications include severe cases uremia to encephalopathy. Judging the relative impact of these disturbances
of hyperkalemia, fluid overload, acidosis or manifestations of uremia (e.g. on outcomes and balancing the risks inherent in providing acute RRT with
pericarditis). Both severity of these conditions and their refractoriness to the risks attributable to these disturbances can be difficult.
medical management have been included in the classification of an emergent Furthermore, the effect of these abnormalities is variable between individuals
indication. and over time. If one conceptualizes the potential for adverse effects from
For example, a patient presenting with a serum potassium of 9 mmol/L and kidney dysfunction as a ‘demand’ for kidney function and the residual kidney
cardiac irritability requires emergent dialysis whereas for a patient with a function as ‘capacity’ then it is possible to consider a demand-capacity
level of 7 mmol/L and no EKG changes, medical management might be relationship that changes over time and is unique to the patient.82
attempted first. Determining the degree of severity and refractoriness is Thus, a demand-capacity imbalance may exist because demand is high and
always a matter of clinical judgment and continues to be an area of significant capacity is only marginally reduced or demand is only marginally increased
heterogeneity. In recent trials testing alternative strategies for initiation of but capacity is significantly compromised (Figure 13). Alternatively, both
RRT in AKI, a series of clinical criteria were used as exclusion criteria and thus high demand and low capacity may co-exist. The nature of the demand-capacity
were thought to represent the standard of care as to when to initiate (see imbalance for a given patient and the expectation as to how this relationship
Table 14).80,81 will change over time guides decision-making about the timing of RRT (see
Conversely, anything judged to not be emergent is classified as a non-emergent Figure 14).
indication. Most commonly, non-emergent indications include fluid overload In general, when a given patient’s demand-capacity imbalance is not expected
that is less severe than what is judged to be emergent and metabolic/solute to resolve before they begin to be adversely affected by it, they should be
imbalances. started on RRT without delay.

46 47
 RENAL REPLACEMENT THERAPY

Figure 13. Demand and capacity - a conceptual model. Figure 14 continued

Source: Acute Dialysis Quality Initiative 17. www.adqi.org. Used with permission.
The top two panels represent no RRT—the left illustrates early reversal of AKI and the
right shows progressive renal failure and increasing discrepancy between renal function
.Demand Capacity Demand – capacity balance capacity and physiological demands.
The two bottom panels illustrate the effect of RRT (dashed lines) with (left) early (E) or
Demand Capacity later (L) initiation and two different demand-capacity discrepancy patterns. On the right
the patient scenario illustrated is different with high underlying disease burden and either
initiation of continuous RRT on day 2 transitioning to intermittent RRT on day 4 (dashed
+

line marked as C-I) or initiation of intermittent therapy on day 4 (I).

Disease burden
+

Normal
function
Capacity Demand

Solute Load Capacity 2 Modalities

Demand The various types of RRT available can be classified according to whether
Gap they are applied, or intended for application, 24 hours a day—known as
Reduced
+ continuous therapies; or whether their application is for short treatments,
Volume Load function often lasting 3-4 hours—known as intermittent therapy (Figure 15). In recent
Capacity Demand years, a variety of hybrid therapies (with a variety of terms to describe them)
have emerged. These therapies are provided for longer durations and often
more frequently than traditional intermittent RRT but are not continuous
Figure 14. Four patient scenarios. therapies. Figure 15 depicts characteristics and advantages/disadvantages
Source: Acute Dialysis Quality Initiative 17. www.adqi.org. Used with permission. of each of the RRT modalities.
Kidney Kidney
Function Function Figure 15. Characteristics and risks of different RRT modalities.
Demand

Demand

Source: Acute Dialysis Quality Initiative 17. www.adqi.org. Used with permission.

CRRT/PD PIRRT/ IHD

1 2 3 4 5 1 2 3 4 5
SLED
Time (days) Time (days)
Kidney
Function
E C-I hemodynamic stability
Demand

Demand

RRT
L RRT stability of intracranial pressure
I
rate of fluid removal
rapidity of metabolic and acid base correction
risk of osmolar shifts
risk of infections
immobilization
1 2 3 4 5 1 2 3 4 5
Time (days) Time (days) speed of small solute clearance, incl potassium, drugs

Demand-Capacity
Discrepancy

Endogenous Technology
CRRT: continuous renal replacement therapy; IHD: intermittent hemodialysis;
PIRRT: prolonged intermittent renal replacement therapy; SLED: slow efficiency dialysis;
The bars represent total demand including chronic disease (blue), acute illness (orange) and
PD: peritoneal dialysis.
solute/fluid excess (green).

48 49
 RENAL REPLACEMENT THERAPY

The second aspect of modality to understand concerns the solute transport Thus, a “dose” of RRT can be measured by the amount of ultrafiltrate produced
principles that are used to achieve clearance. There are two distinct forms, and replaced using convection. The dose using diffusion is similarly estimated
diffusion and convection (Figure 16). by the volume of dialysate as long as the dialysate is fully saturated (i.e.
equilibrium between the concentration of the solute in the plasma and spent
Figure 16. Solute transport principles used in renal replacement dialysate is reached). In practice, this is achieved by regulating the dialysis
therapy. flow rate relative to the blood flow.
Continuous RRT (CRRT) may be either diffusive (continuous hemodialysis) or
Diffusion Convection use convection (continuous hemofiltration) or both (continuous hemodiafiltration).
Although hemofiltration can be delivered intermittently, for practical reasons,
intermittent therapies are mainly diffusive.

3 Management considerations
A detailed discussion of application of RRT is beyond the scope of this
document. For a handbook reference on CRRT the reader is referred to:
* Continuous Renal Replacement Therapy (2 ed.)
nd

Edited by John A. Kellum, Rinaldo Bellomo, and Claudio Ronco

Oxford University Press. Feb 2016; ISBN-13: 9780190225537
While a more comprehensive treatment of the subject can be found in:
* Critical Care Nephrology (3 ed.)
rd

Edited by Claudio Ronco, Rinaldo Bellomo, John A. Kellum,

and Zaccaria Ricci
Elsevier, 2019; ISBN-13: 978-0323449427
With diffusion, solute transport is determined by concentration gradients between
plasma and dialysate and is limited by solute size with larger molecules diffusing less However, two specific management considerations will be discussed here -
well compared to smaller molecules. With convection, there is bulk flow of water with
solute driven by a pressure gradient. Molecular size has far less impact on clearance when net ultrafiltration rate and modality transition.
convection is used.
* Net ultrafiltration rate
Net ultrafiltration (NUF) rate is defined as the total effluent rate minus the
Diffusion is the movement of molecules from an area of high concentration
sum of replacement fluid and spent dialysate. When NUF rate exceeds
(e.g. plasma) to an area of low concentration (e.g. dialysate). When dialysate
1.75 mL/kg/hr, there is an association with increased mortality.83,84 The
is run countercurrent to the blood flow, a maximum concentration gradient
mechanisms responsible for this relationship are unclear but likely include
will exist along the dialyzer. Larger molecules, up to the pore size cutoff of
an effect on organ perfusion which can be jeopardized by rapid removal of
the membrane, will still diffuse down their concentration gradient but this
fluids from the intravascular space.85 These findings support the practice of
will occur more slowly as the molecule size increases. Thus, diffusion favors
ordering NUF in relation to body weight (rather than just mL/hr) and limiting
smaller molecules.
NUF rate to <1.75 mL/kg/hr except when required to reverse life-threatening
Convection, by contrast, involves bulk flow of plasma water across the
fluid overload.
membrane driven by a pressure gradient. Solutes are dragged across the
membrane with the water as long as they are smaller than the pore size cutoff. * Modality transition
Convection does not depend on molecule size and there is no concentration Over time, many patients will recover kidney function after AKI and will be
gradient per se because there is no dialysate. able to be liberated from RRT. Other patients may require transition to more
Clearance is achieved by replacing the removed plasma water and solute with chronic modes of therapy. Figure 17 illustrates the modality of transition
sterile fluid that has a lower (or zero) concentration of the solute of interest. across different patient experiences.
50 51
 RENAL REPLACEMENT THERAPY

Figure 17. Potential pathways following an episode of AKI, including

transition.
Source: Acute Dialysis Quality Initiative 17. www.adqi.org. Used with permission.

. FOLLOW-UP FOR PATIENTS WITH

Complete ACUTE KIDNEY INJURY
Total Renal Functional Capacity

1st Insult
recovery
2 Insult
nd Partial
recovery
As discussed in Chapter 1, AKI is by definition, an abrupt event resulting in a
loss of kidney function. However, injury to the kidney may result in various
patterns of functional change over time. Figure 18 illustrates the various
ESRD
patient trajectories following an injurious event (e.g. nephrotoxic medication,
sepsis, surgery).33,86 Importantly, some events never result in measurable
CRRT PIRRT IHD changes in kidney function - they remain subclinical. Other cases produce
clinical evidence of AKI and then either resolve or persist. Unfortunately, some
cases of AKI only appear to resolve while underlying injury leads to subsequent
ESRD: end stage renal disease; CRRT: continuous renal replacement therapy;
PIRRT: prolonged intermittent renal replacement therapy; IHD: intermittent hemodialysis. progression to chronic kidney disease.

Figure 18. Clinical trajectories following AKI.86

Reprinted with permission of the American Thoracic Society. Copyright © 2021 American Thoracic Society. All rights
reserved. Ronco, C., Ferrari, F. & Ricci, Z., 2017, Recovery after Acute Kidney Injury: A New Prognostic Dimension
of the Syndrome, Am J Respir Crit Care Med, 195, 711-714. The American Journal of Respiratory and Critical Care
Medicine is an official journal of the American Thoracic Society.
Acute Kidney Disease (3 months)

Full Recovery
Highly Susceptible (Baseline GFR > 90
Kidney Creatinine Domain ml/min and RFR >
(Baseline GFR > 90 (sCr KDIGO Clinical) 30 ml/min
ml/min and
RFR < 30 ml/min)
or Established CKD Kidney Recovery
(GFR > 60 ml/min)
Biomarker Domain
(Subclinical)

KDIGO
Adaptive
Increased Risk Acute Kidney Injury Repair
Acute Kidney Stress Acute Kidney Injury
(AKI with Damage) (AKI with dysfunction)
(AKS)
Apparent Full
Recovery
Organ Death (Baseline GFR > 90
Dialysis ml/min and RFR
< 30 ml/min
CKD
(GFR< 60 ml/min)
Maladaptive
Repair Sclerosis
Fibrosis

Recovery Patterns:
a) Early sustained reversal
b) Late reversal
Normal Kidney c) Relapsing AKI with recovery
Normal Baseline d) Relapsing AKI without recovery Organ Death
Partial Recovery
GFR and intact RFR e) Nonreversal Dialysis
(GFR < 60 ml/min)
(>30 ml/min)

52 53
 FOLLOW-UP FOR PATIENTS WITH ACUTE KIDNEY INJURY

Patients who sustained an episode of AKI are at risk for subsequent CKD. As
1 Post-AKI Phenotypes such, monitoring kidney function as well as management of CKD risk-factors
For patients sustaining AKI, a variety of recovery phenotypes have been (hypertension, diabetes, etc.) is critical.
identified with profound implications for health.33 For most patients, their Furthermore, patients with unstable kidney function at hospital discharge
clinical state at hospital discharge dictates long-term outcomes. Table 15 list are at particularly high risk for adverse drug events. This can occur both
the various recovery phenotypes, their definitions and effect on survival for because kidney function worsens and drug accumulation causes toxicity, but
critically ill patients. also because kidney function may improve and result in treatment failures if
drug dosing is not adjusted. As such, careful attention to drug selection and
Table 15. Recovery after Acute Kidney Injury.33 dosing on follow-up visits is vital. Figure 19 provides a framework for
management of patients post-AKI based on the AKD stage they are in after
Adapted from Kellum, et al. Am J Respir Crit Care Med. 2017;195:784-791.
the first week.
Survival
Phenotype Definition Frequency Figure 19. Evolution of AKI into AKD.
at 1 year
Reversal of AKI within 1-week Source: Acute Disease Quality Initiative 16. www.adqi.org. Used with permission.
Early sustained
and sustained through hospital 26.6% 90%
reversal
discharge

Late recovery
No reversal within 1 week but
recovery prior to discharge
9.7% 75% AKD
Clinical
Early reversal but relapse of AKI with
Relapse-recovery 22.5% 69% KDIGO
recovery prior to discharge
AKI Stages Clinical/Pathophysiological:
Early reversal but relapse of AKI AKD Sequelae:
Relapse-no recovery 14.7% 42% Persistent damage/loss
without recovery prior to discharge of function New or worse
Serum Creatinine/Injury Markers lll Repair/recovery CKD
AKI is persistent throughout New or
No reversal 26.5% 40% Complications (i.e.,
hospital stay electrolytes, fluid, acceleration
Initiation hemodynamics) to ESRD
CV event risk
Frequency and hazard ratios are based on data from a study of just under ll
Hypertension
17,000 critically ill patients with stage 2-3 AKI.33 Reversal was defined as the Sepsis risk
Clinical Outcomes:
absence of AKI criteria for at least 24-hours. Recovery was ascertained at l Persistent loss/worsening Malignancy
risk
hospital discharge and required survival and absence of renal replacement Relapsed/Recurrent AKI
GI Bleed risk
Functional Recovery
therapy in addition to no evidence of AKI. Subclinical Osteoporosis
Dialysis dependance and fracture
Death risk

2 Post-discharge monitoring and management Proteinuria

Injury Biomarkers
Others

Since post-discharge complications are more common among patients who

do not recover renal function by hospital discharge, this group represents Diagnosis/Recognition Evolution
the highest priority for follow-up. In general, such patients should be seen (7 days) (7-90 days)
within 1-2 weeks of discharge.
Patients with late recovery or those having relapse of AKI with subsequent
recovery are the next highest risk category and should receive follow-up soon Patients with AKI can recover and can evolve into AKD. Subjects who recover
after discharge - by day 30 at the latest. The lowest risk group are patients from AKI and/or AKD may still be at risk for long-term sequelae.
with early sustained reversal. These patients might not require specific post-
discharge follow-up but should have their renal function checked along with
other outpatient monitoring.
54 55
 FOLLOW-UP FOR PATIENTS WITH ACUTE KIDNEY INJURY

Although many patients who are hospitalized with AKI or developing AKI in Figure 21. Kidney Health Assessment and Response.
hospital will have a protracted length of stay, others may be discharged early,
Source: Acute Disease Quality Initiative 22. www.adqi.org. Used with permission.
often before renal function has stabilized. Close follow-up for these patients
is critical for the reasons discussed above. Classifying patients according to
their AKD stage and then using the stage to guide the intensity of follow-up Population
has been proposed by the ADQI 16 workgroup (Figure 20).87 (National monitoring for variation in AKI incidence)

Figure 20. Layered Approach to AKD Follow-Up.

Source: Acute Disease Quality Initiative 16. www.adqi.org. Used with permission.
Periodic Periodic
High-Risk Population

A Layered Approach to AKD Education

Follow-up Care
Acute exposure Acute exposure
Intensity of Kidney Function Monitoring

Medications Imaging Surgery Sick

Earlier and More Frequent

Stage III Nephrology

Referral

Stage II ? Others
AKI History Kidney Health Assessment CKD/Creatinine
AKD on CKD, DM, CHF, Blood Pressure (ABCD) Drugs/Dipstick
cirrhosis, malignancy Documenting AKD

Stage I Patient Education

Medication Reconciliation
Nephrotoxin Avoidance
Kidney Health Response (4Ms)
AKD Stage Intensification of Follow-up Care Medication adjustment
Minimize exposures
Message care team and patient
Monitor

Based on the stage of AKD, different levels of follow-up may be appropriate

for patients with AKD.
Kidney Health Assessment includes AKI history, Blood pressure, CKD, serum Creatinine
Finally, anyone developing AKI is at subsequent risk for another episode of level, Drug list, and urine dipstick. Exposures (MISS) include Nephrotoxic Medications,
AKI, in addition to development of CKD. Frequent kidney health assessments Imaging, Surgery, Sickness. Kidney Health Response (4Ms) that encompasses Medication
review to withhold unnecessary medications (e.g. non-steroidal anti-inflammatory drugs),
and appropriate responses may help mitigate these risks.88-90 Figure 21 the Minimization of nephrotoxic exposures (e.g. intravenous contrast), Messaging the
illustrates this approach. This approach has also been adapted for pediatrics91 healthcare team and patient to alert the high-risk of AKI, and Monitoring for AKI and its
consequences.
and neonates.92

56 57
LIST OF ABBREVIATIONS

ACE Angiotensin-converting enzyme KDIGO Kidney disease: improving global outcomes

AIN Allergic interstitial nephritis KIM-1 Kidney injury molecule-1
AKD Acute kidney disease L-FABP Liver type fatty acid binding protein
AKI Acute kidney injury MMP Matrix metalloproteinase
ALP Alkaline phosphatase NAG N-acetyl-beta-D-glucosaminidase
ARBs Angiotensin receptor blockers NGAL Neutrophil gelatinase associated lipocalin
CCL C-C motif chemokine ligand NKD No known kidney diseases or disorders
CKD Chronic kidney disease NSAIDs Nonsteroidal anti-inflammatory drugs
CPB Cardiopulmonary bypass NUF Net ultrafiltration
CRRT Continuous renal replacement therapy PAMPs Pathogen-associated molecular patterns
DAMPS Damage-associated molecular patterns PRRs Pattern recognition receptors
DKK3 Dickkopf-3 RFR Renal functional reserve
eGFR Estimated GFR RRT Renal replacement therapy
ESRD End stage renal disease S-AKI Sepsis associated AKI
FENa Fractional excretion of sodium SCr Serum creatinine
FEUrea Fractional excretion of urea TIMP-2 Tissue inhibitor of metalloproteinase-2
GFR Glomerular filtration rate TLRs Toll-like receptors
GGT Gamma-glutamyl transferase TTP Thrombotic thrombocytopenic purpura
GST Glutathione S-transferase PD Peritoneal dialysis
HGF Hepatocyte growth factor PENK Proenkephalin
HUS Hemolytic uremic syndrome PIRRT Prolonged intermittent renal replacement therapy
ICU Intensive care unit RBP Retinol binding protein
IGFBP-7 Insulin-like growth factor-binding protein7 ROS Reactive oxygen species
IHD Intermittent haemodialysis SLED Slow low efficiency dialysis
kDa Kilodalton UO Urine output

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In vitro diagnostics serving

public health
A major player in in vitro diagnostics for more than 50 years,
bioMérieux has always been driven by a pioneering spirit and
unrelenting commitment to improve public health worldwide.
Our diagnostic solutions bring high medical value to healthcare
professionals, providing them with the most relevant and reliable
information, as quickly as possible, to support treatment decisions
and better patient care.
bioMérieux’s mission entails a commitment to support medical
education, by promoting access to diagnostic knowledge for
as many people as possible. Focusing on the medical value of
diagnostics, our collection of educational booklets aims to raise
awareness of the essential role that diagnostic test results play
in healthcare decisions.

Other educational booklets are available.

Consult your local bioMérieux representative, or visit
www.biomerieux.com/en/education/educational-booklets
Photo credits: Getty Images / Printed in France / théra / RCS Lyon B 398 160 242.

The information in this booklet is for educational purposes only and is not
intended to be exhaustive. It is not intended to be a substitute for professional
medical advice. Always consult a medical director, physician, or other qualified
health provider regarding processes and/or protocols for diagnosis and
treatment of a medical condition. bioMérieux assumes no responsibility or
liability for any diagnosis established or treatment prescribed by the physician.

bioMérieux S.A. • 69280 Marcy l’Étoile • France

Tel.: + 33 (0)4 78 87 20 00 • Fax: +33 (0)4 78 87 20 90
www.biomerieux.com