Jurnal AKI

Review Article
Page 1 of 22
The role of the clinical laboratory in the detection and monitoring

of acute kidney injury
Konstantinos Makris
Clinical Biochemistry Department, KAT General Hospital, Kifissia, Athens, Greece

Correspondence to: Dr. Konstantinos Makris, PhD, EurSpLM, FAACC. Clinical Biochemist, Clinical Biochemistry Department, KAT General
Hospital, 2 Nikis Street, 14561 Kifissia, Athens, Greece. Email: [email protected].
Abstract: Acute kidney injury (AKI) is a common syndrome presenting in multiple clinical settings and is
frequently associated with serious short and long term adverse outcomes, which not only have impact on the
patient but also on the health service increasing hospitalisation time and the costs related to the treatment.
Early diagnosis and identification of the aetiology are essential for the management of the patients. During
the last ten years, significant advances have been made towards the definition of this syndrome. The current
consensus definitions of AKI include both changes in serum creatinine concentration and urine output.
Although proposal have been made for the inclusion of novel biomarkers in the diagnostic workup of AKI as
independent diagnostic markers these are not currently included in these definitions. In this review we will
focus on these definitions and we will try to highlight their strengths and limitations in diagnosis and staging
of AKI. Moreover, we will try to highlight the contribution of the clinical laboratory in AKI diagnosis in
both the clinical and research settings.
Keywords: Acute kidney injury (AKI); serum creatinine (sCr); urine output (UO); urine chemistries; urine
microscopy
Received: 29 June 2018; Accepted: 13 July 2018; Published: 10 August 2018.

doi: 10.21037/jlpm.2018.07.06
View this article at: http://dx.doi.org/10.21037/jlpm.2018.07.06
Introduction co-morbidities, and also geographical location (4,5,7,8).

Increasing evidence from several studies has been shown
Acute kidney injury (AKI) is a clinical syndrome that
the clinical importance of AKI demonstrating that AKI is
is characterised by a rapid deterioration of kidney
associated with serious short- and long-term complications
function that disorganises metabolic, electrolyte and fluid
(increased mortality and morbidity). Moreover, there is a
homeostasis over a period of hours to days. AKI complicates
the course and worsens the outcome in a significant number consistent association with increased long-term risk of poor
of hospitalised patients (1,2). AKI is well recognised as outcomes such as, progression to chronic kidney disease
a major health problem that affects millions of patients (CKD) and mortality, longer hospitalisation time and
worldwide. It is often diagnosed in the context of other utilisation of health resources (9-15).
acute illnesses and is particularly common in critically ill The clinical consequences of AKI mainly include the
patients (3). The incidence of AKI is 3–20% in hospitalised accumulation of waste products, electrolytes, and fluid, but
patients and 30–60% in the intensive care unit (ICU) (4-6). also has less obvious effects, such as reduced immunity and
The clinical spectrum of AKI is wide ranging from small dysfunction of non-renal organs (distant organ cross-talk)
subclinical changes in the levels of biochemical markers of (16-18).
kidney function to overt renal failure that requires renal AKI is also associated with augmented healthcare costs.
replacement therapy (RRT). The impact and prognosis The prolonged hospitalisations, in association with the
of AKI can vary considerably depending on the age of the worse outcomes and the diminished quality of life, after
patient, the severity of AKI, the clinical setting, presence of discharge, have recognised AKI as a major public health
© Journal of Laboratory and Precision Medicine. All rights reserved. jlpm.amegroups.com J Lab Precis Med 2018;3:69
Page 2 of 22 Journal of Laboratory and Precision Medicine, 2018
problem (19-21). The reality is even worse if we consider of a precise definition of ARF resulted in more than
the lack of effective interventions to prevent AKI in patients 30 definitions in the medical literature, which caused wide
at-risk and the lack of therapeutic interventions in those variation in the reported incidence and clinical significance
affected with AKI. of ARF. This situation resulted in wide differences on the
These observations strengthen the importance: incidence and outcome, and comparisons between studies
(I) To early diagnose AKI in hospitalised patients, was difficult if not impossible (24,25). Although these
in order to implement any available therapeutic definitions were developed by researchers in different
intervention to mitigate its impact and clinical studies, in clinical practice the situation was much
(II) To identify those hospitalised patients that are at worse. Because of the lack of a uniform definition, each
increased risk to develop AKI, in order to prevent institution has developed its own criteria according to their
its development. individual practices. More than 200 different definitions
In order to accomplish this task, we need three things: were used in clinical practice as a survey revealed (26). It
(I) A diagnostic system that will be based in both was clear that a consensus definition was urgently needed to
clinical evaluation and laboratory workup in order bring order in research and clinical practice. On the other
to help clinicians to identify patients at risk; hand, it was realised that the syndrome was much broader
(II) A clear clinical definition of this syndrome that will and the clinical manifestations, depending on the cause,
help clinicians to determine the cause and stage of were ranging from sub-clinical to overt disease. However,
AKI and these definitions were focusing on the subset of patients
(III) Laboratory support that will confirm the diagnosis, with more severe acute kidney disease (AKD) and those
help clinicians to stage and monitor the patients with renal failure requiring dialysis treatment. It became
during their interventions, and predict the outcome. clear that a much broader definition was necessary to cover
How the clinical laboratories can support these three all clinical phenotypes.
demands? In this article, we will review the developments
in AKI definition and investigate laboratory contribution to Risk, Injury, Failure, Loss, and End-Stage Renal Disease
diagnosis and monitoring of patients. Classification
The term AKI became the preferred term in 2004 when

Lost in definitions ARF was redefined with the consensus criteria known
The traditional definition as RIFLE (an acronym of the Risk-Injury-Failure-Loss-
End stage kidney disease) (27). The birth of the RIFLE
Before 2004 when we used the term acute renal failure (ARF) classification opened a new era for the definition of AKI
we tried to define a clinical syndrome that was characterised (Table 1). This was the first consensus definition based
by a “rapid fall in the rate of glomerular filtration (GFR), on serum creatinine (sCr) levels, estimated GFR and
which clinically was manifested as an abrupt and sustained urine output (UO), which provided a platform through
increase in the serum levels of urea and creatinine with an which comparative epidemiology could be judged. This
associated disruption of salt and water homeostasis” (22). classification greatly improved the early detection of AKI.
However, this definition had several important limitations However, the term AKI has been proposed to encompass
that had serious implications for clinical practice. the entire spectrum of acute changes in renal function,
The terms “rapid”, “abrupt” and “sustained” were not from minor changes in markers of renal function until
specifically defined. Depending on the cause, ARF can the need for RRT. AKI is not synonym to acute tubular
evolve within hours or days. The rapidity of onset may necrosis (ATN), nor to ARF. Instead, it encompasses
correlate with the severity of the episode, but this is not both and also includes other less severe conditions. As a
clear or implied within this definition (23). syndrome, it includes patients without actual structural
There was no precise “biochemical definition” for damage to the kidney but with functional impairment
ARF, which had as a result, mainly in research studies, relative to physiologic demand. Including such patients
investigators to use different definitions: some used absolute in the classification of AKI is clinically attractive because
or percentage increases in creatinine levels, whereas these are precisely the patients who may benefit from early
others have used the patient’s need for dialysis. The lack intervention. However, it means that AKI includes both
Journal of Laboratory and Precision Medicine, 2018 Page 3 of 22
Table 1 RIFLE criteria for classification/staging of AKI. The severity of injury or outcome is determined by either sCr levels or GFR, whichever
indicates the more severe renal failure [modified from reference (27)]
Stage Change in serum creatinine Change in GFR Urine output
Risk 1.5-fold increase Decrease >25% UO <0.5 mL/kg/h for >6 h
Injury 2.0-fold increase Decrease >50% UO <0.5 mL/kg/h for >12 h
Failure 3.0-fold increase or sCr >4.0 mg/dL (350 μmol/L) with an Decrease >75% UO <0.5 mL/kg/h for >24 h or anuria for
acute increase of 0.5 mg/dL (44 μmol/L) 12 h
Loss Loss of kidney function requiring dialysis lasting for >4weeks
ESRD Loss of kidney function requiring dialysis lasting for >3 months
ESRD, end-stage renal disease; AKI, acute kidney injury; GFR, glomerular filtration rate; sCr, serum creatinine; UO, urine output.
injury and/or impairment. the RIFLE criteria, which aimed to improve the sensitivity
Rather than focusing exclusively on patients with renal of AKI diagnostic criteria for adults (35). There were
failure or on those who receive dialysis or who have a several changes: the risk, injury, and failure stages became
clinical syndrome defined by tubular necrosis or pathology Stages 1, 2, and 3. An absolute increase in sCr of at least
(which is usually absent anyway), the strong association of 0.3 mg/dL (26.5 μmol/L) within 48 hours was added to
AKI with hospital mortality demands to change the way we Stage 1 which was supposed to make the definition more
think about this disorder. sensitive; the GFR criterion was removed as a marker
The RIFLE definition was designed to establish the of AKI; patients starting RRT were classified as Stage 3,
presence or absence of clinical AKI and to describe the irrespectively of sCr values; and outcome classes were
severity of this syndrome in a given patient. It did not aim removed. The characteristics of this system are outlined in
to predict mortality or any adverse outcome (28). However, Table 2.
several studies have shown that there was an association Only one criterion (sCr or UO) has to be fulfilled in
between AKI severity (as described by RIFLE class) with order to qualify for a stage. Time becomes more important
higher mortality and longer hospital and ICU stay (29). The for AKI diagnosis in the AKIN definition: changes between
RIFLE criteria have been used in therapeutic trials for AKI, two sCr values within a 48-hour period are required,
as well as in studies aiming to clarify the pathophysiology while 1 week was proposed by the Acute Dialysis Quality
of AKI (30,31). Finally, a paediatric version (pRIFLE) Initiative (ADQI) group in the original RIFLE criteria.
proposed in 2007 (32). However, this definition was not Severity of AKI in AKIN is staged over the course of 7 days
perfect. Very soon, Pickering et al. showed that there was by the fold-change in sCr from baseline
a mismatch between increases in sCr concentration and The AKIN criteria have partially addressed the
decreases in GFR [estimated with Modification of Diet in limitations of the RIFLE system. Although they were not
Renal Disease (MDRD) or Cockroft-Gault formulae] in designed to define the cause of AKI, an attempt is made to
the descriptions of risk and failure severity stages (33). A exclude cases of reversible (or transient) azotaemia or urinary
1.5-fold increase in sCr corresponds to a one-third decrease tract obstructions to be characterised as AKI, something
(not 25%) in GFR and a three-fold increase corresponds that was not possible with the RIFLE criteria (35).
to a two-third decrease in GFR (not 75%). If the GFR is However transient azotaemia must be acknowledged as a
not directly measured but estimated by a formula, then form of “mild” AKI, since studies have shown it can lead to
results might be also different depending on the formula adverse outcomes (36).
used. With the MDRD formula a 1.5-fold increase in sCr
corresponds to a 37% decrease in GFR, and a three-fold
Kidney Disease: Improving Global Outcomes
increase in sCr to a 72% decrease in GFR (34).
In 2012, the Acute Kidney Injury Working Group of
KDIGO (Kidney Disease: Improving Global Outcomes)
Acute Kidney Injury Network (AKIN)
revised the AKI definition again (Table 3). This was based
In 2007, the AKIN group proposed a modified version of on the previous two classifications, and had the aim of
Table 2 Acute kidney injury network criteria for classification/staging AKI. the stage of injury is determined by either serum creatinine level or
urinary output whichever indicates the more severe stage of renal injury. The GFR criterion has been removed [modified from reference (35)]
Stage Change in serum creatinine Urine output
Stage 1 Absolute increase in sCr >0.3 mg/dL (>26.5 μmol/L) or > 1.5- to UO <0.5 mL/kg/h for >6 h
2.0-fold from baseline
Stage 2 Increase in sCr >2.0- to 3.0-fold from baseline UO <0.5 mL/kg/h for >12 h
Stage 3 Increase in sCr >3-fold from baseline or increase of sCr UO <0.5 mL/kg/h for >24 h or anuria for 12 h
to >4.0 mg/dL (>354 μmol/L) with an acute increase of at least
0.5 mg/dL (44 μmol/L)
sCr, serum creatinine; UO, urine output.
Table 3 AKI definition and staging according to KDIGO criteria [modified from reference (37)]
Definition: AKI is defined as any of the following
Increase in sCr >0.3 mg/dL (>26.5 μmol/L) within 48 hours; or
Increase in sCr >1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; or
Urine volume <0.5 mL/kg/h for 6 hours
Staging: AKI is staged for severity according to the following criteria
Stage 1: 1.5–1.9 times baseline or >0.3 mg/dL (>26.5 μmol/L) absolute increase in sCr; urine volume <0.5 mL/kg/h for 6–12 h
Stage 2: sCr >2.0–2.9 times baseline; urine volume <0.5 mL/kg/h for >12 h
Stage 3: sCr >3.0 times from baseline, or increase in sCr to >4.0 mg/dL (>353.6 μmol/L), or initiation of renal replacement therapy or, in
patients <18 years, decrease in eGFR to <35 mL/min per 1.73 m2; urine volume <0.3 mL/kg/h for >24 h or anuria for >12 h
sCr, serum creatinine; eGFR, estimated glomerular filtration rate; AKI, acute kidney injury.
unifying the definition of AKI (37). By KDIGO definition, Challenges of applying diagnostic criteria in
AKI is diagnosed by an absolute increase in sCr, at least clinical practice
0.3 mg/dL (26.5 μmol/L) within 48 hours or by a 50%
The issue of time
increase in sCr from baseline within 7 days, or a urine
volume of less than 0.5 mL/kg/h for at least 6 hours. Time is important in order to define and diagnose AKI.
A patient’s progress can be staged over the entire time AKI is defined as occurring within 7 days period whereas
frame encompassed by an episode of AKI. An increase in CKD starts when kidney disease is persisting for more than
sCr up to 3 times from baseline, or a sCr of more than 3 months. Several studies have shown that some patients
4.0 mg/dL (354 μmol/L) or initiation of RRT, are all may have a slow (but constant) increase of sCr over the
classified as Stage 3. course of several days or even weeks and therefore they
KDIGO made one additional change to the criteria: A do not fulfil the consensus criteria for AKI (38,39). The
patient can be classified as Stage 3 due to sCr >4.0 mg/dL conditions that affect the kidneys can be divided to acute
(353.6 μmol/L), and in this case it is not required an acute or chronic depending on their duration and whereas CKD
increase of ≥0.5 mg/dL (44.2 μmol/L) to make the diagnosis. is well defined AKI definitions are still evolving. KDIGO
Moreover, it is stated that a rolling baseline can be used in its latest guidelines addressed this issue, introducing the
over 48-hour and 7-day periods for diagnosis of AKI, while concept of AKD and proposed an operational definition to
in RIFLE or AKIN it is not clear how this is handled. cover for these cases (37). The AKD definition requires:
Finally, changes were also made to severity Stage 3 to enable GFR <60 mL/min/1.73 m 2 for <3 months, a decrease
incorporation of paediatric patients into both definition and in GFR by ≥35 %, and an increase in sCr by >50 %
staging. for <3 months or evidence of structural kidney damage for <3
months. These criteria are currently under revision (2,37). the need to increase efforts to find a true pre-admission sCr
measurement that will represent the baseline renal function
of the patient (45,46). Looking back into patients’ medical
The issue of baseline renal function
records (when these are available) to obtain a true baseline
The concept of all AKI definitions is one that requires “a sCr when the patient was to a stable condition, have been
rapid decline in renal function from baseline levels”. This also proposed. There are two ways:
concept is not only needs a definition of a timeframe within (I) To use a short time-frame—that is trying to
which this decline occurs, it also assumes that the patient’s find a measured sCr value within 7 days prior to
baseline sCr level (which reflects patient’s premorbid admission;
kidney function) is also known. This baseline sCr value (II) To use a longer time frame—that is trying to find a
is necessary to compare with the current value in order measured sCr value between 7 and 365 days prior
to define and stage AKI. Moreover, the baseline renal to admission.
function is necessary in order to evaluate the extent of renal KDIGO allows to use the second option since in the
function recovery after the AKI event, which is a clinically general population and in patients with no progressive CKD
important end point (28). Unfortunately, the baseline sCr we can assume that a sCr measurement within the last year
level might not be known in a lot of patients, depending and not so close to the event that caused the hospitalisation
on the population studied. Several studies proposed ways will reflect their true baseline renal function (28,37,44,47).
to estimate this baseline sCr value in various ways. These However, the issue of how to approach a patient when
included the admission sCr level, the minimum sCr level a true baseline sCr value is missing, has not been solved
during hospitalisation, a back-calculation using the MDRD yet, especially when we have to deal with patients at the
equation, or the lowest value among these. It is a very emergency department. If a patient is admitted with an
important decision to be made by the clinician because elevated sCr value, and the true baseline cannot retrieve
this is the decision that seriously affects the prevalence, the immediately, a safe diagnosis of AKI can be done only
severity (or staging of patient), and the mortality risk which retrospectively. This underlines the serious limitation of sCr
associated with various stages of AKI. as a reliable AKI definition criterion in the acute setting and
The admission sCr levels is unlikely to be representative the need of a more reliable marker that can be used in the
of the true baseline state since it is possible to have been acute care setting.
modified by the acute illness that caused the hospitalisation.
The lowest sCr level measured during hospitalisation also
The issue of sCr as a measure of kidney function
has a number of disadvantages. First, this measurement
is determined too late since the patient’s hospitalisation Although GFR is considered the best indicator of
must have ended in order to identify the nadir value and, renal function and its assessment can aid the clinician
therefore, this measurement cannot be used in daily clinical in estimating the degree of renal dysfunction or the
practice and by definition, is a retrospective baseline. progression of established kidney disease or the estimation
Second, the nadir sCr value is likely to be lower or higher of drug dosing, it does not provide information on the cause
than the true baseline level, thereby we may overestimate or of kidney disease. It is usually assessed by the renal clearance
underestimate the true incidence of AKI. of a marker that achieves stable plasma concentration,
When no information on pre-admission renal function is inert and is freely filtered by the glomerulus but not
is available, for adults, the ADQI has recommended reabsorbed, secreted or metabolised (48-51). Such an ideal
the back-calculation of the baseline sCr value using endogenous marker does not exist and for many years sCr
the MDRD formula, assuming an estimated GFR of has been used as a marker of renal function in both AKI and
75 mL/min/1.73 m 2. Although convenient, the validity CKD. Creatinine is a metabolite of creatine. Creatine is a
of this approximation, as well as that of other surrogate molecule that is synthesised from the amino acids glycine
measures of baseline renal function, is questionable and and arginine in liver, pancreas and kidneys and serves as
has been the subject of several recent studies and reviews a reserve of high-energy phosphates in skeletal muscle
(28,40-44). Some degree of misclassification of AKI exists (Figure 1). Creatinine is produced from creatine in the
when someone uses a method to back-calculate the baseline muscles and its production is determined by the amount of
sCr value in both adults and children and this highlights creatine generated in liver, pancreas and kidneys, creatine
Creatine from food

(red meat)
Systemic
circulation
Creatinine
Liver and
generation
pancreas
Arginine + glycine +
Creatine muscles
methionine
Creatine→Creatine-P→Creatinine
Kidneys
Creatinine
clearance
Excretion with urine
Figure 1 Creatinine production and clearance. Creatine is produced in the liver, pancreas and kidneys, and ingested from food. It is then
transported through blood to the other organs, (i.e., muscle) where, through phosphorylation, it becomes the high-energy compound
phosphocreatine. muscle contains approximately 98% of the total body pool of creatine of which 60–70% exits as phosphocreatine and the
remainder as free creatine. Creatine conversion to phosphocreatine is catalyzed by creatine kinase. Formation of creatinine occurs the non-
enzymatic dehydration of creatine (and phosphocreatine) in the muscle. Creatinine is removed from the blood primarily by the kidneys,
mainly by glomerular filtration, but also by proximal tubular secretion. Little or no tubular reabsorption of creatinine occurs. Production of
creatinine is highly dependent on muscle mass, diet, age, sex and race.
ingested (i.e., intake of red meat) and muscle function. It important than secretion and appears later in the evolution
has a molecular weight of 113 Da, and fulfils most of the of the CKD, in patients with already significant alteration in
requirements for a filtration marker. It is freely filtered by urinary flow in some clinical settings such as decompensated
the glomeruli, is not metabolised by the kidney, it is not heart failure and uncontrolled diabetes (34,52). Since
bound to any protein and it is not toxic (2,52). there is little to no tubular reabsorption of creatinine, its
Creatinine is completely cleared by renal excretion when renal clearance is often used to estimate GFR, although its
renal function is normal. The proximal tubules also secrete usefulness has been questioned even when the patient is
creatinine, which accounts for 10–20% of the excreted load, stable (55).
and this results in overestimation of GFR when measured Under stable kidney function, sCr concentration can
by creatinine clearance (CrCl) (52-56). When GFR is also reflect skeletal muscle mass if its non-muscle-mass-
reduced, the contribution of tubular creatinine secretion dependent variations (such as due to renal function or meat
increases and may reach 50% of total CrCl, but it is highly intake) can be accurately accounted for. In people with
variable among individuals. Tubular reabsorption is less stable kidney function and UO, a 24-h urine creatinine
(uCr) is usually a constant number based on skeletal muscle Standardisation Program developed a reference method
mass and any variation observed is due to changes in meat based on isotope dilution mass spectrometry (IDMS) and it
consumption (57,58). Given the fact that sCr co-varies has been requested that all manufacturers standardise their
closely with skeletal muscle mass, its utility in estimating commercial kits to this IDMS reference procedure and their
GFR using equations such as MDRD or CKD-EPI may calibrators to be traceable to a higher-order method by
not be appropriate when subjects exhibit weight variations 2007 (59,64,65). However, several studies since then have
during follow up as in the case of critically ill patients. shown that several commercial methods still provide results
Muscle loss might be misinterpreted as improvement of that are deviate significantly from the true value as this is
renal function (58). determined by the IDMS reference method. The enzymatic
The fact that creatinine is a product of muscle catabolism assays seem to perform better in aspect and exhibit less
makes the interpretation of its results problematic in inter-assay variability compared to Jaffe assays (66-68).
patients with extremely low or high muscular mass (59). Enzymatic assays seem also to perform better than Jaffe
This may explain why the same sCr value correspond assays in terms of precision (64,69).
to different GFR in subjects of different age, sex and sCr is measured as a concentration and is therefore
ethnicity (59). affected by variations in volume status. Aggressive fluid
In health, it is produced at a constant rate and the rate administration may dilute creatinine in blood. Studies
of production is matched by the rate of renal excretion. have shown the effect of fluid accumulation on sCr
However, large and sustained falls in production have been concentration. Increase of total body water dilutes sCr
demonstrated during critical illness. A true fall in GFR may altering the volume distribution resulting in overestimation
not be adequately reflected by sCr in patients with sepsis, of kidney function, and underestimation of AKI severity.
liver disease, and/or muscle wasting (60,61). Moreover, the diagnosis of AKI may be delayed or missed
Creatinine-based criteria for AKI often do not take in patients with significant fluid shifts or fluid overload
into account underlying renal reserve. Up to 50% of the (70-72). A recent study revealed that AKI was diagnosed
kidney function maybe lost before we see any detectable or classified differently in up to 18 % of patients after sCr
rise in sCr. The role of creatinine as a marker of renal levels were adjusted for net fluid balance and estimated total
function is limited by the fact that its half-life increases body water. Affected patients had mortality rates similar to
from approximately 4 h to 24–72 h if the GFR decreases, those with AKI that was present before adjustment. The
depending on the degree of decrease (62). As such, the researchers suggested the use of an adjusted creatinine on
serum concentration may take 24–36 h to rise after a the basis of fluid balance (71). More recently Pickering
definite renal insult (2). et al. proposed a model that combined volume and
SCr concentrations are also affected by drugs, which creatinine kinetics to assess changes in renal function. This
compete with tubular secretion. In this case, sCr levels may model also takes into account fluid type, the rate of fluid
fluctuate without a change in renal function (2,59,63). infusion and urine output (73).
The measurement of sCr in the clinical lab is performed
either by enzymatic or the Jaffe methods. Both are
The issue of small changes in sCr
colorimetric and although the enzymatic methods are
exhibiting better specificity and sensitivity both methods Current consensus definitions require small changes in
are not fully specific for the measurement of creatinine (59). sCr (26.5 μmol/L or 0.3 mg/dL or 50% from baseline to
No method is free from interferences and substances like peak) for diagnosis of AKI. These definitions do not take
bilirubin or drugs may interfere with certain analytical into account the magnitude of baseline creatinine value,
techniques, more commonly with Jaffe-based assays. the intra-individual biological variation (CVi) of sCr and
Harmonisation of sCr measurement between laboratories the numerous factors that interfere with its laboratory
is important, especially when a physician is seeking past measurement (44,59).
measurements from patients’ medical records that may In a patient with normal kidney function (i.e., sCr levels
have been performed in a different laboratory and with 0.70 mg/dL), a rise by 0.3 mg/dL may indeed be due to an
a different commercial assay and wants to compare with important reduction in GFR. In contrast, in patients with
the current value. Theoretically standardisation of sCr underlying CKD, (i.e., baseline sCr levels 3.0 mg/dL) a rise
measurements has been achieved since the Creatinine by 0.3 mg/dL may be within the acceptable daily variation
and simply reflect an inconsequential change in GFR. This We can calculate objectively the true change is sCr
is particularly relevant when diagnosing AKI Stage 3 using that represents a true change in patients’ health status by
KDIGO guidelines, defined by a rise in sCr to >4.0 mg/dL calculating the reference change value (RCV) using the
(≥353.6 μmol/L). A patient with a baseline sCr of following formula: RCV = 21/2 * Z * (CVA2 + CVI2)1/2 where,
3.9 mg/dL (345 μmol/L) whose sCr rises by 0.3 mg/dL in CVA = analytical CV, CVI = within subject BV and when
48 h would be classified as having KDIGO AKI Stage 3, Z =1.96, then a change in any direction (two-tailed) to the
whereas the same absolute rise would be defined as AKI RCV is “significant” with 95% probability (82).
Stage 1 in a patient with normal baseline renal function BV can also show the way to the clinical laboratory
(44,74-76). for optimal analytical performance based on objective
In the literature, there are studies that demonstrate that criteria (83). An optimal CVA is considered the half of the
even smaller changes (i.e., 8.8 or 0.1 mg/dL or 1–24%, CVI. The CVI for sCr (can be found in the literature) is 5.9%
baseline to peak) in patients, are independently associated for healthy people and it is the median from 28 published
with a 45% increase of end-stage renal disease (ESRD) or a studies. Therefore, an optimal performance for sCr requires
two-fold risk for CKD (77-81). These associations of such CVA ≤3.0. Enzymatic methods for sCr measurement
small changes with adverse outcome, in published studies, are exhibiting lower CVA compared to Jaffe methods
are questionable and may reveal the ability of confounders (5.5% vs. 2.0%) and fulfil better the quality criteria
and not AKI to influence the development of CKD. (59,64,69). This means that depending on the method used
Moreover, there are questions beyond the association of by the lab significant changes in sCr can be either 19% (Jaffe
small changes and outcome. The first question is how these methods) or 13% (enzymatic methods) .
minimal changes are defined. In most cases the definition This approach has several implications for research and
is arbitrary and not uniform across all studies. Another clinical practice:
important question is whether these changes represent true (I) The clinician must know the lab’s method that sCr
changes in a patient’s health status or just random variation. was measured;
The answer is not so straightforward. These studies do not (II) In a clinical practice, as in research practice, we
take into account the variability in sCr measurement and its cannot combine results from different labs even
relevance to AKI. These small changes in sCr do not always when they perform the same method since CVA
reflect true changes in renal function as may be within the may differ;
limits of the combined analytical and biological variation (III) The fixed value (0.3 mg/dL), that the current criteria
(BV). It depends also on the baseline sCr of a specific use to define AKI, may need a reconsideration.
patient. In order to estimate if a change in sCr represents Relative increases from baseline for each patient
a true change in patients’ health status and it is not just a that take into account the analytical and BV maybe
random variation we must take into account not only the should be incorporated into AKI definition (84,85).
base line value but also the analytical and BV, the major Several examples in the literature have shown that if
sources of variation in laboratory results (43,44,59). For we apply the fixed KDIGO’s criteria in the definition of
every analyte we measure in the lab there is a physiological AKI, may be underestimated if the patient (adult or child)
random variation around a homeostatic set point that can be has a baseline value at the low end of normal range (i.e.,
measured and is expressed as a coefficient of variation (CV). 0.7 mg/dL) and on the other hand may be overestimated if
This homeostatic set point and CV is different for each the patient is a CKD with a baseline 3.0 mg/dL (43,44,59).
individual and is termed within subject or CVi. Briefly, CVi Some restrictions on the RCV calculation must be noted
can be calculated from serial measurements in a number of here. It is well known that BV is not the same in health and
stable patients, under the same conditions, on a relatively disease. Patients with chronic conditions (such as CKD,
short period of time. This variation is independent from liver disease or diabetes) might exhibit higher BV than
analytical variation, cannot reduced and should be taken healthy subjects (86-91). Therefore, the baseline renal
into account together with analytical variation once we function as well as chronic conditions should be taken into
try to determine when two consecutive measurements, of account (when these are known) and the appropriate BVI
the same analyte in a patient, differ and this difference is incorporated into calculations (90). The estimates of BV
of clinical significance. A part of BV of creatinine could be were derived from healthy subjects or stable CKD patients
explained from to day-to-day variations in true GFR. under highly standardised conditions, in the absence of
factors that interfere with assay specificity. In acutely ill Group (BVWG) established by the European Federation
people BV is higher and therefore higher RCV values of Clinical Chemistry and Laboratory Medicine (EFLM)
might be needed in order to determine that a change is (90,102-104).
clinically significant. Therefore, the use of BV derived
from healthy people may underestimate the true RCV
The issue of UO
in patients with acute conditions (as those with AKI).
However, in such conditions it is difficult to estimate how UO is a rapid bedside test for renal function and oliguria
much of the observed variation is random. In consequence has been one of the oldest biomarkers for renal injury (105).
the use of healthy population RCVs might lead to labelling It can be measured in real time, it is easy to measure and
many hospitalised patients’ test results as having changed inexpensive. It is an important clinical marker since urine
significantly. Such changes could be called “false positives” flow variations trigger first attempts to therapy but, like
since real RCV would be higher than in the healthy creatinine, it is not renal specific (106,107).
population. On the other hand, the RCV published in the Although the relation of oliguria with ARF has been
literature, uses the assumption that the values found in the made more than 200 years ago, its systematic inclusion
studied subjects are forming a Gaussian distribution. This in the definition of AKI occurs with the adoption of the
assumes truly random variation and also means that there RIFLE criteria as an alternative to sCr criteria. It remained
is no correlation between successive results (82,92). This unchanged in the AKIN and KDIGO criteria. UO
seems to be reasonable when we perform tests at medium criteria and sCr elevations have been considered of equal
to long-term intervals between samples. However, when importance in all AKI consensus definitions (105).
we perform tests more frequently (on a daily basis), this The theoretical advantages of UO over sCr include:
serial correlation might exist. Estimates of within subject (I) The speed of the response. A rapid reduction of
BV over short periods of time might be smaller than long- UO may be the earliest indication of decreased
term estimates. This auto-correlation could make the CVi kidney function. For example, if GFR were to
and therefore RCV smaller. Therefore, the RCV that suddenly fall to zero, a rise in sCr would not be
uses CVi from healthy people will lead to “false negative” detectable for several hours. On the other hand,
changes. However, these two effects tend to balance each UO would be affected immediately;
other out and thus calculating RCV from healthy subjects (II) Low UO is defined by a predefined cut-off value.
is valid and widely applicable (82). The estimation of There is no need to look for a baseline UO. In
RCV has generated debate and discussion regarding the contrast, sCr based definitions depend on a baseline
statistical approach that should be applied, especially when sCr value which is often unknown and has to be
the analyte under investigation does not exhibit a normal estimated by processes that introduce significant
distribution. When the analytes exhibit normal distribution, errors;
the standard approach proposed by Fraser can be applied (III) Certain conditions (infections, sepsis, malnutrition)
for the determination of RCV. On the other hand, a non- seriously affect creatinine production and make sCr
parametric approach might be more appropriate for the use an unreliable surrogate marker of GFR.
determination of RCV in analytes that do not follow the Oliguria is a complex process. There are multiple
normal distribution and are highly skewed. However, the mechanisms that can potentially cause oliguria in AKI,
different approaches that have been proposed need careful therefore it is not highly specific or sensitive marker of
validation (93-98). parenchymal ischaemic injury (108). These mechanisms
And finally, despite the significant amount of work include overall reduction or regional intra-renal differences
relating to BV over the last 50 years, the published in blood flow and redistribution, glomerular injury,
papers are of varying quality in terms of study designs altered intra-glomerular haemodynamics, impaired tissue
and presentation as well as the use of non-standardised oxygenation causing preferential ischaemia to the S3
terminology to describe the data. This delivers a high segment of the proximal convoluted tubule and the oxygen-
degree of uncertainty around published estimates of BV avid thick ascending loop of Henle, loss of osmolar gradient,
(99-101). It is well recognised that there is a need to further interstitial oedema or inflammation and finally tubular or
develop criteria to better characterise BV data and this work lower urinary tract obstruction (108). The decline of GFR
has been undertaken by the Biological Variation Working and UO in response to a decrease of renal blood flow (RBF)
is classically referred to as pre-renal azotaemia, which does not parallel the fall of GFR, in a timeframe that is
can evolve into structural damage if renal hypoperfusion clinically useful. The insensitivity of this surrogate marker
persists. Into this context UO is used not only as a marker as a measure of GFR is not uniformly appreciated. Neither
of AKI, but also to guide fluid resuscitation in critically sCr nor one of several derived equations to estimate GFR
ill patients. The mechanisms of diuresis regulation are (eGFR), based primarily on the sCr, can be used in AKI,
discussed in two excellent reviews (108,109). Oliguria nor can they be used reliably over the entire range of GFR
does not occur at the same time with sCr changes, so this to estimate it safely (59,76).
criterion might be used to identify AKI earlier or may also In higher GFRs very large changes in GFR are needed
contribute to select different patients from those selected by to result in small changes in sCr and the opposite is true
sCr criteria (110,111). for lower GFRs. In addition, the formulas that use a single
However, the major difficulty to measure UO over a measurement of sCr to estimate GFR, were derived in
period of time of 6 to 12 hours is that can be measured patients with CKD and rely on the assumption that the
accurately only in patients with a urine catheter. Another patient is in steady state and creatinine production and
problem of UO, as a biomarker, is that may change in excretion remains constant, which is not the case in AKI
conditions not related to AKI: patients where changes in sCr are usually delayed and follow
(I) As a physiological response (reflects conditions GFR changes. On the other hand, during the recovery
associated with antidiuresis related to hypovolaemia); phase the improvement of GFR usually precedes the sCr
(II) As an indicator of stress (oliguria may occur due to decline by several days. These problems were highlighted in
pain, surgery trauma) and finally a recent, excellent article that documents the need for a true
(III) As an indicator of failing glomerular flirtation. GFR measurement in patients with AKI (76). Moreover,
It is well recognised that hydration status, use of diuretics mathematical models have been proposed to predict GFR
and haemodynamic status influence UO in the absence of on the basis of sCr changes during AKI but do not seem
AKI. On the other hand, it is also known that severe AKI to be practical for routine applications (70). Jelliffe et al.
can occur with normal UO. However, the ADQI group developed an equation, that has been validated recently, to
has decided in the RIFLE consensus definition to use UO estimate GFR in the setting of non-steady kidney function
criteria to define and stage AKI which remained and in (117,118). Other methods that have been proposed include
the subsequent definitions (AKIN, KDIGO) (27,35,37). continuous monitoring of the GFR for ICU patients and
The accuracy and the usefulness of this criterion in clinical short time urine collections (2–8 h) with a blood sample for
practice are not well verified. The measurement of UO CrCl determination (119,120).
has to be done manually and inputted into the hospital’s On the other hand, we can measure GFR with a direct
information system, which renders it to clerical errors. method. The gold standard for GFR determination,
There are difficulties in measuring, monitoring and is the renal clearance of inulin. However, it is rarely
recording accurately UO. Therefore, it is often omitted as performed due to inconvenience and high cost. Today a
criterion from clinical studies (29). number of filtration markers and several protocols have
The UO criterion has been assessed in several studies, been proposed to replace it (121). Of note here is that the
where mostly critically ill patients are involved. However, proposed protocols do not include only urinary clearance
the number of studies is relatively small compared to those but plasmatic clearance has also proposed. Iohexol, a non-
that use sCr criteria (106,107,110,112-116). ionic contrast agent, is most suited to replace inulin as the
marker of choice for GFR determination. Iohexol fulfils
all requirements for an ideal GFR marker (low extra-renal
The issue of GFR measurement in AKI
excretion, low protein binding, it is secreted nor reabsorbed
GFR, which measures the amount of plasma filtered by the kidney). In addition, iohexol is virtually non-toxic
through glomeruli within a given period of time, is a and carries a reasonable cost. Moreover, as iohexol is
physiologic process and as such a direct indicator of kidney stable in plasma, administration and sample analysis can
function. It is well known that the reduction of the GFR, be separated in both space and time, allowing access to
secondary to either AKI or CKD, are accompanied by GFR determination across different settings. Iohexol can
increases in sCr. However, sCr is an insensitive surrogate be measured by high performance liquid chromatography
biomarker in the measurement of GFR, since its increase with ultraviolet detection (HPLC-UV), X-ray fluorescence
(XRF) and liquid chromatography-tandem mass renal perfusion, and a structural renal impairment (“renal
spectrometry (LC-MS/MS), with HPLC-UV to be the AKI” or “intrinsic AKI”), in which there is tubular damage
most commonly used method in Europe. This method is leading to an inability to properly reabsorb electrolytes,
sensitive, specific and reproducible, enabling the use of very including sodium.
low doses of iohexol, since it presents with very low limits of In situations associated with transient hypovolaemia
detection. Additionally, an international external proficiency or hypoperfusion, healthy kidneys respond by increasing
program (operated by Equalis AB in Sweden), allows the urine osmolarity and reducing sodium and/or urea or
inter-laboratory comparison of results. This method can be uric acid excretion. However, this physiological response
easily adopted in most modern clinical laboratories today. may be variable and confounded by CKD and various
Plasma clearance measurement is the protocol of choice as medical interventions, such as diuretic therapy, use of
it combines a reliable GFR determination with convenience antibiotics (aminoglycosides), and cardiopulmonary
for the patient. Single-sample protocols dominate, but bypass (127-129). Whereas the presence of low fractional
multiple-sample protocols may be more accurate in specific excretion of sodium (<1%), uric acid (<12%), and urea
situations (122,123). However, the methods of iohexol (<35%) together with a normal urinary sediment may
administration (single bolus or continuous infusion) is a support the diagnosis of functional AKI, the absence of
matter of debate especially for patients with AKI (124,125). these typical urinary electrolyte abnormalities would
not exclude it (Table 4) (130,131). Finally, low fractional
excretion of sodium (FENa) values have also been observed
Complementary tools to aid AKI diagnosis and
in experimental sepsis with increased RBF as well as
management
in the first hours of sepsis in humans (115,132,133).
In certain clinical circumstances, it is necessary to use Moreover, urinary electrolytes and FENa, fractional
additional tools to diagnose AKI, especially in clinical excretion of urea (FEUrea), or uric acid (FEUA) has not
cases where sCr and UO, don not change significantly, been consistently shown to have clear correlations with
are misleading, or cannot be interpreted accurately. This clinical and histopathological findings (134-136). As such,
is particularly relevant for ICU patients in whom critical the interpretation of urinary electrolytes is challenging
illness is usually accompanied by the presence of fluid especially in the critical care setting (137). A single
overload, muscle wasting, sepsis, and reduced effective measurement of urinary electrolytes has a limited role in
circulating volume all of which may completely mask the determining the differential diagnosis of AKI in critically ill
diagnosis of AKI. Several research groups have proposed patients. Instead, serial monitoring of urinary electrolytes
that novel biomarkers could be used to define and stage may be more useful as sequential alterations in urine
AKI in conjunction with RIFLE or AKIN criteria. A composition have been shown to parallel the development
meta-analysis of data from 19 studies conducted in eight and severity of AKI (138-140). However, whether serial
countries, involving 2,538 patients, of whom 487 (19.2%) measurement of urine electrolytes can also help diagnosing
developed AKI, reported that neutrophil gelatinase- the aetiology of AKI remains unclear.
associated lipocalin (NGAL) levels in plasma, serum or
urine seem to be of diagnostic and prognostic value for
Measurement of urinary Sodium in 24-hour collections
AKI, RRT and mortality, especially in patients who have
undergone cardiac surgery, as well as in children population. Twenty-four-hour urine collections are regarded as the
NGAL can allows the early diagnosis of AKI in a few hours, “gold standard” to measure sodium urinary excretion and
after the onset of kidney damage with increased specificity are useful to estimate daily dietary salt intake particularly in
and sensitivity (126). the management of patients with hypertension. However,
this method have problems mainly due to the difficulties
associated with the accurate collection of a complete
Urinary electrolytes
24-h collection (141-143). In hospitalised patients and
For many years the measurement of urine electrolytes was especially in critically care setting disturbances in fluid
a useful tool in AKI management. Its main utility was to and electrolytes are the most common problems and
distinguish a functional renal impairment (“pre-renal AKI” are associated with increased morbidity and mortality
or “pre-renal azotaemia”), generally associated with low (144,145). Severe burns, trauma, brain trauma and heart
Table 4 Use of urinary indices to differentiate pre-renal, renal, and post-renal kidney injury (modified from reference 44)
Test Pre-renal azotemia Intrinsic AKI Post-renal obstruction
Urine Na (mmol/L) <20 >40 >40
FENa <1% >2% Variable
FEUrea <35% >35% –
Urine/serum creatinine >40 <20 <20
Specific gravity >1.020 1.008–1.012 ~1.010
Osmolality (mOsm/KgrH2O) >500 <300 (near serum) <500
Urine/serum osmolality >1.5 <1.3 <1.5

AKI, acute kidney injury.
failure can lead to disturbances in fluid and electrolyte old but he cut-off they proposed were derived from a small
homeostasis. Reduced perfusion to the kidney (due to number of patients with very increased serum urea and
hypovolaemia or hypotension), activation of hormonal creatinine suggesting that only patients with severe AKI
systems (renin-angiotensin-aldosterone and vasopressin), were included. Moreover, patients receiving diuretics or
tubular damage (caused by ischaemia or nephrotoxic drugs) were non-oliguric were excluded (151,152). FENa is a
and inappropriate use of fluids and electrolyte solutions are measure of the extraction of sodium and water from the
the most common causes. Hypernatraemia is very common glomerular filtrate. It is the ratio of the sodium filtration
and important electrolyte disorder in critically ill patients rate to the overall GFR rate (estimated by the renal
and is related to increased administration of solutions filtration of creatinine). A euvolaemic person with normal
containing sodium, renal water loss (i.e., use of diuretics), renal function and moderate salt intake in a steady state will
and decreased capacity to excrete sodium especially in the have FENa approximately 1%. When interpreting FENa it
setting of AKI (137,144,146). It seems that 24-hour urine is necessary to consider whether the patient has pre-existing
collections have a role in calculation of total electrolyte CKD as these patients might exhibit FENa >1% in the
excretion and may be helpful to prevent the effect of absence of AKI depending on their GFR and daily dietary
electrolyte overload in multiple organs (147). Moreover, sodium intake (153,154). In a case of pre-renal azotaemia
hypernatraemia is often thought to be hypovolaemic the epithelial cells of proximal tubules reabsorb filtered
since it is associated with increased water loss. However, sodium resulting in a very low concentration of sodium in
hypervolaemic hypernatraemia has been described in ICU urine (<20 mmol/L) and FENa <1%, whereas in established
patients that are recovering from AKI, a condition that is AKI concentration of sodium in urine is higher than 40
characterised by massive retention of total body sodium mmol/L and the resulting FENa is >1%. A low FENa or
and total body water. Recent studies have shown that this low urine sodium reflects poor renal perfusion of any cause,
condition might not be so rare as it was initially thought not exclusively volume depletion. However, there are many
and measurement of electrolytes in urine may be helpful in causes for a low FENa despite AKI and for a high FENa
diagnosis and management (148-150). despite pre-renal AKI. The use of diuretic agents, the
presence of sepsis, myoglobinuria, acute glomerulonephritis,
cirrhosis, congestive heart failure, and contrast induced
FENa
nephropathy may seriously affect the performance of this
The calculation of the fraction of a urine solute that is test (127,155-160). A detailed list of the limitations of this
excreted compared to the amount that is filtered is a test is presented in the articles Perazella et al. and Diskin
concept that was developed in the early 1970s. During this et al. (128,161).
decade, FENa was developed for use as diagnostic tool
to distinguish pre-renal azotaemia from ATN. However,
Fractional excretion of urea (FEUrea)
the studies that proposed urinary Sodium and FENa as a
useful tool for this distinction are not only several decades The calculation of FEUrea is based on the same principle as
FENa. Urea conservation accompanies water conservation readily available. Traditionally urinalysis is a manual method
and it has been shown that its reabsorption occurs mainly that includes visual inspection of urine, chemical analysis
(57%) at the proximal segment of the nephron, it is and microscopic analysis of the sediment. There is no
practically not affected by diuretic agents, which act distally reference method for urine sediment microscopy. Manual
to the proximal tubule (162,163). Therefore, it should be urine sediment analysis is still the gold standard in the
more reliable than FENa. However, studies that evaluated laboratory. In most laboratories a bright field microscopy of
the performance of FEUrea in various clinical settings unstained native urine is the mainstream urine examination
(including ICU patients) have produced discordant results (172,173).
(127,164-167). A low FEUrea is usually indicative of pre- Recent technological advances have led to the production
renal AKI, however recent studies indicate that ageing, sex of automated instruments based on flow cytometry or
certain drugs and sepsis may alter FEUrea (128,159,168). digitised microscopy and are currently available for routine
This is understandable since urea movement across use in large clinical laboratories. These tools allow the
membranes is modulated by specific urea transporters, examination of large numbers of samples in a short period
drugs or disease entities may interfere with urea’s active of time. One major advantage of these instruments is that
transport and therefore alter FEUrea (128). the actual images of selected urine samples can be stored
in a computer and transmitted easily to nephrologist for
clinical evaluation (174).
How can the clinical lab be of help?
However, preanalytical protocols still vary between
It is easy to implement these calculated tests in a clinical laboratories. The preanalytical phase is the most important
lab’s routine. A fresh random urine collection (not and the most vulnerable part of urinalysis. It accounts for
catheterised) is required, together with a blood sample, and no less than 75% of all laboratory errors. In an effort to
calculations can be made within the laboratory information standardise urinalysis EFLM (European Federation for
system (LIS). However, the utility of standardised Laboratory Medicine) has produced a European guideline
interpretive comments for these tests are a matter of debate. which provide specific instructions for urinary sediment
Personalised interpretive comments can be made by the analysis. UM can provide very valuable information when
Clinical Chemist only if he/she has access to patients’ performed by a skilled operator, using a freshly collected
history and putative diagnosis, and may be limited by non-catheterised urine sample (175).
regulatory restrictions. When performed properly, the presence and the
In conclusion the interpretation of urinary electrolytes type of casts in urine sediment can differentiate the
is challenging, with many limitations affecting urine aetiology of AKI. Visualisation of red cell casts is due to
concentrations and fractional excretion indices. Serial glomerulonephritis, whereas the presence of renal tubular
monitoring of urinary electrolytes may be more useful than epithelial cells and coarse granular or muddy brown casts as
individual measurements, as sequential alterations in urine well as casts containing tubular epithelial cells is indicative
composition have been shown to parallel the development of ATN (Table 5) (176). On the other hand, absent sediment
and severity of AKI. However, whether serial measurement or the presence of occasional hyaline casts is indicative of
of urine electrolytes can also help diagnosing the aetiology pre-renal azotaemia (152,169,170,177). An ischaemic or
of AKI remains unclear nephrotoxic insult causes tubular injury, which results in
apoptosis or necrosis of the renal tubular epithelial cells.
These are shed into the tubular lumen where they are
Urine microscopy (UM)
excreted free or form casts which can be examined in fresh
UM is an important tool for the diagnosis and management urine sediments. Since pre-renal azotaemia and AKI are
of several pathological conditions that affect the kidneys. not separate clinical entities but rather are a continuum, the
Examination of urinary sediment is one of the oldest tests presence of cells and casts would be expected to increase
used to evaluate AKI in clinical nephrology (152,169,170). with the severity of the disease. It is logical to try to assess
Evaluation of urine sediment is often considered as a these findings quantitatively (178,179). However, evidence
complementary measure for the diagnosis and the severity that establishes the diagnostic value of UM has largely been
of AKI since it can provide additional information (136,171). lacking. Two systematic reviews evaluated the usefulness
UM has many advantages: it is cheap, non-invasive and of urinary microscopy and suggested that it may have a
Table 5 Urine microscopy findings

Urine sediment Finding Suggestive of
Cells Squamous epithelial cells Normal
Renal tubular epithelial cells Acute tubular injury
Red cells (non-dysmorphic) Bleeding that can be anywhere in the urinary tract (not glomerular bleeding)
Dysmorphic red cells Glomerular disease (if the urine sample is not fresh)
White blood cells Normal if <3 per high power field
>3 urinary tract infection, pyelonephritis, interstitial nephritis
Casts Red cell casts Diagnostic of glomerular disease (glomerulonephritis, lupus nephritis, vasculitis)
White blood cell casts Renal Infection (pyelonephritis, interstitial nephritis)
Hyaline casts Normal or pre-renal disease
Granular casts and/or muddy Tubular necrosis (muddy brown casts contain necrotic tubular epithelia cells)
brown casts
Crystals Urate/phosphate Not specific finding of acute kidney injury
Healthy individual may have some crystals in urine
Abnormal crystal presentation in patients’ urine may be indicative of metabolic disorders,

due to medications, or indicative of postrenal obstruction
Microorganisms Bacteria Indicative of urinary tract infection but can be present due to sample contamination
limited role for the diagnosis, classification and prognosis if performed by an experienced clinical chemist or
of septic AKI (134,135). However recent data show that nephrologist, outperforms automated urinalysis systems
UM may have a complementary role for the discrimination mainly because the latter uses non-centrifuged urine, and
of septic from non-septic AKI (180). Another systematic should be preferred (185-187). Centrifugation increases
review evaluated the usefulness of urinary microscopy for the probability of locating casts. Finally, the development
the differentiation between pre-renal AKI and ATN and of a standardised and validated scoring system based on
suggested that its clinical utility may be increased by the use the number of tubular epithelial cells and renal casts is
of a simple urinary scoring system, based on the number of necessary (181).
renal tubular epithelial cells and casts (181).
In conclusion examination of urinary sediment can be
Generating e-alerts for AKI. The contribution of
helpful in differentiation of prerenal AKI from ATN, may
the clinical laboratory
have a role in determining the severity of AKI and can be
more specific than some novel biomarkers in early detection The term “e-alert” has been used widely the last few years
of AKI, although lacks sensitivity (131,179,182). in the research setting of AKI. It is an area that the clinical
However, we must point out that the clinical utility laboratory can contribute not only by the laboratory
of UM may be limited for several reasons. First apart of results but also has the infrastructure (LIS) that is required
renal biopsy, there is no gold standard that would be able to implement these e-alerts. We believe that it worth
to diagnose AKI in a given patient, therefore we cannot discuss in brief first what these e-alerts are and second
judge the performance of any biomarker objectively to look at the recent research developments in this fast-
and its usefulness is likely to remain controversial. evolving area.
Second interpretation of UM is highly dependent on the “e-alerts” or “early warning systems” are intended
training and experience of the user, and the clinical lab to enable earlier detection of AKI and comprise of two
should guarantee its competency in the preparation and essential components. The first component is the detection
interpretation of UM (183,184). Third manual microscopy, of AKI, which is a rule-based or mathematical process that
requires the creation of an algorithm to compare a patient’s manuscript.

current sCr levels with a previous one using the current Funding: None.
internationally accepted diagnostic criteria and can be
incorporated into laboratory’s LIS. Wherever possible, sCr
Footnote
measurements are considered before inpatient admission
and patients needing chronic dialysis are excluded. The Provenance and Peer Review: This article was commissioned
same principle can be applied to UO data. Theoretically and by the Guest Editor (Pierre Delanaye) for the series
depending on the AKI definition that will be used and the “Nephrology and clinical chemistry” published in Journal of
algorithm we can achieve diagnosis and staging of a patient. Laboratory and Precision Medicine. The article has undergone
The second component is the “alerting process” and this external peer review.
has to do with how these changes are communicated to the
patient’s physician. During the alerting process, treating Conflicts of Interest: The author has completed the ICMJE
physicians can be informed about the reduction in renal uniform disclosure form (available at http://dx.doi.
function in various ways. One way can be just a simple org/10.21037/jlpm.2018.07.06). The series “Nephrology
list of affected patients with or without mention of their and clinical chemistry” was commissioned by the editorial
AKI’s severity grade. Another way is by using technically office without any funding or sponsorship. The author has
sophisticated early warning systems that will alert doctors no other conflicts of interest to declare.
with a message. This can be linked to recommendations to
treating physicians (188-190). Ethical Statement: The author is accountable for all
The drivers behind this concept were the recognition that aspects of the work in ensuring that questions related
routine clinical practice often was not fast enough to diagnose to the accuracy or integrity of any part of the work are
AKI timely, especially on weekends and most often patients appropriately investigated and resolved.
were managed by non-specialist nephrologists (191-194).
Open Access Statement: This is an Open Access article
distributed in accordance with the Creative Commons
Conclusions
Attribution-NonCommercial-NoDerivs 4.0 International
A universally accepted definition of AKI is necessary for License (CC BY-NC-ND 4.0), which permits the non-
its diagnosis and management. Current developments commercial replication and distribution of the article with
to standardise the definition of AKI are significant and the strict proviso that no changes or edits are made and the
despite the uncertainties that still exist in several areas, original work is properly cited (including links to both the
have helped in both clinical management and research. formal publication through the relevant DOI and the license).
However, these definitions which are based on sCr See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
changes and UO do not allow a biochemical definition of
this syndrome and clinical judgement is necessary. These
References
definitions are designed not to replace clinical diagnosis
but rather to complement or assist it. The contribution 1. Makris K, Spanou L. Acute Kidney Injury: Definition,
of the clinical lab is hugely important not only to help Pathophysiology and Clinical Phenotypes. Clin Biochem
clinicians interpret correctly these changes but also to Rev 2016;37:85-98.
highlight their limitations. Evolution of AKI definitions 2. Ostermann M, Joannidis M. Acute kidney injury 2016:
should take these concerns into account. The contribution diagnosis and diagnostic workup. Crit Care 2016;20:299.
of the lab emerges also in new areas as in the creation 3. Bellomo R, Ronco C, Mehta RL, et al. Acute kidney injury
of electronic alerts as it has the infrastructure (LIS) to in the ICU: from injury to recovery: reports from the
implement them. 5th Paris International Conference. Ann Intensive Care
2017;7:49.
4. Lameire NH, Bagga A, Cruz D, et al. Acute kidney injury:
Acknowledgments
an increasing global concern. Lancet 2013;382:170-9.
I would like to thank Dr. Loukia Spanou, MD. for 5. Rewa O, Bagshaw SM. Acute kidney injury-
her valuable comments during the preparation of this epidemiology, outcomes and economics. Nat Rev
Nephrol 2014;10:193-207. 20. Silver SA, Chertow GM. The Economic Consequences of
6. Hoste EA, Bagshaw SM, Bellomo R, et al. Epidemiology Acute Kidney Injury. Nephron 2017;137:297-301.
of acute kidney injury in critically ill patients: the 21. Silver SA, Long J, Zheng Y, et al. Cost of Acute Kidney
multinational AKI-EPI study. Intensive Care Med Injury in Hospitalized Patients. J Hosp Med 2017;12:70-6.
2015;41:1411-23. 22. Lameire NH, Vanholder RC. Acute renal failure:
7. Olowu WA, Niang A, Osafo C, et al. Outcomes of acute pathophysiology and prevention. In: Davison AM,
kidney injury in children and adults in sub-Saharan Africa: Cameron JS, Grunfeld JP, et al. editors. Oxford textbook
a systematic review. Lancet Glob Health 2016;4:e242-50. of clinical nephrology. 3rd edition. Oxford (UK): Oxford
8. Abd ElHafeez S, Tripepi G, Quinn R, et al. Risk, University Press, 2005:1445-64.
Predictors, and Outcomes of Acute Kidney Injury in 23. Kellum JA, Levin N, Bouman C, et al. Developing a
Patients Admitted to Intensive Care Units in Egypt. Sci consensus classification system for acute renal failure. Curr
Rep 2017;7:17163. Opin Crit Care 2002;8:509-14.
9. Chertow GM, Burdick E, Honour M, et al. Acute kidney 24. Bagshaw SM, Gibney RT. Conventional markers of kidney
injury, mortality, length of stay, and costs in hospitalized function. Crit Care Med 2008;36:S152-8.
patients. J Am Soc Nephrol 2005;16:3365-70. 25. Hilton R. Defining acute renal failure. CMAJ
10. Thakar CV, Christianson A, Himmelfarb J, et al. Acute 2011;183:1167-9.
kidney injury episodes and chronic kidney disease risk in 26. Ricci Z, Ronco C, D'Amico G, et al. Practice patterns in
diabetes mellitus. Clin J Am Soc Nephrol 2011;6:2567-72. the management of acute renal failure in the critically ill
11. An HJ, Yu CS, Yun SC, et al. Adjuvant chemotherapy with patient: an international survey. Nephrol Dial Transplant
or without pelvic radiotherapy after simultaneous surgical 2006;21:690-6.
resection of rectal cancer with liver metastases: analysis of 27. Bellomo R, Ronco C, Kellum JA, et al. Acute renal
prognosis and patterns of recurrence. Int J Radiat Oncol failure - definition, outcome measures, animal models,
Biol Phys 2012;84:73-80. fluid therapy and information technology needs: the
12. Bellomo R, Kellum JA, Ronco C. Acute kidney injury. Second International Consensus Conference of the
Lancet 2012;380:756-66. Acute Dialysis Quality Initiative (ADQI) Group. Crit
13. Singbartl K, Kellum JA. AKI in the ICU: definition, Care 2004;8:R204-12.
epidemiology, risk stratification, and outcomes. Kidney Int 28. Ricci Z, Cruz DN, Ronco C. Classification and staging of
2012;81:819-25. acute kidney injury: beyond the RIFLE and AKIN criteria.
14. Perinel S, Vincent F, Lautrette A, et al. Transient and Nat Rev Nephrol 2011;7:201-8.
Persistent Acute Kidney Injury and the Risk of Hospital 29. Ricci Z, Cruz D, Ronco C. The RIFLE criteria and
Mortality in Critically Ill Patients: Results of a Multicenter mortality in acute kidney injury: A systematic review.
Cohort Study. Crit Care Med 2015;43:e269-75. Kidney Int 2008;73:538-46.
15. Adams HH, Hibar DP, Chouraki V, et al. Novel genetic 30. Bagshaw SM, Gibney RT, McAlister FA, et al. The SPARK
loci underlying human intracranial volume identified Study: a phase II randomized blinded controlled trial of
through genome-wide association. Nat Neurosci the effect of furosemide in critically ill patients with early
2016;19:1569-82. acute kidney injury. Trials 2010;11:50.
16. White LE, Hassoun HT. Inflammatory Mechanisms of 31. Lentini P, de Cal M, Cruz D, et al. The role of advanced
Organ Crosstalk during Ischemic Acute Kidney Injury. Int oxidation protein products in intensive care unit patients
J Nephrol 2012;2012:505197. with acute kidney injury. J Crit Care 2010;25:605-9.
17. Yap SC, Lee HT. Acute kidney injury and extrarenal organ 32. Akcan-Arikan A, Zappitelli M, Loftis LL, et al. Modified
dysfunction: new concepts and experimental evidence. RIFLE criteria in critically ill children with acute kidney
Anesthesiology 2012;116:1139-48. injury. Kidney Int 2007;71:1028-35.
18. Doi K, Rabb H. Impact of acute kidney injury on distant 33. Pickering JW, Endre ZH. GFR shot by RIFLE: errors in
organ function: recent findings and potential therapeutic staging acute kidney injury. Lancet 2009;373:1318-9.
targets. Kidney Int 2016;89:555-64. 34. Endre ZH, Pickering JW, Walker RJ. Clearance and
19. Collister D, Pannu N, Ye F, et al. Health Care beyond: the complementary roles of GFR measurement
Costs Associated with AKI. Clin J Am Soc Nephrol and injury biomarkers in acute kidney injury (AKI). Am J
2017;12:1733-43. Physiol Renal Physiol 2011;301:F697-707.
35. Mehta RL, Kellum JA, Shah SV, et al. Acute Kidney Injury 50. Delanaye P. How Measuring Glomerular Filtration
Network: report of an initiative to improve outcomes in Rate? Comparison of Reference Methods. In: Sahay
acute kidney injury. Crit Care 2007;11:R31. M. editor. Basic Nephrology and Acute Kidney Injury.
36. Uchino S, Bellomo R, Bagshaw SM, et al. Transient IntechOpen, 2012.
azotaemia is associated with a high risk of death 51. Levey AS, Inker LA, Coresh J. GFR estimation:
in hospitalized patients. Nephrol Dial Transplant from physiology to public health. Am J Kidney Dis
2010;25:1833-9. 2014;63:820-34.
37. Kidney Disease: Improving Global Outcomes (KDIGO) 52. Perrone RD, Madias NE, Levey AS. Serum creatinine as
Acute Kidney Injury Work Group-KDIGO Clinical an index of renal function: new insights into old concepts.
Practice Guideline for Acute Kidney Injury. Kidney Int Clin Chem 1992;38:1933-53.
2012;Sup 2:1-138. 53. Bauer JH, Brooks CS, Burch RN. Clinical appraisal of
38. Ostermann M, Chang RW. Challenges of defining acute creatinine clearance as a measurement of glomerular
kidney injury. QJM 2011;104:237-43. filtration rate. Am J Kidney Dis 1982;2:337-46.
39. Chu R, Li C, Wang S, et al. Assessment of KDIGO 54. Shemesh O, Golbetz H, Kriss JP, et al. Limitations of
definitions in patients with histopathologic evidence creatinine as a filtration marker in glomerulopathic
of acute renal disease. Clin J Am Soc Nephrol patients. Kidney Int 1985;28:830-8.
2014;9:1175-82. 55. Payne RB. Creatinine clearance: a redundant clinical
40. Anema SG, Lee SK, Lowe EK, et al. Rheological investigation. Ann Clin Biochem 1986;23:243-50.
properties of acid gels prepared from heated pH-adjusted 56. van Acker BA, Koomen GC, Koopman MG, et al.
skim milk. J Agric Food Chem 2004;52:337-43. Creatinine clearance during cimetidine administration
41. Pickering JW, Endre ZH. Back-calculating baseline for measurement of glomerular filtration rate. Lancet
creatinine with MDRD misclassifies acute kidney injury 1992;340:1326-9.
in the intensive care unit. Clin J Am Soc Nephrol 57. Baxmann AC, Ahmed MS, Marques NC, et al. Influence
2010;5:1165-73. of muscle mass and physical activity on serum and urinary
42. Siew ED, Matheny ME, Ikizler TA, et al. Commonly creatinine and serum cystatin C. Clin J Am Soc Nephrol
used surrogates for baseline renal function affect the 2008;3:348-54.
classification and prognosis of acute kidney injury. Kidney 58. Patel SS, Molnar MZ, Tayek JA, et al. Serum creatinine
Int 2010;77:536-42. as a marker of muscle mass in chronic kidney disease:
43. Thomas ME, Blaine C, Dawnay A, et al. The definition results of a cross-sectional study and review of literature. J
of acute kidney injury and its use in practice. Kidney Int Cachexia Sarcopenia Muscle 2013;4:19-29.
2015;87:62-73. 59. Delanaye P, Cavalier E, Pottel H. Serum Creatinine: Not
44. Makris K, Spanou L. Acute Kidney Injury: Diagnostic So Simple! Nephron 2017;136:302-8.
Approaches and Controversies. Clin Biochem Rev 60. Doi K, Yuen PS, Eisner C, et al. Reduced production of
2016;37:153-75. creatinine limits its use as marker of kidney injury in sepsis.
45. Cruz DN, Ricci Z, Ronco C. Clinical review: RIFLE and J Am Soc Nephrol 2009;20:1217-21.
AKIN--time for reappraisal. Crit Care 2009;13:211. 61. Schetz M, Gunst J, Van den Berghe G. The impact of
46. Gaiao S, Cruz DN. Baseline creatinine to define acute using estimated GFR versus creatinine clearance on the
kidney injury: is there any consensus? Nephrol Dial evaluation of recovery from acute kidney injury in the
Transplant 2010;25:3812-4. ICU. Intensive Care Med 2014;40:1709-17.
47. Abazov VM, Abbott B, Abolins M, et al. Search for doubly 62. Chiou WL, Hsu FH. Pharmacokinetics of creatinine
charged higgs boson pair production in the decay to mu(+) in man and its implications in the monitoring of renal
mu(+)mu(-)mu(-) in pp collisions at sqrt[s]=1.96 TeV. Phys function and in dosage regimen modifications in patients
Rev Lett 2004;93:141801. with renal insufficiency. J Clin Pharmacol 1975;15:427-34.
48. Stevens LA, Levey AS. Measurement of kidney function. 63. Delanaye P, Mariat C, Cavalier E, et al. Trimethoprim,
Med Clin North Am 2005;89:457-73. creatinine and creatinine-based equations. Nephron Clin
49. Stevens LA, Coresh J, Greene T, et al. Assessing kidney Pract 2011;119:c187-93; discussion c193-4.
function--measured and estimated glomerular filtration 64. Myers GL, Miller WG, Coresh J, et al. Recommendations
rate. N Engl J Med 2006;354:2473-83. for improving serum creatinine measurement: a report
from the Laboratory Working Group of the National 78. Newsome BB, Warnock DG, McClellan WM, et al. Long-
Kidney Disease Education Program. Clin Chem term risk of mortality and end-stage renal disease among
2006;52:5-18. the elderly after small increases in serum creatinine level
65. Peake M, Whiting M. Measurement of serum creatinine- during hospitalization for acute myocardial infarction.
-current status and future goals. Clin Biochem Rev Arch Intern Med 2008;168:609-16.
2006;27:173-84. 79. Ishani A, Nelson D, Clothier B, et al. The magnitude of
66. Pieroni L, Delanaye P, Boutten A, et al. A multicentric acute serum creatinine increase after cardiac surgery and
evaluation of IDMS-traceable creatinine enzymatic assays. the risk of chronic kidney disease, progression of kidney
Clin Chim Acta 2011;412:2070-5. disease, and death. Arch Intern Med 2011;171:226-33.
67. Boutten A, Bargnoux AS, Carlier MC, et al. Enzymatic 80. Cruz DN, Ferrer-Nadal A, Piccinni P, et al. Utilization of
but not compensated Jaffe methods reach the desirable small changes in serum creatinine with clinical risk factors
specifications of NKDEP at normal levels of creatinine. to assess the risk of AKI in critically lll adults. Clin J Am
Results of the French multicentric evaluation. Clin Chim Soc Nephrol 2014;9:663-72.
Acta 2013;419:132-5. 81. Liotta M, Olsson D, Sartipy U, et al. Minimal changes in
68. Hoste L, Deiteren K, Pottel H, et al. Routine serum postoperative creatinine values and early and late mortality
creatinine measurements: how well do we perform? BMC and cardiovascular events after coronary artery bypass
Nephrol 2015;16:21. grafting. Am J Cardiol 2014;113:70-5.
69. Cobbaert CM, Baadenhuijsen H, Weykamp CW. Prime 82. Fraser C. Biological Variation: From Principles to Practice.
time for enzymatic creatinine methods in pediatrics. Clin Washington, DC: AACC Press, 2001.
Chem 2009;55:549-58. 83. Oosterhuis WP. Analytical performance specifications
70. Moran SM, Myers BD. Course of acute renal failure in clinical chemistry: the holy grail? J Lab Precis Med
studied by a model of creatinine kinetics. Kidney Int 2017;2:7.
1985;27:928-37. 84. Sottas PE, Kapke GF, Leroux JM. Adaptive Bayesian
71. Macedo E, Bouchard J, Soroko SH, et al. Fluid analysis of serum creatinine as a marker for drug-induced
accumulation, recognition and staging of acute kidney renal impairment in an early-phase clinical trial. Clin
injury in critically-ill patients. Crit Care 2010;14:R82. Chem 2012;58:1592-6.
72. Liu KD, Thompson BT, Ancukiewicz M, et al. Acute 85. Sottas PE, Kapke GF, Leroux JM. Adaptive Bayesian
kidney injury in patients with acute lung injury: impact of approach to clinical trial renal impairment biomarker
fluid accumulation on classification of acute kidney injury signal from urea and creatinine. Int J Biol Sci
and associated outcomes. Crit Care Med 2011;39:2665-71. 2013;9:156-63.
73. Pickering JW, Ralib AM, Endre ZH. Combining creatinine 86. Fraser CG, Williams P. Short-term biological variation
and volume kinetics identifies missed cases of acute kidney of plasma analytes in renal disease. Clin Chem
injury following cardiac arrest. Crit Care 2013;17:R7. 1983;29:508-10.
74. Palevsky PM, Liu KD, Brophy PD, et al. KDOQI US 87. Holzel WG. Intra-individual variation of analytes in serum
commentary on the 2012 KDIGO clinical practice from patients with chronic liver diseases. Clin Chem
guideline for acute kidney injury. Am J Kidney Dis 1987;33:1133-6.
2013;61:649-72. 88. Holzel WG. Intra-individual variation of some analytes in
75. Ostermann M. Diagnosis of acute kidney injury: Kidney serum of patients with chronic renal failure. Clin Chem
Disease Improving Global Outcomes criteria and beyond. 1987;33:670-3.
Curr Opin Crit Care 2014;20:581-7. 89. Holzel WG. Intra-individual variation of some analytes in
76. Molitoris BA, Reilly ES. Quantifying Glomerular serum of patients with insulin-dependent diabetes mellitus.
Filtration Rates in Acute Kidney Injury: A Requirement Clin Chem 1987;33:57-61.
for Translational Success. Semin Nephrol 2016;36:31-41. 90. Ricos C, Iglesias N, Garcia-Lario JV, et al. Within-subject
77. Lassnigg A, Schmid ER, Hiesmayr M, et al. Impact of biological variation in disease: collated data and clinical
minimal increases in serum creatinine on outcome in consequences. Ann Clin Biochem 2007;44:343-52.
patients after cardiothoracic surgery: do we have to revise 91. Carter JL, Parker CT, Stevens PE, et al. Biological
current definitions of acute renal failure? Crit Care Med Variation of Plasma and Urinary Markers of Acute Kidney
2008;36:1129-37. Injury in Patients with Chronic Kidney Disease. Clin
Chem 2016;62:876-83. Biomarkers of Acute Kidney Injury: Star Struck Lovers or

92. Fraser CG, Harris EK. Generation and application of data Strangers in the Night? Nephron 2016;134:183-90.
on biological variation in clinical chemistry. Crit Rev Clin 106. Prowle JR, Liu YL, Licari E, et al. Oliguria as predictive
Lab Sci 1989;27:409-37. biomarker of acute kidney injury in critically ill patients.
93. Fokkema MR, Herrmann Z, Muskiet FA, et al. Reference Crit Care 2011;15:R172.
change values for brain natriuretic peptides revisited. Clin 107. Kellum JA, Sileanu FE, Murugan R, et al. Classifying AKI
Chem 2006;52:1602-3. by Urine Output versus Serum Creatinine Level. J Am Soc
94. Ceriotti F, Boyd JC, Klein G, et al. Reference intervals for Nephrol 2015;26:2231-8.
serum creatinine concentrations: assessment of available 108. Cerda J. Oliguria: an earlier and accurate biomarker of
data for global application. Clin Chem 2008;54:559-66. acute kidney injury? Kidney Int 2011;80:699-701.
95. Braga F, Ferraro S, Ieva F, et al. A new robust statistical 109. Legrand M, Payen D. Understanding urine output in
model for interpretation of differences in serial test results critically ill patients. Ann Intensive Care 2011;1:13.
from an individual. Clin Chem Lab Med 2015;53:815-22. 110. Macedo E, Malhotra R, Bouchard J, et al. Oliguria is an
96. Lund F, Petersen PH, Fraser CG, et al. Calculation of early predictor of higher mortality in critically ill patients.
limits for significant bidirectional changes in two or Kidney Int 2011;80:760-7.
more serial results of a biomarker based on a computer 111. Selby NM, Fluck RJ, Kolhe NV, et al. International
simulation model. Ann Clin Biochem 2015;52:434-40. Criteria for Acute Kidney Injury: Advantages and
97. Lund F, Petersen PH, Fraser CG, et al. Calculation of Remaining Challenges. PLoS Med 2016;13:e1002122.
limits for significant unidirectional changes in two or 112. Macedo E, Malhotra R, Claure-Del Granado R, et
more serial results of a biomarker based on a computer al. Defining urine output criterion for acute kidney
simulation model. Ann Clin Biochem 2015;52:237-44. injury in critically ill patients. Nephrol Dial Transplant
98. Makris K, Stefani D, Makri E, et al. Evaluation of a 2011;26:509-15.
particle enhanced turbidimetric assay for the measurement 113. Wlodzimirow KA, Abu-Hanna A, Slabbekoorn M, et al.
of neutrophil gelatinase-associated lipocalin in plasma A comparison of RIFLE with and without urine output
and urine on Architect-8000: Analytical performance criteria for acute kidney injury in critically ill patients. Crit
and establishment of reference values. Clin Biochem Care 2012;16:R200.
2015;48:1291-7. 114. Md Ralib A, Pickering JW, Shaw GM, et al. The urine
99. Carobene A, Braga F, Roraas T, et al. A systematic output definition of acute kidney injury is too liberal. Crit
review of data on biological variation for alanine Care 2013;17:R112.
aminotransferase, aspartate aminotransferase and 115. Vanmassenhove J, Glorieux G, Hoste E, et al. Urinary
gamma-glutamyl transferase. Clin Chem Lab Med output and fractional excretion of sodium and urea as
2013;51:1997-2007. indicators of transient versus intrinsic acute kidney injury
100. Bartlett WA, Braga F, Carobene A, et al. A checklist for during early sepsis. Crit Care 2013;17:R234.
critical appraisal of studies of biological variation. Clin 116. Leedahl DD, Frazee EN, Schramm GE, et al. Derivation
Chem Lab Med 2015;53:879-85. of urine output thresholds that identify a very high risk of
101. Simundic AM, Kackov S, Miler M, et al. Terms and AKI in patients with septic shock. Clin J Am Soc Nephrol
symbols used in studies on biological variation: the need 2014;9:1168-74.
for harmonization. Clin Chem 2015;61:438-9. 117. Jelliffe R. Estimation of creatinine clearance in patients
102. Ricos C, Alvarez V, Cava F, et al. Current databases on with unstable renal function, without a urine specimen.
biological variation: pros, cons and progress. Scand J Clin Am J Nephrol 2002;22:320-4.
Lab Invest 1999;59:491-500. 118. Bouchard J, Macedo E, Soroko S, et al. Comparison
103. Perich C, Minchinela J, Ricos C, et al. Biological variation of methods for estimating glomerular filtration rate in
database: structure and criteria used for generation and critically ill patients with acute kidney injury. Nephrol Dial
update. Clin Chem Lab Med 2015;53:299-305. Transplant 2010;25:102-7.
104. Ricos C, Alvarez V, Perich C, et al. Rationale for using 119. Rabito CA, Panico F, Rubin R, et al. Noninvasive, real-
data on biological variation. Clin Chem Lab Med time monitoring of renal function during critical care. J
2015;53:863-70. Am Soc Nephrol 1994;4:1421-8.
105. Lehner GF, Forni LG, Joannidis M. Oliguria and 120. Pickering JW, Frampton CM, Walker RJ, et al. Four hour
creatinine clearance is better than plasma creatinine for biochemistry in experimental septic acute renal failure.
monitoring renal function in critically ill patients. Crit Nephrol Dial Transplant 2006;21:3389-97.
Care 2012;16:R107. 133. Langenberg C, Wan L, Egi M, et al. Renal blood flow
121. Soveri I, Berg UB, Bjork J, et al. Measuring GFR: a in experimental septic acute renal failure. Kidney Int
systematic review. Am J Kidney Dis 2014;64:411-24. 2006;69:1996-2002.
122. Delanaye P, Ebert N, Melsom T, et al. Iohexol plasma 134. Bagshaw SM, Langenberg C, Bellomo R. Urinary
clearance for measuring glomerular filtration rate in biochemistry and microscopy in septic acute renal failure:
clinical practice and research: a review. Part 1: How to a systematic review. Am J Kidney Dis 2006;48:695-705.
measure glomerular filtration rate with iohexol? Clin 135. Bagshaw SM, Langenberg C, Wan L, et al. A systematic
Kidney J 2016;9:682-99. review of urinary findings in experimental septic acute
123. Delanaye P, Melsom T, Ebert N, et al. Iohexol plasma renal failure. Crit Care Med 2007;35:1592-8.
clearance for measuring glomerular filtration rate in 136. Bagshaw SM, Gibney RT. Acute kidney injury: clinical
clinical practice and research: a review. Part 2: Why to value of urine microscopy in acute kidney injury. Nat Rev
measure glomerular filtration rate with iohexol? Clin Nephrol 2009;5:185-6.
Kidney J 2016;9:700-4. 137. Maciel AT, Vitorio D. Urine biochemistry assessment in
124. Dixon JJ, Lane K, Dalton RN, et al. Validation of a critically ill patients: controversies and future perspectives.
continuous infusion of low dose Iohexol to measure J Clin Monit Comput 2017;31:539-46.
glomerular filtration rate: randomised clinical trial. J 138. Maciel AT, Park M. Urine assessment in the critically ill: a
Transl Med 2015;13:58. matter of both quantity and quality. Rev Bras Ter Intensiva
125. Dixon JJ, Lane K, Dalton RN, et al. Continuous Infusion 2013;25:184-5.
of Low-Dose Iohexol Measures Changing Glomerular 139. Maciel AT, Park M, Macedo E. Physicochemical analysis
Filtration Rate in Critically Ill Patients. Crit Care Med of blood and urine in the course of acute kidney injury in
2018;46:e190-7. critically ill patients: a prospective, observational study.
126. Haase M, Bellomo R, Devarajan P, et al. Accuracy of BMC Anesthesiol 2013;13:31.
neutrophil gelatinase-associated lipocalin (NGAL) 140. Maciel AT, Vitorio D. Urine biochemistry in the early
in diagnosis and prognosis in acute kidney injury: a postoperative period after cardiac surgery: role in
systematic review and meta-analysis. Am J Kidney Dis acute kidney injury monitoring. Case Rep Crit Care
2009;54:1012-24. 2013;2013:103450.
127. Pepin MN, Bouchard J, Legault L, et al. Diagnostic 141. Bentley B. A review of methods to measure dietary sodium
performance of fractional excretion of urea and fractional intake. J Cardiovasc Nurs 2006;21:63-7.
excretion of sodium in the evaluations of patients with 142. McLean RM. Measuring population sodium intake: a
acute kidney injury with or without diuretic treatment. Am review of methods. Nutrients 2014;6:4651-62.
J Kidney Dis 2007;50:566-73. 143. Mente A, O'Donnell MJ, Dagenais G, et al. Validation
128. Diskin CJ, Stokes TJ, Dansby LM, et al. Toward the and comparison of three formulae to estimate sodium and
optimal clinical use of the fraction excretion of solutes in potassium excretion from a single morning fasting urine
oliguric azotemia. Ren Fail 2010;32:1245-54. compared to 24-h measures in 11 countries. J Hypertens
129. Prowle J, Bagshaw SM, Bellomo R. Renal blood 2014;32:1005-14; discussion 1015.
flow, fractional excretion of sodium and acute kidney 144. Lee JW. Fluid and electrolyte disturbances in critically ill
injury: time for a new paradigm? Curr Opin Crit Care patients. Electrolyte Blood Press 2010;8:72-81.
2012;18:585-92. 145. Lindner G, Funk GC. Hypernatremia in critically ill
130. Fenske W, Stork S, Koschker AC, et al. Value of patients. J Crit Care 2013;28:216 e11-20.
fractional uric acid excretion in differential diagnosis of 146. Hoorn EJ, Betjes MG, Weigel J, et al. Hypernatraemia
hyponatremic patients on diuretics. J Clin Endocrinol in critically ill patients: too little water and too much salt.
Metab 2008;93:2991-7. Nephrol Dial Transplant 2008;23:1562-8.
131. Hall IE, Coca SG, Perazella MA, et al. Risk of poor 147. Besen BA, Gobatto AL, Melro LM, et al. Fluid and
outcomes with novel and traditional biomarkers at clinical electrolyte overload in critically ill patients: An overview.
AKI diagnosis. Clin J Am Soc Nephrol 2011;6:2740-9. World J Crit Care Med 2015;4:116-29.
132. Langenberg C, Wan L, Bagshaw SM, et al. Urinary 148. Kahn T. Hypernatremia with edema. Arch Intern Med
1999;159:93-8. 164. Kaplan AA, Kohn OF. Fractional excretion of urea as a

149. Sam R, Hart P, Haghighat R, et al. Hypervolemic guide to renal dysfunction. Am J Nephrol 1992;12:49-54.
hypernatremia in patients recovering from acute kidney 165. Carvounis CP, Nisar S, Guro-Razuman S. Significance of
injury in the intensive care unit. Clin Exp Nephrol the fractional excretion of urea in the differential diagnosis
2012;16:136-46. of acute renal failure. Kidney Int 2002;62:2223-9.
150. Sarahian S, Pouria MM, Ing TS, et al. Hypervolemic 166. Darmon M, Vincent F, Dellamonica J, et al. Diagnostic
hypernatremia is the most common type of performance of fractional excretion of urea in the
hypernatremia in the intensive care unit. Int Urol evaluation of critically ill patients with acute kidney injury:
Nephrol 2015;47:1817-21. a multicenter cohort study. Crit Care 2011;15:R178.
151. Espinel CH. The FENa test. Use in the differential 167. Pons B, Lautrette A, Oziel J, et al. Diagnostic accuracy
diagnosis of acute renal failure. JAMA 1976;236:579-81. of early urinary index changes in differentiating transient
152. Miller TR, Anderson RJ, Linas SL, et al. Urinary from persistent acute kidney injury in critically ill patients:
diagnostic indices in acute renal failure: a prospective multicenter cohort study. Crit Care 2013;17:R56.
study. Ann Intern Med 1978;89:47-50. 168. Musch W, Verfaillie L, Decaux G. Age-related increase in
153. Sodium homeostasis in chronic renal disease. Kidney Int plasma urea level and decrease in fractional urea excretion:
1982;21:886-97. clinical application in the syndrome of inappropriate
154. Gotfried J, Wiesen J, Raina R, et al. Finding the cause of secretion of antidiuretic hormone. Clin J Am Soc Nephrol
acute kidney injury: which index of fractional excretion is 2006;1:909-14.
better? Cleve Clin J Med 2012;79:121-6. 169. Espinel CH, Gregory AW. Differential diagnosis of acute
155. Fang LS, Sirota RA, Ebert TH, et al. Low fractional renal failure. Clin Nephrol 1980;13:73-7.
excretion of sodium with contrast media-induced acute 170. Esson ML, Schrier RW. Diagnosis and treatment of acute
renal failure. Arch Intern Med 1980;140:531-3. tubular necrosis. Ann Intern Med 2002;137:744-52.
156. Vaz AJ. Low fractional excretion of urine sodium in 171. Claure-Del Granado R, Macedo E, Mehta RL. Urine
acute renal failure due to sepsis. Arch Intern Med microscopy in acute kidney injury: time for a change. Am J
1983;143:738-9. Kidney Dis 2011;57:657-60.
157. Corwin HL, Schreiber MJ, Fang LS. Low fractional 172. Cameron JS. A history of urine microscopy. Clin Chem
excretion of sodium. Occurrence with hemoglobinuric- Lab Med 2015;53 Suppl 2:s1453-64.
and myoglobinuric-induced acute renal failure. Arch 173. Bunjevac A, Gabaj NN, Miler M, et al. Preanalytics of
Intern Med 1984;144:981-2. urine sediment examination: effect of relative centrifugal
158. Zarich S, Fang LS, Diamond JR. Fractional excretion of force, tube type, volume of sample and supernatant
sodium. Exceptions to its diagnostic value. Arch Intern removal. Biochem Med (Zagreb) 2018;28:010707.
Med 1985;145:108-12. 174. Becker GJ, Garigali G, Fogazzi GB. Advances in Urine
159. Diskin CJ, Stokes TJ, Dansby LM, et al. The comparative Microscopy. Am J Kidney Dis 2016;67:954-64.
benefits of the fractional excretion of urea and sodium 175. Aspevall O, Hallander H, Gant V, et al. European
in various azotemic oliguric states. Nephron Clin Pract guidelines for urinalysis: a collaborative document
2010;114:c145-50. produced by European clinical microbiologists and clinical
160. Bagshaw SM, Bennett M, Devarajan P, et al. Urine chemists under ECLM in collaboration with ESCMID.
biochemistry in septic and non-septic acute kidney Clin Microbiol Infect 2001;7:173-8.
injury: a prospective observational study. J Crit Care 176. Perazella MA. The urine sediment as a biomarker of
2013;28:371-8. kidney disease. Am J Kidney Dis 2015;66:748-55.
161. Perazella MA, Coca SG. Traditional urinary biomarkers 177. Perazella MA, Parikh CR. How can urine microscopy
in the assessment of hospital-acquired AKI. Clin J Am Soc influence the differential diagnosis of AKI? Clin J Am Soc
Nephrol 2012;7:167-74. Nephrol 2009;4:691-3.
162. Materson BJ. Insights into intrarenal sites and mechanisms 178. Chawla LS, Dommu A, Berger A, et al. Urinary sediment
of action of diuretic agents. Am Heart J 1983;106:188-208. cast scoring index for acute kidney injury: a pilot study.
163. Hropot M, Fowler N, Karlmark B, et al. Tubular action Nephron Clin Pract 2008;110:c145-50.
of diuretics: distal effects on electrolyte transport and 179. Perazella MA, Coca SG, Kanbay M, et al. Diagnostic
acidification. Kidney Int 1985;28:477-89. value of urine microscopy for differential diagnosis of
acute kidney injury in hospitalized patients. Clin J Am Soc chemistry and detection of bacteriuria. Clin Chim Acta
Nephrol 2008;3:1615-9. 2007;377:98-102.
180. Bagshaw SM, Haase M, Haase-Fielitz A, et al. A 187. Sharda N, Bakhtar O, Thajudeen B, et al. Manual
prospective evaluation of urine microscopy in septic and urine microscopy versus automated urine analyzer
non-septic acute kidney injury. Nephrol Dial Transplant microscopy in patients with acute kidney injury. Lab
2012;27:582-8. Med 2014;45:e152-5.
181. Kanbay M, Kasapoglu B, Perazella MA. Acute tubular 188. Selby NM. Electronic alerts for acute kidney injury. Curr
necrosis and pre-renal acute kidney injury: utility of urine Opin Nephrol Hypertens 2013;22:637-42.
microscopy in their evaluation- a systematic review. Int 189. Horne KL, Selby NM. Recent developments in electronic
Urol Nephrol 2010;42:425-33. alerts for acute kidney injury. Curr Opin Crit Care
182. Perazella MA, Coca SG, Hall IE, et al. Urine microscopy 2015;21:479-84.
is associated with severity and worsening of acute kidney 190. Haase M, Kribben A, Zidek W, et al. Electronic Alerts for
injury in hospitalized patients. Clin J Am Soc Nephrol Acute Kidney Injury. Dtsch Arztebl Int 2017;114:1-8.
2010;5:402-8. 191. Stevens PE, Tamimi NA, Al-Hasani MK, et al. Non-
183. Tsai JJ, Yeun JY, Kumar VA, et al. Comparison and specialist management of acute renal failure. QJM
interpretation of urinalysis performed by a nephrologist 2001;94:533-40.
versus a hospital-based clinical laboratory. Am J Kidney 192. Mehta RL, McDonald B, Gabbai F, et al. Nephrology
Dis 2005;46:820-9. consultation in acute renal failure: does timing matter? Am
184. Fogazzi GB, Garigali G, Pirovano B, et al. How to J Med 2002;113:456-61.
improve the teaching of urine microscopy. Clin Chem Lab 193. James MT, Wald R, Bell CM, et al. Weekend hospital
Med 2007;45:407-12. admission, acute kidney injury, and mortality. J Am Soc
185. Chien TI, Kao JT, Liu HL, et al. Urine sediment Nephrol 2010;21:845-51.
examination: a comparison of automated urinalysis systems 194. Selby NM, Crowley L, Fluck RJ, et al. Use of
and manual microscopy. Clin Chim Acta 2007;384:28-34. electronic results reporting to diawgnose and monitor
186. Chien TI, Lu JY, Kao JT, et al. Comparison of three AKI in hospitalized patients. Clin J Am Soc Nephrol
automated urinalysis systems--Bayer Clinitek Atlas, Roche 2012;7:533-40.
Urisys 2400 and Arkray Aution Max for testing urine
doi: 10.21037/jlpm.2018.07.06
Cite this article as: Makris K. The role of the Clinical
Laboratory in the detection and monitoring of Acute Kidney
Injury. J Lab Precis Med 2018;3:69.

Jurnal AKI

Uploaded by

Copyright:

Available Formats

Jurnal AKI

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Jurnal AKI

Uploaded by

Copyright:

Available Formats

Review Article

The role of the clinical laboratory in the detection and monitoring

Clinical Biochemistry Department, KAT General Hospital, Kifissia, Athens, Greece

Received: 29 June 2018; Accepted: 13 July 2018; Published: 10 August 2018.

Introduction co-morbidities, and also geographical location (4,5,7,8).

The term AKI became the preferred term in 2004 when

Risk 1.5-fold increase Decrease >25% UO <0.5 mL/kg/h for >6 h

Injury 2.0-fold increase Decrease >50% UO <0.5 mL/kg/h for >12 h

Loss Loss of kidney function requiring dialysis lasting for >4weeks

sCr, serum creatinine; UO, urine output.

Increase in sCr >0.3 mg/dL (>26.5 μmol/L) within 48 hours; or

Urine volume <0.5 mL/kg/h for 6 hours

Staging: AKI is staged for severity according to the following criteria

Creatine from food

Excretion with urine

Urine Na (mmol/L) <20 >40 >40

FENa <1% >2% Variable

FEUrea <35% >35% –

Urine/serum creatinine >40 <20 <20

Specific gravity >1.020 1.008–1.012 ~1.010

Osmolality (mOsm/KgrH2O) >500 <300 (near serum) <500

Urine/serum osmolality >1.5 <1.3 <1.5

Table 5 Urine microscopy findings

Cells Squamous epithelial cells Normal

Renal tubular epithelial cells Acute tubular injury

White blood cells Normal if <3 per high power field

>3 urinary tract infection, pyelonephritis, interstitial nephritis

White blood cell casts Renal Infection (pyelonephritis, interstitial nephritis)

Hyaline casts Normal or pre-renal disease

Crystals Urate/phosphate Not specific finding of acute kidney injury

Healthy individual may have some crystals in urine

Abnormal crystal presentation in patients’ urine may be indicative of metabolic disorders,

requires the creation of an algorithm to compare a patient’s manuscript.

Chem 2016;62:876-83. Biomarkers of Acute Kidney Injury: Star Struck Lovers or

1999;159:93-8. 164. Kaplan AA, Kohn OF. Fractional excretion of urea as a

You might also like