Hindawi Publishing Corporation

Critical Care Research and Practice

Volume 2013, Article ID 721810, 6 pages
http://dx.doi.org/10.1155/2013/721810

Review Article
Estimating Kidney Function in the Critically Ill Patients

Gemma Seller-Prez,1 Manuel E. Herrera-Gutirrez,1,2 Javier Maynar-Moliner,3

Jos A. Snchez-Izquierdo-Riera,4 Anibal Marinho,5 and Jos Luis do Pico6
1
Department of Critical Care Medicine, University Hospital Carlos Haya, 29018 Malaga, Spain
2
University of Malaga School of Medicine, Spain
3
Department of Critical Care Medicine, Santiago Hospital, Vitoria, Spain
4
Department of Critical Care Medicine, Hospital 12 de Octubre, Madrid, Spain
5
Department of Critical Care Medicine, Centro Hospitalario de Porto, Portugal
6
Department of Critical Care Medicine, Hospital Municipal de Necochea, Argentina

Correspondence should be addressed to Manuel E. Herrera-Gutierrez; [email protected]

Received 12 March 2013; Accepted 12 April 2013

Academic Editor: Stephen M. Pastores

Copyright 2013 Gemma Seller-Perez et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.

Glomerular filtration rate (GFR) is an accepted measure for assessment of kidney function. For the critically ill patient, creatinine
clearance is the method of reference for the estimation of the GFR, although this is often not measured but estimated by equations
(i.e., Cockroft-Gault or MDRD) not well suited for the critically ill patient. Functional evaluation of the kidney rests in serum
creatinine (Crs) that is subjected to multiple external factors, especially relevant overhydration and loss of muscle mass. The
laboratory method used introduces variations in Crs, an important fact considering that small increases in Crs have serious
repercussion on the prognosis of patients. Efforts directed to stratify the risk of acute kidney injury (AKI) have crystallized in
the RIFLE or AKIN systems, based in sequential changes in Crs or urine flow. These systems have provided a common definition
of AKI and, due to their sensitivity, have meant a considerable advantage for the clinical practice but, on the other side, have
introduced an uncertainty in clinical research because of potentially overestimating AKI incidence. Another significant drawback
is the unavoidable period of time needed before a patient is classified, and this is perhaps the problem to be overcome in the near
future.

1. Epidemiology of Acute when this is based in the new systems for stratification, as
Kidney Injury in the ICU RIFLE [3] or AKIN [4], more than 30% of ICU patients are
found to present with some degree of AKI [5], and mortality
Acute kidney injury (AKI) can be defined as a decrease of rate increases according to this degree of renal dysfunction
the glomerular filtration rate (GFR) that appears acutely, [6, 7]. These figures are a good measure of the magnitude of
is maintained for some time, causes an accumulation of the problem, and even when functional recovery after AKI
waste products from metabolism and uremic toxins, and is good, it has been demonstrated that the development of
conditions a mishandling of body fluids and a loss of the severe AKI can lead to an increase in long-term mortality [8]
ability to maintain homeostasis of electrolytes and acid-base with an estimation of the incidence of chronic kidney disease
balance. In the intensive care setting, AKI presents with a high (CKD) after an episode of AKI as high as 7.8 per 100 patients
incidence and, once established, has an important impact in per year [9, 10].
the patient and the resources [1, 2]. This scenario has put in evidence the necessity of new
The reported incidence of AKI in the intensive care units tools for continuous assessment of kidney function given that
(ICUs) shows a wide variability depending on the population the classical approach of measurements of isolated determi-
analyzed and the criteria employed for its definition, but nations of serum creatinine (Crs) has proven insufficient [11].
2 Critical Care Research and Practice

150 4
Functional reserve
2 0.37
3
100
GFR

Crs
50
1

0 0
100 90 80 70 60 40 20 0 0 100 200 300
Functional renal mass (%) CrCl-24 h

Figure 1: When enough renal mass is present, GFR changes in (a)

response to patient necessities, but when damage is severe this renal 3
reserve is lost. Adapted from [12]. 2 0.29

2. Measuring Kidney Function 2

1/Crs
2.1. Glomerular Filtration Rate. One way to evaluate renal
function is studying its capability to maintain an adequate
rate of filtration in the glomerulus, that is, the GFR. The GFR 1
is a measure of the amount of blood filtered per unit of time
but not necessarily of kidney damage. We must keep in mind
that a direct relationship between renal mass and changes
in GFR does not exist until late in the process of damage 0
because the kidneys are able to compensate the loss of renal 0 100 200 300
mass through a raise in the filtration rate in those nephrons CrCl-24 h
still functioning (Figure 1) [12]. GFR can be estimated by (b)
the measurement of the rate of elimination (clearance) of
different molecules that are filtered by the glomerulus but Figure 2: Relationship between serum creatinine and creatinine
not secreted or reabsorbed by the tubule, and the use of clearance. Data from the authors, adapted from [13].
endogenous molecules naturally producing in the organism
has been proposed for this purpose, mainly Crs.

2.2. Serum Creatinine. Crs is an organic protein resulting

from the degradation of creatine, produced and eliminated at on the other hand, changes in Crs after a serious renal insult
a constant rate, exclusively cleared by the kidneys, and filtered depend largely on the basal figures as well, so that 24 hours
at the glomerulus without significant tubular reabsorption after a 90% fall in the creatinine clearance (CrCl), the increase
or tubular secretion. Its main drawback is based on the of Crs might be up to 246% when kidney function is normal
fact that changes in Crs do not follow a linear relationship but only 174% when the patient already featured a dysfunction
with changes in GFR, so that when detecting changes in in stage 2 of the KDIGO guidelines [18] or as low as 74% when
its concentration we must not assume similar changes in the patient was in stage 4, for a virtually identical absolute
the GFR (Figure 2) [16]. Also, Crs being an endogenous increase in the Crs (between 1.8 and 2 mg/dL). For this reason,
molecule, its metabolism is subjected to interpersonal vari- some authors have advocated for a definition of AKI based
ations depending on different factors [17]. Taking into con- upon changes of Crs levels for a given period (between 24 and
sideration these aspects, Crs is still the parameter univer- 48 hours) instead of absolute serum levels [19]. This approach
sally adopted for the diagnosis of kidney failure, but we palliates the problem derived from the delayed raise in Crs
must keep in mind that its value reflects the functionality (more than 48 hours) following a change in GFR (Figure 3)
of the kidney and not necessarily the presence of actual [14, 15, 18, 19].
damage.
Crs is a functional parameter and its role in the diagnosis
of renal injury is closely related to what we can address as 2.3. Fluids and Crs. Another key point when assessing serial
renal reserve. When a patient initially presenting a normal changes in Crs is the repercussion of the balance of fluids.
Crs concentration surpasses 2 mg/dL, he or she may have lost In those situations when aggressive hydration has been
approximately 50% of the functioning renal mass [12, 14], but necessary and water balance is positive, the relative serum
Critical Care Research and Practice 3

concentration of Crs decreases and therefore underestimates Primary prevention

the real value [2023]. 100
Secondary prevention
Aggression
2.4. Crs Assay. The method described by Jaffe for the assay 80
of Crs has been the cornerstone for the diagnosis of the renal
failure until recently but shows variations for a range from

Initiation
60 Damage control
0.06 to 0.31 mg/dL, a range previously considered safe but is

GFR
now considered to be of potential prognostic value [24, 25].
40
This fact has favored its displacement by the enzymatic assay Repair
[26].
20
Extension
2.5. Creatinine Clearance. This method does in effect show
a lineal relationship with GFR and is less affected by the 0
delayed changes of Crs after GFR decrement but shares all 0 1 2 4 6 8 10 12 14
the other problems of the Crs already mentioned. In routine Days
ICU clinical practice, CrCl measured with diuresis of 24 GFR
hours is not operational, and different investigators have Creatinine
sought alternatives more adapted to the ICU environment.
Figure 3: Relationship between glomerular filtration rate (GFR) and
An approach is the measurement of CrCl with samples of
serum creatinine (Crs) in time. Adapted from [14, 15].
urine collected in shorter intervals of time, making repetitive
measures more feasible, urine samples from simultaneous
patients easier to handle, and (the most critical aspect)
without delay for the results [27]. Different timings for 3. Stratification of AKI
collection of urine have been validated by some authors,
From the moment the aggression occurs until the kidneys
ranging from one hour by Hoste et al. [28], two hours by
begin to show alterations and dysfunction, different mech-
Herrera-Gutierrez et al. [13] or periods from two to twelve
anisms of compensation have been launched that which
hours by Wilson and Soullier [29]. In addition, these studies
produce a decrease in the GFR [37] but, due to the lack of
show how among those patients with Crs in normal or near-
sensible methods of diagnosis, we acknowledge the presence
normal range (below 1.5 mg/dL) up to 25% already had a
of this renal failure once this initial phase has already been
significantly diminished CrCl and also put in evidence that
surpassed. This problem is worsened because there is not a
equations for estimation of GFR in the ICU (Cockroft-Gault
clear definition of what we must consider AKI [38, 39] but
and MDRD) are not adequate [13, 28]. However, despite the
the definition of two systems aimed to stratify acute kidney
scarcity of studies addressing the validity of these equations
dysfunction based on sequential changes of Crs (RIFLE and
in the acute patient (and specifically in the ICU patient)
AKIN) has come to fill this gap for the AKI patient (Figure 4)
and the general agreement against its use in this scenario,
[3, 4].
these equations (especially MDRD) have become the usual
The RIFLE (an acronym for risk, injury failure, loss,
tool for estimation of CrCl and guiding prescription of drugs
and end-stage) system made a proposal for a new definition
that require adjustment in the presence of renal dysfunc-
considering AKI as a dynamic process. Another major
tion [30, 31]. When an exact measure is deemed necessary
advantage of this system was its simplicity, advocating for the
none of these equations replaces a measurement of CrCl
use of biomarkers universally affordable (Crs and diuresis).
[32].
In 2007, the AKIN (acute kidney injury network) group
designed a new stratification system based on the premises
2.6. Cys-C. Cys-C is a low molecular weight protein pro- of the RIFLE system but incorporating the findings from
duced by all nucleated cells at a constant rate, being filtered Lassnigg et al. that demonstrated how small increases in
by the glomerulus and reabsorbed and metabolized in the Crs carry a proportional increase in mortality [24, 4043].
proximal tubule without tubular secretion and only minimal These two systems have been evaluated in large series of UCI
extrarenal elimination. Cys-C has shown promising results patients and are currently consolidated as reference, but both
as an estimator of GFR in patients with stable renal function systems present some problems [44] and their introduction
[33, 34]. has conditioned a substantial increase in the incidence of AKI
published, having in fact increased on the order of 2 to 10
2.7. Biomarkers of Kidney Injury. Different biomarkers of times [45].
kidney injury have recently been evaluated with mixed The problem, shared by both systems, is the need for
results [35]. It is still necessary to define the kinetics of a minimum timeframe to proceed with the classification,
these molecules and their relationship to the development of which in RIFLE extends up to a week and in AKIN for 48
kidney injury [36]. Another important point to emphasize is hours. This inevitable time window will condition a delay in
that these new biomarkers are not aimed to the assessment of the detection of AKI. Yet another problem with RIFLE arises
renal function (do not estimate GFR) and therefore can not from the possibility to choose indistinctly between CrCl or
replace but are complementary to Crs or Cys-C. Crs, even when these values are not linearly related and do not
4 Critical Care Research and Practice

RIFLE AKIN

Crs 1.5 or Diuresis < 0.5 Crs 1.5 or Diuresis <0.5

1
mL/kg/h mL/kg/h

Stage
GFR 25% > 0.3 mgr/dL

Risk
6 hours 6 hours

Diuresis < 0.5 Diuresis <0.5

Crs 2 or mL/kg/h

Stage 2
mL/kg/h Crs 2

Injur
GFR 50% 12 hours 12 hours

Crs 3 or Diuresis < 0.3 Diuresis <0.3

mL/kg/h Crs 3 or mL/kg/h

re

3
GFR 75% or

Stage
Failu
24 hours or Crs 4 mgr/dL 24 hours or
Crs 4 mgr/dL
Anuria > 12 h Anuria >12 h

Loss

Loss
of function >4 weeks
ESRD
Esrd
>3 months

Crs : Serum creatinine

GFR : Glomerular filtration rate

Figure 4: RIFLE and AKIN classification systems [3, 4].

change simultaneously in time [46]. Another relevant aspect Serum creatinine is the key factor in the evaluation
and one that questions the consistency of these systems is the of kidney function because it is affordable, reproducible,
finding of similar outcomes for patients in the AKIN 1 and and easy to perform, but clinicians must be aware of its
2 levels with a significant increment for level 3 and with a limitations, among others that it is a functional marker and
similar behavior for RIFLE [47] that could be suggesting the not a marker of injury, that changes in Crs are delayed after
convenience for a reappraisal of the ranges of Crs considered changes in GFR, or that fluid changes in critically ill patients
in each level. can seriously difficult the capability of Crs to detect small
changes in kidney function.
New trends in stratification (ADQI or AKIN) could have
4. Conclusion a significant impact in clinical practice, alerting the clinicians
of the real value of small changes in Crs, and the novel
A proper definition for AKI should establish the presence or biomarkers of kidney damage (in particular of tubular injury)
absence of the disease, report on its severity and prognosis, may in the near future have a role in the diagnosis of AKI once
and, perhaps more important, should be easy to understand they are included in the classification systems.
and implement [48]. Although these assumptions have been
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Parkinsons
Disease

Computational and
Mathematical Methods
in Medicine
Behavioural
Neurology
AIDS
Research and Treatment
Oxidative Medicine and
Cellular Longevity
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