Editorial
Acute kidney injury (AKI) in cirrhosis: Should we change
current definition and diagnostic criteria of renal failure in cirrhosis?
Vicente Arroyo
Liver Unit, Centre Esther Koplowitz-IDIBAPS, Hospital Clinic, University of Barcelona, Spain
See Articles, pages 474–481 and pages 482–489
AKI is a new name/concept of acute renal failure (ARF) proposed
by a group of scientific societies (AKI network), which is being
widely accepted by critical care and nephrology physicians [1].
It is based mainly on studies correlating changes in serum creat-
inine vs. morbidity and mortality in ICU patients. The term AKI
therefore defines an abrupt decrease in kidney function. AKI def-
inition modifies two traditional paradigms of ARF. First, the rele-
vance of differentiating functional (prerenal) ARF from acute
tubular necrosis disappears with the AKI concept. This differenti-
ation is difficult and correlates poorly with renal histology, clini-
cal features, and prognosis. Second, whereas a marked increase in
serum creatinine was required for the diagnosis of ARF in the
past, a small increase in serum creatinine (P0.3 mg/dl or P50%
over baseline) is required for the diagnosis of AKI. AKI may be
graded into three stages according to the magnitude of increase
in serum creatinine: Stage 1: 150–200%; Stage 2: >200–300%;
Stage 3: >300% or of at least 0.5 mg/dl in patients with baseline
serum creatinine of P4 mg/dl or renal replacement therapy. Mor-
bidity and mortality increase in parallel with the AKI stages (no
AKI to AKI-3).
Despite the fact that the AKI concept has been elaborated
mainly for ICU patients, there is a movement to extend the AKI
concept to patients with decompensated cirrhosis. This editorial
discusses the traditional criteria used in the diagnosis of renal
failure in cirrhosis, the evidence currently available supporting
a change to the AKI criteria and, finally, the impact of the concept
of acute-on-chronic liver failure (ACLF) on the assessment of
patients with decompensated cirrhosis.
The traditional diagnostic criteria of renal failure in cirrhosis
were proposed 17 years ago [2] and have been improved in subse-
quent years: (1) it is based on the presence of a serum creatinine
over 1.5 mg/dl which represents a GFR below 40 ml/min; (2) the
cause of renal dysfunction is important in the definition (HRS,
hypovolemia, acute tubular necrosis, nephrotoxicity, infections,
chronic nephropathy); (3) HRS is divided into 2 types (type 1
and 2) according to the progression of renal failure; (4) significant
deterioration of renal function (i.e., after therapeutic paracentesis
or diuretics) is defined by an increase in serum creatinine P50% to
q
DOI of original articles: http://dx.doi.org/10.1016/j.jhep.2013.04.036, http://
dx.doi.org/10.1016/j.jhep.2013.03.039.
E-mail address: varroyo@clinic.ub.es
Journal of Hepatology 2013 vol. 59 j 415–417
a final value P1.5 mg/dl [3,4]; (5) renal failure associated with
bacterial infections (in the absence of septic shock) may follow a
rapidly progressive (type-1 HRS), steady (type-2 HRS), and spon-
taneously reversible (transient renal failure) course [5].
This traditional classification correlates with pathophysiolog-
ical features, therapeutic response, and prognosis. For example,
type 2 HRS is usually the extreme expression of the spontaneous
deterioration of the circulatory function that occurs in cirrhosis
as a consequence of splanchnic arterial vasodilation and impair-
ment in cardiac function. It is associated with refractory ascites
and poor survival (months) [6]. Type 1 HRS is an ARF that occurs
secondarily to a rapid deterioration of the cardiocirculatory func-
tion [7] in closed temporal relationship with bacterial infections,
acute alcoholic hepatitis, or other precipitating events, and is
associated with extremely poor survival (days or weeks). Type
1 and type 2 HRS can reverse following treatment with terlipres-
sin and albumin. However, recurrence of renal failure following
discontinuation of treatment is the rule in type 2 HRS and infre-
quent in type 1 [8]. Renal failure due to hypovolemia (i.e., diuret-
ics, diarrhoea) is moderate and usually reversible following
discontinuation of the precipitating cause [9]. Renal failure sec-
ondary to chronic nephropathy is slowly progressive and associ-
ated with better survival than type 2 HRS [9]. Finally, the severity
of renal failure associated with bacterial infection depends on the
resolution of the infection and, in cases without septic shock, on
the clinical course of renal failure [5].
AKI classification is based on three major points: (1) renal
impairment: small increase in serum creatinine (P0.3 mg/dl or
P50% over baseline). This is the most relevant aspect of the AKI
concept. If ARF (or type-1 HRS) could be detected early by small
increments in serum creatinine, even within the normal range
(i.e., from 0.6 to 1 mg/dl), specific measures or treatments could
applied very early to prevent an evolution to more severe forms
of the syndrome; (2) time: the increase in serum creatinine should
be abrupt, within 48 hours; (3) although the Clinical Practice
Guideline for Acute Kidney Injury clearly states that etiology is
important for therapy, it is not needed for diagnosis of AKI and
staging [1].
The substitution of the traditional diagnostic criteria of renal
failure in cirrhosis for AKI requires evidence indicating advanta-
ges of one classification over the other. However, at present such
evidence is lacking. Several studies of AKI in cirrhosis confirm
Editorial
that mortality is higher in patients with AKI than in those
without AKI and increases in parallel with AKI staging [10–12].
However, this is also the case after classifying patients on the
basis of traditional criteria and there is no comparative study
between both types of stratification. Up to now, it was unknown
whether increments in serum creatinine P0.3 mg/dl, but below
1.5 mg/dl (the cut-off level required for diagnosis of renal failure
in the traditional concept), are associated with higher mortality
in comparison to unmodified serum creatinine or increments of
serum creatinine <0.3 mg/dl. Finally, current studies of AKI in cir-
rhosis are insufficiently powered or present methodological pit-
falls that limit the interpretation of data. For example, the
interval between serum creatinine measurements used to define
AKI in many of these studies ranges from days (usually more than
2) to months and this interval is not appropriate for detection of
abrupt changes in renal function [10,11].
The current issue of the Journal of Hepatology publishes two
prospective investigations on AKI in cirrhosis. The study of Fagun-
des et al. [13] includes 375 consecutive patients admitted with
acute complications. Piano et al. [14] included 233 consecutive
patients with ascites. The Piano’s study was especially strict in
the diagnostic criteria of AKI. Serum creatinine was measured at
admission (baseline) and monitored daily during hospitalization.
In both studies, patients with AKI-1 were subdivided into two
groups, those with an increase in serum creatinine P0.3 mg/dl
but without reaching 1.5 mg/dl and those in whom serum creati-
nine reached a peak over 1.5 mg/dl. Both studies showed marked
differences between patients from these two groups. In the study
of Fagundes et al., patients with AKI-1 serum creatinine 61.5
showed a 90-day probability of survival similar to that of patients
without AKI. By contrast, patients with AKI-1 serum creatinine
>1.5 showed significantly lower 90-day probability of survival
than the previous 2 groups. In the study of Piano et al., the in-hos-
pital mortality of patients with AKI-1 was higher, although not
significant, than that of patients without AKI. However, again pro-
gression of AKI and mortality were significantly higher, and reso-
lution of AKI significantly lower in patients with AKI-1 serum
creatinine P1.5 than in patients with AKI-1 serum creatinine
<1.5 mg/dl. Both studies therefore suggest that AKI-1 serum creat-
inine <1.5 mg/dl is a benign condition and that it is the progres-
sion of renal impairment to a significant reduction of GFR
(serum creatinine >1.5 mg/dl) that determines a poor prognosis.
The recent introduction of the concept of acute-on-chronic
liver failure (ACLF) adds a new dimension to the impairment of
renal function in cirrhosis. According to the Canonic study (an
observational investigation in 1343 patients), renal failure in cir-
rhosis is not an independent complication but rather a part of a
complex syndrome, ACLF, in which the impairment in renal func-
tion occurs in the setting of an impairment in the function of
other organs (liver, cerebral, coagulation, respiration, and circula-
tion) as a consequence of an intense inflammatory reaction
related to bacterial infection, alcoholic liver injury, or other, as
yet, unidentified mechanisms [15]. ACLF grade 1 is defined by
the presence of renal failure (creatinine P2 mg/dl) or other single
organ failures associated with renal dysfunction (serum creati-
nine 1.5–1.9 mg/dl) or moderate hepatic encephalopathy (grade
1–2), ACLF-2 by the presence of 2 organ failures, and ACLF-3 by
the presence of 3 or more organ failures. The definition of organ
failures was based on a sequential organ failure assessment
(SOFA) score specifically adapted to cirrhotic patients. The prev-
alence of ACLF at enrolment or during hospitalization was 31%
416 Journal of Hepatology 2013 vol. 59 j 415–417
and the 28-day and 90-day mortality rates were of only 1.9%
and 9.8%, respectively, in patients without ACLF, and of 33% and
51.2% in patients with ACLF (ranging from 23.1% and 40.8% in
ACLF-1 to 74% and 78% in ACLF-3), indicating that stratification
based on the function of the most important vital organs corre-
lates closely with short- and mid-term mortality. There are three
studies assessing AKI and other stratification methods or scores
(Child-Pugh, MELD, APACHE II, APACHE III, SOFA) in critically ill
cirrhotic patients and they all showed SOFA as the most accurate
method in predicting short-term mortality [16–18].
In summary, with the current data, it is not possible to ascer-
tain whether the AKI classification improves the traditional diag-
nostic criteria of renal failure in cirrhosis in terms of prediction of
morbidity and mortality. AKI-1 is associated with increased mor-
tality only in patients with significant decrease in GFR and peak
serum creatinine >1.5 mg/dl. Stratification of cirrhotic patients
on the basis of a single organ function (kidney, liver or brain) is
an oversimplification of the pathophysiological features occur-
ring in patients with decompensated cirrhosis. Not surprisingly,
stratification according to kidney function and the function of
other vital organs is the most accurate system to predict morbid-
ity and mortality in these patients.
Conflict of interest
The author declared that he does not have anything to disclose
regarding funding or conflict of interest with respect to this
manuscript.
References
[1] KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Int Suppl
2012;2:2, doi: 101038/kisup.2012.2.
[2] Arroyo V, Ginès P, Gerbes G, Dudley FJ, Gentilini P, Laffi G, et al. Definition
and diagnostic criteria of refractory ascites and hepatorenal syndrome in
cirrhosis. Hepatology 1996;23:164–176.
[3] Ginès P, Arroyo V, Vargas V, Planas R, Casadefont F, Panes J, et al.
Paracentesis with intravenous infusion of albumin as compared with
peritoneovenous shunting in cirrhosis with refractory ascites. N Engl J Med
1991;325:829–835.
[4] Ginès A, Fernandez-Esparrach G, Monescillo A, Vila C, Domenech E, Abecasis
R, et al. Randomized trial comparing albumin, dextran 70, and polygeline in
cirrhotic patients with ascites treated by paracentesis. Gastroenterology
1996;111:1002–1010.
[5] Follo A, Llovet JM, Navasa M, Planas R, Forns X, Francitorra A, et al. Renal
impairment after spontaneous bacterial peritonitis: incidence, clinical
course, predictive factors and prognosis. Hepatology 1994;20:1495–1501.
[6] Ruiz-del-Arbol L, Monescillo A, Arocena C, Valer P, Ginès P, Moreira V, et al.
Circulatory function and hepatorenal syndrome in cirrhosis. Hepatology
2005;42:439–447.
[7] Ruiz-del-Arbol L, Urman J, Fernandez J, Gonzalez M, Navasa M, Monescillo A,
et al. Systemic, renal and hepatic hemodynamic derangement in cirrhotic
patients with spontaneous bacterial peritonitis. Hepatology
2003;38:1210–1218.
[8] Arroyo V, Fernández J. Management of hepatorenal syndrome in patients
with cirrhosis. Nat Rev Nephrol 2011;7:517–526.
[9] Martin-Llahí M, Guevara M, Torre A, Fagundes C, Resttucia T, Gilabert R, et al.
Prognostic importance of the cause of renal failure in patients with cirrhosis.
Gastroenterology 2011;140:488–496.
[10] Belcher JM, Gracía-Tsao G, Sanyal AJ, Bhogal H, Lim JK, Ansari N, et al.
Association of AKI with mortality and complications in hospitalized patients
with cirrhosis. Hepatology 2013;57:753–762.
[11] Tsien CD, Rabie R, Wong F. Acute kidney injury in decompensated cirrhosis.
Gut 2013;62:131–137.
[12] Ribeiro de Carvalho J, Villela-Nogueira CA, Raggio Luiz R, Lustosa Guzzo P, da
Silva Rosa JM, Rocha E, et al. Acute kidney injury network criteria as a

predictor of hospital mortality in cirrhotic patients with ascites. J Clin
Gastroenterol 2012;46:e21–e26.
[13] Fagundes C, Barreto R, Guevara M, García E, Sola E, Rodriguez E, et al.
Modified acute kidney injury classification for diagnosis and risk stratifica-
tion of impairment of kidney function in cirrhosis. J Hepatol
2013;59:474–481.
[14] Piano S, Rosi S, Maresio G, Fasolato S, Cavallin M, Romano A, et al. Evaluation
of the acute kidney injury network criteria in hospitalized patients with
cirrhosis and ascites. J Hepatol 2013;59:482–489.
[15] Moreau R, Jalan R, Ginès P, Pavesi M, Angeli P, Córdoba J, et al. Acute-on-
chronic liver failure is a distinct syndrome that develops in patients with
acute decompensation of cirrhosis. Gastroenterology 2013. http://
Journal of Hepatology 2013 vol. 59 j 415–417
JOURNAL OF HEPATOLOGY
dx.doi.org/10.1053/j.gastro.2013.02.042, [Epub ahead of print] PMID
23474284.
[16] Pan HC, Jenq CC, Tsai MH, Fan PC, Chang CH, Chang MY, et al. Risk models
and scoring systems for predicting the prognosis in critically ill cirrhotic
patients with acute kidney injury: a prospective validation study. PLoS One
2012;7:e51094. http://dx.doi.org/10.1371/journal.pone.0051094, [Epub
2012 Dec 18].
[17] Jenq CC, Tsai MH, Tian YC, Lin CY, Yan C, Liu NJ, et al. Rifle classification can
predict short-term prognosis in critically ill cirrhotic patients. Intensive Care
Med 2007;33:1921–1930.
[18] Cholongitas E, Calcaruso V, Senzolo M, Path D, Shaw S, O’Beirne J, et al. Rifle
classification as predictive factor of mortality in patients with cirrhosis
admitted to intensive care unit. J Gastroenterol Hepatol 2009;24:1639–1647.
417