INSUFICIENCIA RENAL EN LA CIRROSIS
Pere Ginès Servei d’Hepatologia, Hospital Clínic
Barcelona
V Curso para Residentes AEEH Diagnóstico y tratamiento de las
Enfermedades Hepáticas
Barcelona, 30-31 de Octubre de 2015
ACUTE IMPAIRMENT OF KIDNEY FUNCTION IN CIRRHOSIS
1. Definition:
- Based on serum creatinine concentration
- Direct measurement of GFR impractical and not widely available
2. Definitions used:
- Traditional criteria (IAC criteria)
50% percent increase of serum creatinine over baseline
Cut-off value of serum creatinine: 1.5 mg/dl (133µmol/l)
- AKIN criteria
AKI (Acute Kidney Injury): ≥ 0.3 mg/dL or 50% in serum
creatinine within 48 hours. No cut-off value
Classification in stages of severity: 1, 2 and 3
High sensitivity
Detects impairment of kidney function with “normal” GFR
ACUTE IMPAIRMENT OF KIDNEY FUNCTION IN CIRRHOSIS
1. Definition AKI: Increase in sCr ≥0.3 mg/dL (≥26.5 mmol/L) within 48 h; or a percent increase sCr ≥50% from baseline which is known, or presumed, to have occurred within the prior 7 days
2. Staging of AKI:
Stage AKI CRITERIA
Stage 1 increase in sCr ≥0.3 mg/dL (26.5 mmol/L) or an increase in sCr ≥1.5-fold to twofold from baseline
Stage 2 increase in sCr >two to threefold from baseline
Stage 3 increase of sCr >threefold from baseline or sCr ≥4.0 mg/dL (353.6 mmol/L) with an acute increase ≥0.3 mg/dL (26.5 mmol/L) or initiation of renal replacement therapy
International Club of Ascites (ICA-AKI) new definitions for the diagnosis and
management of AKI in patients with cirrhosis
Gut 2015
ACUTE KIDNEY INJURY IN CIRRHOSIS
1155 hospitalized patients with cirrhosis
0
10
20
30
40
50
60
70
80
90
100
Frequency
No AKI AKI AKI at admission hospitalization
Time (days)
Surv
ival
Prognosis
No AKI
AKI
29%
19%
52%
Huelin P, Piano S, et al (unpublished)
ASSESSMENT OF AKI CLASSIFICATION IN CIRRHOSIS
Prospective studies in nonselected hospitalized patients
Piano et al J Hepatol 2013 Fagundes al J Hepatol 2013
Stage 3
100
80
60
40
0
20
Mort
alit
y (
%)
No AKIN Stage 1 Stage 2
AKIN
n.s. n.s. p<0.01
p<0.001
p<0.0001
p<0.0001
30 60 90
Days
100
80
60
40
0
20 Pro
ba
bili
ty o
f su
rviv
al (%
)
88%
No-AKI
84%
AKI 1A
68%
AKI 1B
42%
AKI 2
31%
AKI 3
sCR <1.5mg/dL
sCR ≥1.5mg/dL
n=233 n=375
AKI 1A: peak creatinine ≤ 1.5 mg/dL
AKI 1B: peak creatinine > 1.5 mg/dL
AKI CLASSIFICATION IN CIRRHOSIS
Take-home message
The new diagnostic criteria of AKI in cirrhosis are
helpful for early detection of acute impairment in
kidney function.
The staging criteria of AKI should be modified and
patients with stage 1 should be categorized in two
groups, 1A and 1B according to a peak value of 1.5
mg/dL of serum creatinine at diagnosis of AKI.
MAIN TYPES OF AKI IN CIRRHOSIS
• HEPATORENAL SYNDROME.
– Associated with bacterial infections.
– Without bacterial infections.
• HYPOVOLEMIA (diuretics, GI bleeding, diarrhea).
• ACUTE TUBULAR NECROSIS (shock).
• NEPHROTOXICITY (NSAIDs)
DIFFERENTIAL DIAGNOSIS OF AKI IN CIRRHOSIS
• HEPATORENAL SYNDROME.
– Associated with bacterial infections.
– Without bacterial infections.
• HYPOVOLEMIA (diuretics, GI bleeding, diarrhea).
• ACUTE TUBULAR NECROSIS (shock, nephrotoxic drugs).
• NEPHROTOXICITY (NSAIDs)
- MEDICAL HISTORY
- PHYSICAL EXAMINATION
- BLOOD TESTS
- URINE TESTS
- ABDOMINAL US
• DIAGNOSTIC CRITERIA OF HEPATORENAL SYNDROME
- Cirrhosis with ascites. - Serum creatinine >133 mmol/l (1.5 mg/dl). - No improvement of serum creatinine after at least 2 days with diuretic withdrawal and
volume expansion with albumin (1 g/kg of body weight up to a maximum of 100 g/day).
- Absence of shock. - No current or recent treatment with nephrotoxic drugs. - Absence of parenchymal kidney disease as indicated by proteinuria >500 mg/day,
microhaematuria (>50 red blood cells per high power field) and/or abnormal renal ultrasonography.
Salerno F et al., Gut 2007
DIFFERENTIAL DIAGNOSIS OF AKI IN CIRRHOSIS
DISTAL TUBULE NGAL GST-π
PROXIMAL TUBULE NGAL IL-18 KIM-1 L-FABP MCP-1 Albumin
GLOMERULUS Creatinine Albumin NGAL
ROLE OF URINE BIOMARKERS IN THE
DIFFERENTIAL DIAGNOSIS OF AKI IN
CIRRHOSIS
Adapted from Koyner et al, Clin J Am Soc Nephrol 2013
VALUE OF NGAL IN THE GENERAL POPULATION OF
EMERGENCY DEPARTMENT PATIENTS’
Nickolas et al J AM Coll Cardiol 2012;59:246
Norm= Healthy subjects
CKD = Chronic Kidney diseases
pAKI = Pre-renal AKI
iAKI = intrinsic AKI
Uncl = unclassified
* p<0.001
** p<0.05
DIFFERENTIAL DIAGNOSIS OF AKI IN CIRRHOSIS
Role of uNGAL
Fagundes et al, J Hepatology 2012
p<0.0001
DIFFERENTIAL DIAGNOSIS OF AKI IN CIRRHOSIS
Role of uNGAL
Verna et al, Dig Dis Sci, 2012
PRE-RENAL
(N = 55) HRS (N = 16) ATN (N = 39) P
NGAL (ng/mL) 54 (17-180) 115 (51-373) 565 (76-1000) <0.001
IL-18 (pg/mL) 15 (15-49) 37 (15-90) 124 (15-325) <0.001
Albumin (mg/dL) 21 (4-70) 24 (13-129) 92 (44-253) <0.001
KIM-1 (ng/mL) 4.4 (1.8-11.7) 7.6 (4.5-10.1) 8.4 (4.1-18.3) 0.03
L-FABP (ng/mL) 9 (4-18) 14 (6-20) 27 (8-103) 0.002
Belcher et al, Hepatology 2014
DIFFERENTIAL DIAGNOSIS OF AKI IN CIRRHOSIS
Usefulness of other urine biomarkers
Biomarker
Diagnosis of ATN vs other types of AKI
AUCROC (95% CI)
p Cut-off level Sensitivity Specificity
NGAL (µg/gr creatinine)
0.957 (0.891-1.00) <0.0001 294 92% 89%
IL-18 (pg/gr creatinine)
0.920 (0.832-1.00) <0.0001 51 83% 89%
Albumin (µg/gr creatinine)
0.858 (0.733-0.983) <0.001 86 75% 85%
TFF3 (µg/gr creatinine)
0.824 (0.667-0.981) 0.001 3040 75% 81%
GSTπ
(µg/gr creatinine) 0.812 (0.647-0.976) 0.002 8.27 83% 78%
DIFFERENTIAL DIAGNOSIS OF AKI IN CIRRHOSIS
Urine biomarkers for diagnosis of ATN vs other types of AKI
Other biomarkers with AUCROC <0.8: β2 microglobulin, Calbinidin, Cystatin C, Clusterin, KIM-1, MCP-1, and Osteopontin.
Ariza et al, Plos One 2015
IDENTIFYING THE TYPE OF ACUTE KIDNEY INJURY IN
CIRRHOSIS
Take-home message
Acute kidney injury in cirrhosis may be due to a
number of causes that have different management.
Rapid identification of the cause is very important to
start specific treatment. Urine biomarkers, particularly
NGAL may be helpful but more information is still
needed before use in clinical practice.
PROGNOSIS OF PATIENTS WITH CIRRHOSIS AND AKI
Relevance of the type of AKI
Time (days)
Surv
ival
Hypovolemia
Miscellaneous
Non-type 1 HRS
Type 1 HRS
ATN
Huelin P, Piano S, et al (unpublished)
RELATIONSHIP OF THE TYPE OF KIDNEY FAILURE AND
SURVIVAL IN CIRRHOSIS
Take-home message
The type of AKI is a very important prognostic factor in
patients with cirrhosis. Hepatorenal syndrome and
ATN have the worst prognosis.
1 3 5 7 9 11 13 15 17 190
1
2
3
4
5
DaysPre
admission
Persistent
AKI
Transient
AKI
$
P=0.01
Se
rum
cre
ati
nin
e (
mg
/dL
)
0
1
2
3
4
5
1 3 5 7 9 11 13 15 17 19
NSAIDs-ASSOCIATED AKI IN CIRRHOSIS
Time course of serum creatinine according to AKI type
Elia C, submited
0 10 20 300
25
50
75
100P
rob
ab
ilit
y o
f s
urv
iva
l (%
)Transient AKI
p< 0.001
Persistent AKI
0
10 20
25
50
75
100
Days
Pro
ba
bil
ity o
f s
urv
iva
l (%
)
30
NSAIDs-ASSOCIATED AKI IN CIRRHOSIS
Survival according to AKI type
Elia C, submited
NSAIDs-ASSOCIATED AKI IN CIRRHOSIS
Take-home message
This is a relatively common cause of AKI in patients
admitted to hospital. Contrary to current belief
outcome is not always good. While kidney function
recovers rapidly in two thirds of patients, one third of
cases develop persistent AKI with high mortality.
Nazar et al. Hepatology 2010
5 15
Pro
babili
ty o
f R
esponse
1.0
0.8
0.7
0.6
0.5
0.3
0.2
0.1
0.0 0 10
Days of Treatment
0.9
0.4
Patients
at risk 39 29 17 5
PHARMACOLOGICAL TREATMENT OF
HEPATORENAL SYNDROME
Probability of response over time
TYPE-1 HEPATORENAL SYNDROME AND SEPSIS
a 0 Responders
Non Responders
Efficacy 65%
Rodríguez E et al., J Hepatol 2014
Effects of early treatment with terlipressin and albumin
TYPE 1 HEPATORENAL SYNDROME
Recurrence after treatment with terlipressin and albumin
5 10 15 20 25 30 35 40 45 50
6.0
5.0
4.0
3.0
2.0
0.0
Seru
m c
reatinin
e (
mg/d
L)
Days
1.0
0
Liver
transplantation
15 33 29 39 59
Terlipressin 1 mg/4 h
Terlipressin 2 mg/day (continuous infusion)
60 55
TREATMENT OF HEPATORENAL SYNDROME
WITH TERLIPRESSIN AND ALBUMIN
Adverse cardiovascular effects
(combined studies, 327 patients)
Arrhythmias
Circulatory overload
Peripheral ichemia
Suspected intestinal ischemia
Arterial hypertension
Myocardial infarction
13 (4%)
11 (3.4%)
6 (1.8%)
4 (1.2%)
3 (0.9%)
2 (0.6%)
Angeli P, Ginès P, et al. Gut 2015
MANAGEMENT OF AKI IN PATIENTS WITH CIRRHOSIS
BARCELONA LIVER CIRRHOSIS STUDY GROUP