INSUFICIENCIA RENAL EN LA CIRROSIS -...

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Huelin P, Piano S, et al (unpublished)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


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


Role of uNGAL

Fagundes et al, J Hepatology 2012

p<0.0001


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


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%


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


Survival according to AKI type

Elia C, submited


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

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