hepatorenal syndrome

P. AngeliDept. of Clinical and Experimental Medicine University of Padova (Italy)

Hepatorenal syndrome

TReviso 8 Giugno 2009

HRS is a functional renal failure caused by intrarenal vasoconstriction which occurs in patients with end stage liver disease as well as in patients with acute liver failure or alcoholic hepatitis.HRS is characterized by impaired renal function, marked alterations in cardiovascular function, and overactivity in the endogenous vasoactive systems.

Hepatorenal syndrome (HRS)

Definition of HRS

F. Salerno, et al. Gut 2007 ; 56 : 1310-1318.

FUNCTIONAL RENAL ABNORMALITIES IN CIRRHOSIS

Abnormality Clinical consequence

• Sodium retention• Water retention• Renal vasoconstriction

• Ascites and edema• Dilutional hyponatremia• Hepatorenal syndrome


Peripheral arterial vasodilation “hypothesis”

Reduction of effective circulating volume

Activation of endogenous vasocontrictor systems

Renal functional abnormalities

Splanchnic arterial vasodilation

Portal hypertension/liver failure

Increased release of NO, CO and other vasodilators

RW. Schrier, et al. Hepatology 1988 ; 8 : 1151-1157.


1. Acute tubular necrosis (41.7%)

2. Prerenal failure (38%)

3. Hepatorenal syndrome (20%)

4. Postrenal failure (0.3%)

Acute renal failure in patients with cirrhosis and ascites


R. Moreau, et al. Hepatology 2003 ; 37 : 233-243.

1. Cirrhosis with ascites;

2. Serum creatinine > 133 µmol/l (1.5 mg/dl);

3. No sustained improvement of serum creatinine (decrease to a level of 133 µmol/l

or less) after at least two days of diuretic withdrawal and volume expansion with

albumin. The recommended dose of albumin is 1 g/kg of body weight per day to

a maximum of 100 g/day;

4. Absence of shock

5. No current or recent treatment with nephrotoxic drugs;

6. Absence of parenchimal disease as indicated by proteinuria >500 mg/day,

microhematuria (>50 red blood cells per high power field) and/or abnormal

renal ultrasonography.

New Diagnostic Criteria



Clinical types

Type 1 HRS : rapidly progressive reduction of renal function as defined by a doubling of the initial serum creatinine to a level > 226 µmol/l or 2.5 mg/dl in less than two weeks. It may occurs spontaneously, but it can also follow a precipitating event.

Clinical pattern: acute renal failure

Type 2: is characterized by moderate renal failure (serum creatinine from 133 to 226 µmol/l or 1.5 to 2.5 mg/dl) with a steady or slowly progressive course.

Clinical pattern: refractory ascites



0

0,2

0,4

0,6

0,8

1%

Probability of survival in patients with HRS

2 4 86 months

P. Gines, et al. Lancet 2003 ; 362 : 1819-1827.

10 12


P < 0.001

Type 2 HRS

Type 1 HRS

Clinical types

Type 1 HRS : rapidly progressive reduction of renal function as defined by a doubling of the initial serum creatinine to a level > 226 µmol/l or 2.5 mg/dl in less than two weeks. It may occurs spontaneously, but it can also follow a precipitating event.

Clinical pattern: acute renal failure

Type 2: is characterized by moderate renal failure (serum creatinine from 133 to 226 µmol/l or 1.5 to 2.5 mg/dl) with a steady or slowly progressive course.

Clinical pattern: refractory ascites



Precipitating events

Spontaneous bacterial peritonitis

Paracentesis without plasma expansion

Gastrointestinal hemorrhage

Alcoholic hepatitis

Unknown


• Renal failure 29 25.0

Onset of renal failure 10 8.6

Impairment of pre-existing renal failure 20 17.2

Type 1 HRS 19 16.4

Cirrhotic patients with ascites and SBP (n° 116)

Prevalence and types of renal failure (RF) precipitated by spontaneous bacterial peritonitis (SBP)


P. Angeli, et al. Aliment. Pharmacol. Ther. 2006 ; 23 : 75-84.

n ° %

Prevalence of renal failure in the different types of bacterial infections in patients with cirrhosis and ascites

0

25

50

75

100

Pneumoniae UTI SBP Biliary or GITract

Cellulitis Collture+ Inf. Colture - Inf.

Renal failure Progressive renal failure

(%)

P < 0.0001 P < 0.0001


S. Fasolato, et al. Hepatology 2007 ; 45 : 223-229.

Subdiaphramatic Infections

• High MELD score• High peak count of neutrophyl

leukocyte in blood• Lack of resolution of infection

Predictive factors of the deveopment of renal failure in cirrhotic patients with ascites


S. Fasolato, et al. Hepatology 2007 ; 45 : 223-229.

0

10

20

30

40

50

Healthy subjects Cirrhosis without SBP Cirrhosis with SBP

* = P < 0.01 vs cirrhosis without SBP

Plasma levels of endotoxin in patients with cirrhosis with and without SBP

*

M. Navasa, et al. Hepatology 1998 ; 27 : 1227-1232.

Hepatorenal syndrome (HRS) pg

/ml

0

20

40

60

80

Correlation between serum level of nitrite and nitrate (NOx) and plasma level of endotoxin in patients with cirrhosis

C. Guarner et al. Hepatology 1993 ; 18 : 1139-1148.


°

50

°

100 150 200 250

°

°

°

°° °°°°

° °°

°°°

°°°°°°°

° °°°°°

° ° °° °° °

°

Endotoxin (pg/ml)

NO

x (n

mol

/ml)

r = 0.65, P < 0.001

CO-Hb (%)

0

1

2

3

Healthy subjects Cirrhosis without SBP Cirrhosis with SBP

D. De Las Heras, et al. Hepatology 2003 ; 38 : 452-459.

* = P < 0.01 vs the other groups

Carbon monoxide production in patients with cirrhosis with and without spontaneous bacterial peritonitis (SBP)

*


Peripheral arterial vasodilation “hypothesis”

Further splanchnic arterial vasodilation

Portal hypertension/liver failure

Further reduction of effective circulating volume

Severe renal arterial vasoconstriction

Maximal activation of endogenous vasocontrictor systems

RW. Schrier, et al. Hepatology 1988 ; 8 : 1151-1157.

Chronic liver failure (CLF)

Further increased release of NO, CO and other vasodilators

Bacterial infections

Plasma renin activity (ng/ml/hr)

0,0

5,0

10,0

15,0

20,0

SBP with HRS SBP without HRS

M. Navasa, et al. Hepatology 1998 ; 27 : 1227-1232.

P < 0.05


Characteristics of patients with cirrhosis and SBP-precipitated HRS


HRS after SBP resolution

No HRS after SBP resolution

P

MAP (mm Hg) 738 838 < 0.025

SVR (dyn sec/cm ) 1268320 968226 N.S.

CO (l/min) 4.60.7 6.82.0 < 0.01

RAP (mm Hg) 4.62.7 4.11.7 N.S.

PCWP (mm Hg) 7.4 2.6 7.02.3 N.S.

HR (bpm) 879 7916 N.S.

5

Systemic heamodynamics before and after the onset of HRS after the resolution of SBP

L. Ruiz-del-Arbol, et. al. Hepatology 2003 ; 38 : 1210-1218.


Baseline At the diagnosis of HRS

P

MAP (mm Hg) 809 757 < 0.001

HVPG (mm Hg) 19.53.0 20.04.0 < 0.005

SVR (dyn sec/cm ) 1158285 1096327 N.S.

CO (l/min) 6.01.2 5.41.3 < 0.001

RAP (mm Hg) 6.92.6 5.72.2 < 0.05

PCWP (mm Hg) 9.2 2.6 7.52.6 < 0.001

Systemic heamodynamics before and after the onset of type 1 HRS in patients with cirrhosis and ascites without a precipitating factor


5


Circulatory dysfunction in HRS

Splanchnic arterial vasodilation

Cardiac output

Cirrhosis Ascites Type 1 HRS

Time

Cha

nges

V. Arroyo, et. al. J. Hepatol. 2007 ; 46 : 935-946.

EFFECTIVE CIRCULATING VOLUME

Portal pressure (mm Hg)

0

10

20

30

At diagnosis of SBP After resolution of SBP

L. Ruiz-del-Arbol. et. al. 2003 ; 38 : 1210-1218.

Pathophysiology of HRS precipitated by SBP


HRS HRS

No HRS No HRS

* = P < 0.025 vs value at diagnosis*

Portal pressure (mm Hg)

0

5

10

15

20

25

30

35

Before HRS HRS

Pathophysiology of HRS non precipitated by SBP


* = P < 0.05 vs value before HRS *


Hepatic blood flow (ml/nin)

0

250

500

750

1000

1250

1500

Before HRS HRS

Pathophysiology of HRS non precipitated by SBP


* = P < 0.005 vs value before HRS

*



Outcome variableCefotaxime(n° = 63)

Cefotaxime plus albumin (n° = 63) P

Renal failure n° (%) 21 (33%) 6 (11%) < 0.002

Death in hospital n° (%) 18 (29%) 6 (10%) < 0.01

Death at 3 months n° (%) 26 (41%) 14 (22%) < 0.03

Effects of albumin infusion on morbility and mortality due to SBP

P. Sort, et al. N. Engl. J. Med. 1999 ; 341 : 403-409.

Plasma renin activity (ng/ml/h)

0,00

5,00

10,00

15,00

20,00

basal 3 days 6 days 9 days

cefotaxime + albumin cefotaxime

* = P < 0.001

* #*

# = P < 0.005

P. Sort, et al. N. Engl. J. Med. 1999 ; 341 : 403-409.


Cardiac index (l/ml/m2)

0

2

4

6

At diagnosis of SBP At resolution of SBP

cefotaxime + albumin cefotaxime

*

* = P < 0.025 vs other group

J. Fernandez, et al. J. Hepatol. 2004 ; 41 : 384-390.


Mean level, µM

Free nitric oxide 0.0034 ± 0.00058

S-nitrosothiol 7.19 ± 5.73

S-nitrosoprotein 7.92 ± 5.45

Mean plasma levels of nitric oxide and S-nitrosothiols in humans

J. S. Stamler, et al. Proc. Natl. Acad. Sci 1992 ; 89 : 7674-7677.


0

25

50

75

100

At diagnosis of SBP on day 4

albumin hydroxyethyl starch

** = P < 0.05 vs value at diagnosis of SBP

J. Fernandez, et al. Hepatology. 2005 ; 42 : 627-634.

Effects of albumin vs hydroxyethyl starch on serum levels of nitrates and nitrites in cirrhotic patients with spontaneous

bacterial peritonitis

dyn

sec•

cm-5


Effects of albumin on expression of inducible NOS (iNOS) in heart of septic mice

Albumin reduces iNos expression in heart

Albumin reduces NO overproduction in heart

Albumin reduces NO overproduction in lung

F. Meziani, et al. Am. J. Pathol. 2007 ; 171 : 1753-1761.

ALBUMIN IN SEPSIS

Albumin β-adgrenergic signaling in cardiac tissue

ALBUMIN IN SEPSIS

0

40

80

120

Dose-responses to isoproterenol in isolated left ventricular papillary muscles from bile duct ligated- (BLD) rats and sham-

operated rats.

H. Liu, et al. Gastroenterology 2000 ; 118 : 937-944.

(Con

trac

tility

% o

f bas

al)

10 10 10 10- 8 - 7 - 6 - 5

BLD

Sham

BLD + L-Name

Isoproterenol (M)


Effects of albumin on cardiac contractility in cirrhotic rats

P. Angeli et al. AALSD 2007

-10.0 -9.5 -9.0 -8.5 -8.0

0

5

10

15

20

25

L

VD

P (m

m H

g)

Control

Cirrhotic + albumin

Cirrhotic

Log . Isoproterenol

* = P < 0.01

**

ALBUMIN AND OXIDATIVE STRESS

Albumin β-adgrenergic signaling in cardiac tissueHepatorenal syndrome (HRS)

2- AR 1- ARACGαs Gαs

Gαi

cAMP

PKA

Troponin I

RGS2

PDE2a

Ca2+

Myofibril

L-type C a2+

Ca 2+

SR

PLN

(-) (-)

(+)

(+)

(+)

(-)

(+)

(+)

β-adgrenergic signaling in cardiac tissueHepatorenal syndrome (HRS)

G. Ceolotto, et al. Hepatology 2008 (in press).

0

1

2

3

4

Gen

e E

xpre

ssio

n (∆

∆Ct)

RGS2 PDE2A Gαi2 Adcy3

Control ratsRats with cirrhosis

*

*

*

*

* = p < 0.01 vs controll

Effects of albumin on β-adgrenergic signaling in cardiac tissue

G. Ceolotto, et al. Hepatology 2008 (in press).

Rats with cirrhosis plus albumin

0

1

2

3

4

P. Angeli et al. AALSD 2007

*

P < 0.01 vs control


0

25

50

75

At diagnosis of SBP At resolution of SBP

albumin hydroxyethyl starch

*

* = P < 0.01 vs value at diagnosis of SBP

J. Fernandez, et al. Hepatology. 2005 ; 42 : 627-634.

Effects of albumin vs hydroxyethyl starch on cardiac function in cirrhotic patients with spontaneous bacterial peritonitis

g m

/m2


• TIPS

• Vasoconstrictors plus albumin

• Extracorporeal liver/renal support

The therapeutic approaches to HRSHepatorenal syndrome (HRS)

0

5

10

15

20

25

Basal Day 5 Day 10 Day 20

* = P < 0.01, ** = P < 0.005 vs basal

**

Plasma renin activity (ng/ml/hr)

Effects of midodrine plus octreotide and albumin in cirrhotic patients with ascites and HRS

P. Angeli , et al. Hepatology 1999 ; 29 : 1690-1697.

**

*


Pharmacologic therapy for HRS (1)

• Albumin (20-40 g/day intravenously) • Terlipressin (0.5-2 mg/4hr or 2-12 mg/24hr

intravenously)

J. Uriz, et al. J. Hepatol. 2000 ; 33 : 43-48.


P. Angeli, et al. Aliment. Pharmacol. Ther. 2006 ; 23 : 75-84.

Pharmacologic therapy for HRS (2)Hepatorenal syndrome (HRS)

• Albumin (20-40 g/day, intravenously) • Midodrine (7.5-12.5 mg t.i.d, orally)• Octreotide (100-200 µg t.i.d, subcutaneously)

P. Angeli, et al. Hepatology 1999 ; 29 : 1690-1697.

• Albumin (20-40 g/day, intravenously) • Noradrenalin (0.5-3 mg/hr, intravenously)

C. Duvoux, et al. Hepatology 2002 ; 36 : 374-380.C. Alessandria, et al. J. Hepatol. 2007 ; 47 : 499-505.

F. Wong, et al. Hepatology 2004 ; 40 : 55-64.

Probability of survival in cirrhotic patients with ascites and type 1 HRS tretaed with terlipressin and albumin vs albumin


0

0,2

0,4

0,6

0,8

1

0-15 days 15-30 days 30-60 days 60-90 days 90-180 days

S. Neri, et al. Dig. Sis. Sci. 2008 ; 53 : 830-835.

Terlipressin plus albumin

Albumin

P < 0.0001

Terlipressin and albumin Albumin Terlipressin

and albuminPlacebo and

albumin

Response (%) 43.5* 8.7 34# 13

Survival (%) At 3 months

27At 3 months

19At 6 months

13At 6 months

9

Terlipressin and albumin vs albumin in cirrhotic patients with ascites and type 1 HRS in two controlled clinical trials

Spain Trial (n° = 45)1 USA Trial (n° = 112)2

* = p <0.025 ; # = p < 0.01

2) A. Sanyal, et al. Gastroenterology 2008 ; 134 : 1360-1368.

1) M. Martin-Llhai, et al. Gastroenterology 2008 ; 134 : 1352-1359


0

0,2

0,4

0,6

0,8

1%

Predictive value of Child-Pugh score (CPT) on survival in patients treated with terlipressin and albumin for Type 1 hepatorenal syndrome

30 90

CPT < 11

CPT 11P < 0.025

60 days

R. Ortega, et al. Hepatology 2002 ; 36 : 941-948.


0

0,2

0,4

0,6

0,8

1%

Recovery of renal function according to the use of albumin

2 4 10 12

Terlipressin plus albumin

Terlipressin

P < 0.05

6 8 days

R. Ortega, et al. Hepatology 2002 ; 36 : 941-948.


Terlipressin and albumin Albumin Terlipressin

and albuminPlacebo and

albumin

Response (%) 43.5* 8.7 34# 13

Survival (%) At 3 months

27At 3 months

19At 6 months

13At 6 months

9

Terlipressin and albumin vs albumin in cirrhotic patients with ascites and type 1 HRS in two controlled clinical trials

Spain Trial (n° = 45)1 USA Trial (n° = 112)2

* = p <0.025 ; # = p < 0.01

2) A. Sanyal, et al. Gastroenterology 2008 ; 134 : 1360-1368.

1) M. Martin-Llhai, et al. Gastroenterology 2008 ; 134 : 1352-1359


Effects of terlipressin on systemic haemodynamics and regional blood flow in cirrhosis

M. Kiszka-Kanowitz, et al. Scand. J. Gastroenterol. 2004 ; 5 : 486-492.

Baseline After terlipressin P

Thorax blood volume (ml) 1471276 1564321 < 0.0025

Stroke volume (ml) 128 35 12340 N.S.

Mean arterial pressure (mm Hg) 8014 9514 < 0.0025

Systemic vascular resistance (dyn • s • m-5) 750 223 1043 321 <0.001


Cardiac output in cirrhotic patients according to the Child-Pugh-Turcotte class

3000

6000

9000

12000

15000

Class A Class B Class C

Basal After i.v. albumin (40 g)

K. Brinch, et al. J. Hepatol. 2003 ; 39 : 24-31.

* = P < 0.025

* *

(ml/min)

* ** * = P < 0.01


Effects of terlipressin on systemic haemodynamics and regional blood flow in cirrhosis

M. Kiszka-Kanowitz, et al. Scand. J. Gastroenterol. 2004 ; 5 : 486-492.

Baseline After terlipressin P

Thorax blood volume (ml) 1471276 1564321 < 0.0025

Stroke volume (ml) 128 35 12340 N.S.

Mean arterial pressure (mm Hg) 8014 9514 < 0.0025

Systemic vascular resistance (dyn • s • m-5) 750 223 1043 321 <0.001


0

1

2

3

-10 -9 -8 -7 -6

Effects of inhibition of inducibile nitric oxide synthesis by L-NIL on the contractile responses to phenylephrine (PHE) in isolated

aortas in LPS-treated cirrhotic rats

* = P < 0.05

R. Moreau et al. Hepatology 2002 ; 36 : 1070-1078.


Con

trac

t ion

( g)

L-NIL placebo

**

*

(log M PHE)

Effects of terlipressin on LPS increase in inducible nitric oxide synthesis m RNA (iNOS) in cirrhotic aortas

0

0,05

0,1

0,15

0,2

Control LPS + placebo LPS + terlipressin

* = P < 0.05 vs other groups*

(ratio iNOS/GAPDH)

Hepatorenal syndrome (HRS) and spontaneous bacterial peritonitis (SBP)

R. Moreau et al. Hepatology 2002 ; 36 : 1070-1078.

Controls

Albumin + LPS

Saline + LPS

o LPS

Vascular contraction to phenyleprhine (Pe) in mesenteric arteriola of septic mice


Albumin in sepsis

Effects of albumin on expression of inducible NOS (iNOS) in aorta of septic mice

Quantification for NO synhesis


Immunohistochemical staining for iNOS

Control LPS Albumin + LPS

Albumin in sepsis

0

0,2

0,4

0,6

0,8

1%

Probability of survival in patients treated for Type 1 hepatorenal syndrome according to improvement of renal function

30 90

Responders

Non respondersP < 0.005

60 days


M. Martin-Llhai, et al. Gastroenterology 2008 ; 134 : 1352-1359.

Events HRS NO-HRS P

5 year survival 60 % 65 % <0.005

Days in ICU post-LT

18 23 6 11 <0.001

Days in Hospital post-LT

42 34 27 18 <0.001

Dyalisis post-LT

35 % 5 % <0.001

Impact of hepatorenal syndrome on the outcome after liver transplanatation

T.A. Gonwa, et al. Transplantation 1995 ; 59 : 361-365.


Events HRS-treated NO-HRS P

3 year survival 100 % 83 % N.S.

Days in ICU 6 1 8 1 N.S.

Days in Hospital

27 3 31 2 N.S.

% of renal failure after LT

22 % 30 % N.S.

Impact of pre-transplant treatment of hepatorenal syndrome on the outcome after liver transplantation

T. Restuccia, et al. J. Hepatol. 2004 ; 40 : 140-146.


• Type 1 HRS is often precipitated by bacterial infections and overall by subdiaphramatic bacterial infections.

• A reduced cardiac output can contribute to the onset of type 1 HRS.

• Type 1 HRS precipitated by bacterial infections may be effectively prevented using albumin together with the antibiotic treatment.

• Vasoconstrictors and albumin are effective in the treatment of type 1 HRS.

• The use of vasoconstrictors and albumin ameliorates the outcome of LT in patients with Type 1 HRS.

Summary

P. Angeli, Aliment. Pharmacol. Ther. 2004 ; 20 : 44-46.


hepatorenal syndrome

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