Hepatorenal syndrome

1
Hepatorenal syndrome
P. Angeli Dept. of Clinical and Experimental
Medicine University of Padova (Italy)
TReviso 8 Giugno 2009
2
Hepatorenal syndrome (HRS)
Definition of HRS
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.
F. Salerno, et al. Gut 2007 56 1310-1318.
3
Hepatorenal syndrome (HRS)
FUNCTIONAL RENAL ABNORMALITIES IN CIRRHOSIS
Abnormality
Clinical consequence

• Sodium retention
• Water retention
• Renal vasoconstriction

• Ascites and edema
• Dilutional hyponatremia
• Hepatorenal syndrome

4
Hepatorenal syndrome (HRS)
Peripheral arterial vasodilation hypothesis
Portal hypertension/liver failure
Increased release of NO, CO and other vasodilators
Splanchnic arterial vasodilation
Reduction of effective circulating volume
Activation of endogenous vasocontrictor systems
Renal functional abnormalities
RW. Schrier, et al. Hepatology 1988 8
1151-1157.
5
Hepatorenal syndrome (HRS)
Acute renal failure in patients with cirrhosis
and ascites

1. Acute tubular necrosis (41.7)
2. Prerenal failure (38)
3. Hepatorenal syndrome (20)
4. Postrenal failure (0.3)

R. Moreau, et al. Hepatology 2003 37
233-243.
6
Hepatorenal syndrome (HRS)
New Diagnostic Criteria

• Cirrhosis with ascites
• Serum creatinine gt 133 µmol/l (1.5 mg/dl)
• 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
• Absence of shock
• No current or recent treatment with nephrotoxic
  drugs
• Absence of parenchimal disease as indicated by
  proteinuria gt500 mg/day, microhematuria (gt50 red
  blood cells per high power field) and/or abnormal
  renal ultrasonography.

F. Salerno, et al. Gut 2007 56 1310-1318.
7
Hepatorenal syndrome (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 gt 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
F. Salerno, et al. Gut 2007 56 1310-1318.
8
Hepatorenal syndrome (HRS)
Probability of survival in patients with HRS

P lt 0.001
Type 2 HRS
Type 1 HRS
2
4
8
6
months
10
12
P. Gines, et al. Lancet 2003 362 1819-1827.
9
Hepatorenal syndrome (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 gt 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
F. Salerno, et al. Gut 2007 56 1310-1318.
10
Hepatorenal syndrome (HRS)
Precipitating events

• Spontaneous bacterial peritonitis
• Paracentesis without plasma expansion
• Gastrointestinal hemorrhage
• Alcoholic hepatitis
• Unknown

11
Hepatorenal syndrome (HRS)
Prevalence and types of renal failure (RF)
precipitated by spontaneous bacterial peritonitis
(SBP)
Cirrhotic patients with ascites and SBP (n 116)

• 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

n


P. Angeli, et al. Aliment. Pharmacol. Ther. 2006
23 75-84.
12
Prevalence of renal failure in the different
types of bacterial infections in patients with
cirrhosis and ascites
Hepatorenal syndrome (HRS)
()
P lt 0.0001
P lt 0.0001
Subdiaphramatic Infections
S. Fasolato, et al. Hepatology 2007 45
223-229.
13
Hepatorenal syndrome (HRS)
Predictive factors of the deveopment of renal
failure in cirrhotic patients with ascites

• High MELD score
• High peak count of neutrophyl leukocyte in blood
• Lack of resolution of infection

S. Fasolato, et al. Hepatology 2007 45
223-229.
14
Hepatorenal syndrome (HRS)
Plasma levels of endotoxin in patients with
cirrhosis with and without SBP
P lt 0.01 vs cirrhosis without SBP
pg/ml

M. Navasa, et al. Hepatology 1998 27
1227-1232.
15
Hepatorenal syndrome (HRS)
Correlation between serum level of nitrite and
nitrate (NOx) and plasma level of endotoxin in
patients with cirrhosis

r 0.65, P lt 0.001



NOx (nmol/ml)


































50
100
150
200
250
Endotoxin (pg/ml)
C. Guarner et al. Hepatology 1993 18
1139-1148.
16
CO-Hb ()
Hepatorenal syndrome (HRS)
Carbon monoxide production in patients with
cirrhosis with and without spontaneous bacterial
peritonitis (SBP)
P lt 0.01 vs the other groups

D. De Las Heras, et al. Hepatology 2003 38
452-459.
17
Chronic liver failure (CLF)
Peripheral arterial vasodilation hypothesis
Portal hypertension/liver failure
Severe renal arterial vasoconstriction
RW. Schrier, et al. Hepatology 1988 8
1151-1157.
18
Plasma renin activity (ng/ml/hr)
Hepatorenal syndrome (HRS)
Characteristics of patients with cirrhosis and
SBP-precipitated HRS
P lt 0.05
M. Navasa, et al. Hepatology 1998 27
1227-1232.
19
Hepatorenal syndrome (HRS)
Systemic heamodynamics before and after the onset
of HRS after the resolution of SBP
HRS after SBP resolution No HRS after SBP resolution P
MAP (mm Hg) 73?8 83?8 lt 0.025
SVR (dyn sec/cm ) 1268?320 968?226 N.S.
CO (l/min) 4.6?0.7 6.8?2.0 lt 0.01
RAP (mm Hg) 4.6?2.7 4.1?1.7 N.S.
PCWP (mm Hg) 7.4 ?2.6 7.0?2.3 N.S.
HR (bpm) 87?9 79?16 N.S.
5
L. Ruiz-del-Arbol, et. al. Hepatology 2003 38
1210-1218.
20
Hepatorenal syndrome (HRS)
Systemic heamodynamics before and after the onset
of type 1 HRS in patients with cirrhosis and
ascites without a precipitating factor
Baseline At the diagnosis of HRS P
MAP (mm Hg) 80?9 75?7 lt 0.001
HVPG (mm Hg) 19.5?3.0 20.0?4.0 lt 0.005
SVR (dyn sec/cm ) 1158?285 1096?327 N.S.
CO (l/min) 6.0?1.2 5.4?1.3 lt 0.001
RAP (mm Hg) 6.9?2.6 5.7?2.2 lt 0.05
PCWP (mm Hg) 9.2 ?2.6 7.5?2.6 lt 0.001
5
L. Ruiz-del-Arbol, et. al. Hepatology 2005 62
439-447.
21
Hepatorenal syndrome (HRS)
Circulatory dysfunction in HRS
Cardiac output
Changes
Splanchnic arterial vasodilation
Cirrhosis
Ascites
Type 1 HRS
Time
V. Arroyo, et. al. J. Hepatol. 2007 46
935-946.
22
Portal pressure (mm Hg)
Hepatorenal syndrome (HRS)
Pathophysiology of HRS precipitated by SBP
P lt 0.025 vs value at diagnosis

HRS
HRS
No HRS
No HRS
L. Ruiz-del-Arbol. et. al. 2003 38 1210-1218.
23
Portal pressure (mm Hg)
Hepatorenal syndrome (HRS)
Pathophysiology of HRS non precipitated by SBP
P lt 0.05 vs value before HRS

L. Ruiz-del-Arbol, et. al. Hepatology 2005 62
439-447.
24
Hepatic blood flow (ml/nin)
Hepatorenal syndrome (HRS)
Pathophysiology of HRS non precipitated by SBP
P lt 0.005 vs value before HRS

L. Ruiz-del-Arbol, et. al. Hepatology 2005 62
439-447.
25
Hepatorenal syndrome (HRS)
Effects of albumin infusion on morbility and
mortality due to SBP
Outcome variable Cefotaxime (n 63) Cefotaxime plus albumin (n 63) P
Renal failure n () 21 (33) 6 (11) lt 0.002
Death in hospital n () 18 (29) 6 (10) lt 0.01
Death at 3 months n () 26 (41) 14 (22) lt 0.03
P. Sort, et al. N. Engl. J. Med. 1999 341
403-409.
26
Plasma renin activity (ng/ml/h)
Hepatorenal syndrome (HRS)
P lt 0.001
P lt 0.005



P. Sort, et al. N. Engl. J. Med. 1999 341
403-409.
27
Cardiac index (l/ml/m2)
Hepatorenal syndrome (HRS)
P lt 0.025 vs other group


J. Fernandez, et al. J. Hepatol. 2004 41
384-390.
28
Mean plasma levels of nitric oxide and
S-nitrosothiols in humans
Hepatorenal syndrome (HRS)
Mean level, µM
Free nitric oxide 0.0034 0.00058
S-nitrosothiol 7.19 5.73
S-nitrosoprotein 7.92 5.45
J. S. Stamler, et al. Proc. Natl. Acad. Sci 1992
89 7674-7677.
29
Hepatorenal syndrome (HRS)
Effects of albumin vs hydroxyethyl starch on
serum levels of nitrates and nitrites in
cirrhotic patients with spontaneous bacterial
peritonitis
P lt 0.05 vs value at diagnosis of SBP


dyn?seccm-5
J. Fernandez, et al. Hepatology. 2005 42
627-634.
30
ALBUMIN IN SEPSIS
Effects of albumin on expression of inducible NOS
(iNOS) in heart of septic mice
Albumin reduces iNos expression in heart
F. Meziani, et al. Am. J. Pathol. 2007 171
1753-1761.
31
ALBUMIN IN SEPSIS
Albumin ß-adgrenergic signaling in cardiac tissue
32
Hepatorenal syndrome (HRS)
Dose-responses to isoproterenol in isolated left
ventricular papillary muscles from bile duct
ligated- (BLD) rats and sham-operated rats.
Sham
BLD L-Name
(Contractility of basal)
BLD
10
10
10
10
- 8
- 7
- 6
- 5
Isoproterenol (M)
H. Liu, et al. Gastroenterology 2000 118
937-944.
33
ALBUMIN AND OXIDATIVE STRESS
Effects of albumin on cardiac contractility in
cirrhotic rats
25
Control
20
Cirrhotic albumin

15

Cirrhotic
LVDP (mm Hg)
10
5
P lt 0.01
?
0
-10.0
-9.5
-9.0
-8.5
-8.0
Log . Isoproterenol
P. Angeli et al. AALSD 2007
34
Hepatorenal syndrome (HRS)
Albumin ß-adgrenergic signaling in cardiac tissue
35
Hepatorenal syndrome (HRS)
ß-adgrenergic signaling in cardiac tissue
AC
()
?2- AR
?1- AR
Gas
Gas
(-)
Gai
(-)
RGS2
()
(-)
PDE2a
cAMP
()
()
PKA
PLN
L-type C a2
Troponin I
Ca2
SR
Ca 2
()
Myofibril
G. Ceolotto, et al. Hepatology 2008 (in press).
36
Hepatorenal syndrome (HRS)
Effects of albumin on ß-adgrenergic signaling in
cardiac tissue
p lt 0.01 vs controll
P lt 0.01 vs control

Control rats
Rats with cirrhosis


Gene Expression (??Ct)

RGS2 PDE2A Gai2
Adcy3
G. Ceolotto, et al. Hepatology 2008 (in press).
37
Hepatorenal syndrome (HRS)
Effects of albumin vs hydroxyethyl starch on
cardiac function in cirrhotic patients with
spontaneous bacterial peritonitis
P lt 0.01 vs value at diagnosis of SBP


g ? m/m2
J. Fernandez, et al. Hepatology. 2005 42
627-634.
38
Hepatorenal syndrome (HRS)
The therapeutic approaches to HRS

• TIPS
• Vasoconstrictors plus albumin
• Extracorporeal liver/renal support

39
Effects of midodrine plus octreotide and albumin
in cirrhotic patients with ascites and HRS
Hepatorenal syndrome (HRS)
Plasma renin activity (ng/ml/hr)
P lt 0.01, P lt 0.005 vs basal



P. Angeli , et al. Hepatology 1999 29
1690-1697.
40
Hepatorenal syndrome (HRS)
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.
41
Hepatorenal syndrome (HRS)
Pharmacologic therapy for HRS (2)

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

• 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.
42
Hepatorenal syndrome (HRS)
Probability of survival in cirrhotic patients
with ascites and type 1 HRS tretaed with
terlipressin and albumin vs albumin
Terlipressin plus albumin
P lt 0.0001
Albumin
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.
43
Hepatorenal syndrome (HRS)
Terlipressin and albumin vs albumin in cirrhotic
patients with ascites and type 1 HRS in two
controlled clinical trials

Terlipressin and albumin Albumin Terlipressin and albumin Placebo and albumin
Response () 43.5 8.7 34 13
Survival () At 3 months 27 At 3 months 19 At 6 months 13 At 6 months 9
Spain Trial (n 45)1
USA Trial (n 112)2
p lt0.025 p lt 0.01
1) M. Martin-Llhai, et al. Gastroenterology 2008
134 1352-1359
2) A. Sanyal, et al. Gastroenterology 2008
134 1360-1368.
44
Hepatorenal syndrome (HRS)
Predictive value of Child-Pugh score (CPT) on
survival in patients treated with terlipressin
and albumin for Type 1 hepatorenal syndrome

CPT lt 11
P lt 0.025
CPT ? 11
30
90
60
days
R. Ortega, et al. Hepatology 2002 36 941-948.
45
Hepatorenal syndrome (HRS)
Recovery of renal function according to the use
of albumin

Terlipressin plus albumin
P lt 0.05
Terlipressin
2
4
10
12
6
8
days
R. Ortega, et al. Hepatology 2002 36 941-948.
46
Hepatorenal syndrome (HRS)
Terlipressin and albumin vs albumin in cirrhotic
patients with ascites and type 1 HRS in two
controlled clinical trials

Terlipressin and albumin Albumin Terlipressin and albumin Placebo and albumin
Response () 43.5 8.7 34 13
Survival () At 3 months 27 At 3 months 19 At 6 months 13 At 6 months 9
Spain Trial (n 45)1
USA Trial (n 112)2
p lt0.025 p lt 0.01
1) M. Martin-Llhai, et al. Gastroenterology 2008
134 1352-1359
2) A. Sanyal, et al. Gastroenterology 2008
134 1360-1368.
47
Hepatorenal syndrome (HRS)
Effects of terlipressin on systemic haemodynamics
and regional blood flow in cirrhosis
Baseline After terlipressin P
Thorax blood volume (ml) 1471?276 1564?321 lt 0.0025
Stroke volume (ml) 128 ?35 123?40 N.S.
Mean arterial pressure (mm Hg) 80?14 95?14 lt 0.0025
Systemic vascular resistance (dyn s m-5) 750 ?223 1043 ?321 lt0.001
M. Kiszka-Kanowitz, et al. Scand. J.
Gastroenterol. 2004 5 486-492.
48
Cardiac output in cirrhotic patients according to
the Child-Pugh-Turcotte class
Hepatorenal syndrome (HRS)
(ml/min)

P lt 0.025
P lt 0.01



K. Brinch, et al. J. Hepatol. 2003 39 24-31.
49
Hepatorenal syndrome (HRS)
Effects of terlipressin on systemic haemodynamics
and regional blood flow in cirrhosis
Baseline After terlipressin P
Thorax blood volume (ml) 1471?276 1564?321 lt 0.0025
Stroke volume (ml) 128 ?35 123?40 N.S.
Mean arterial pressure (mm Hg) 80?14 95?14 lt 0.0025
Systemic vascular resistance (dyn s m-5) 750 ?223 1043 ?321 lt0.001
M. Kiszka-Kanowitz, et al. Scand. J.
Gastroenterol. 2004 5 486-492.
50
Hepatorenal syndrome (HRS)
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

Contraction (g)


P lt 0.05
(log M PHE)
L-NIL
placebo
R. Moreau et al. Hepatology 2002 36 1070-1078.
51
Effects of terlipressin on LPS increase in
inducible nitric oxide synthesis m RNA (iNOS) in
cirrhotic aortas
Hepatorenal syndrome (HRS) and spontaneous
bacterial peritonitis (SBP)
(ratio iNOS/GAPDH)
P lt 0.05 vs other groups

R. Moreau et al. Hepatology 2002 36 1070-1078.
52
Albumin in sepsis
Vascular contraction to phenyleprhine (Pe) in
mesenteric arteriola of septic mice
F. Meziani, et al. Am. J. Pathol. 2007 171
1753-1761.
53
Albumin in sepsis
Effects of albumin on expression of inducible NOS
(iNOS) in aorta of septic mice
F. Meziani, et al. Am. J. Pathol. 2007 171
1753-1761.
54
Hepatorenal syndrome (HRS)
Probability of survival in patients treated for
Type 1 hepatorenal syndrome according to
improvement of renal function

Responders
Non responders
P lt 0.005
30
90
60
days
M. Martin-Llhai, et al. Gastroenterology 2008
134 1352-1359.
55
Impact of hepatorenal syndrome on the outcome
after liver transplanatation
Hepatorenal syndrome (HRS)
Events HRS NO-HRS P
5 year survival 60 65 lt0.005
Days in ICU post-LT 18 ? 23 6 ? 11 lt0.001
Days in Hospital post-LT 42 ? 34 27 ? 18 lt0.001
Dyalisis post-LT 35 5 lt0.001
T.A. Gonwa, et al. Transplantation 1995 59
361-365.
56
Impact of pre-transplant treatment of hepatorenal
syndrome on the outcome after liver
transplantation
Hepatorenal syndrome (HRS)
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.
T. Restuccia, et al. J. Hepatol. 2004 40
140-146.
57

Hepatorenal syndrome (HRS)
Summary

• 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.

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