AND WITH HRS - Oslo universitetssykehus

Hepatorenalt syndrom
HRS
Zbigniew Konopski Dr. Med.
Seksjonsleder, Hepatologi
Gastromedisinsk avdeling
Oslo Universitetssykehus
Cirrhosis and Portal Hypertensjon
Garcia-Tsao Hepatology 2008
HRS – Diagnostic criteria
• Cirrhosis with ascites
• Serum creatinine >133 μmol/l (1.5 mg/dl)
• No improvement of serum creatinine (decrease to a
level of ≤133 μmol/l) after at least 2 days with diuretic
withdrawal and volume expansion with albumin; the
recommended dose of albumin is 1 g/kg of body
weight per day 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, microhematuria (>50 red
blood cells per high power field) and/or abnormal renal
ultrasonography
Differential diagnosis between
HRS and ATN
HRS
• Shock excluded
• No resp. to volume
• Urin Na < 20 mmol/L
• FENa < 1
• Granular casts –
• Urin osmolarity < 500
ATN
• Recent shock
• No resp. to volume
• Urin Na > 40 mmol/L
• FENa > 1
• Granular casts +
• Urin osmolarity > 350
Types of HRS
Type 1 HRS : is an acute functional renal failure
accompanied by multiorgan failure that
develops in close temporal relationship to a
precipitating event, commonly an infection
Clinical pattern: acute renal failure
Type 2 HRS: is the extreme expression of this
circulatory dysfunction, which manifests as
slowly progressive functional renal failure
associated with refractory ascites.
Clinical pattern: refractory ascites
F. Salerno, et al. Gut 2007 ; 56 : 1310-1318.
Gines et al. Seminars in Liver Disease 2008
Pathophysiology of Portal Hypertension
Porto-systemic
collaterals:
Spleno-renal
Spleno-caval
Porto-caval
Increased resistance
PORTAL HYPERTENSION
BacTra
NO
v
Varices
Encephalopathy
Splanchnic arterial
Vasodilatation
Renal
vasoconstriction
increase in flow
Increased Card.Out.
v
Hypotension
Effective hypovolvemia
Hyperdynamic
circulation
Activation SNS,, RAA, VP/ADH
Na and Water retention
Hypervolemia
Murray Epstein 1969
Vasoconstriction:
Skin, brain, muscle, liver
”Cirrhotic cardiomyopathy”
Definition
”A cardiac dysfunction in patients with cirrhosis characterised
by impaired contractile responsiveness to stress and/or altered
diastolic relaxation with electrophysiological abnormalities in
”
Impaired cardiac responses to systemic
vasodilatation
the absence of other known cardiac disease
Ring-Larsen et al.
100
10
80
Cardiac Inde x
MAP (mmHg )
7.5
60
5
2.5
40
0
Normals Ascites
HRS
Normals Ascites
Fernandez-Seara et al. 1987
HRS
PLASMA NOREPINEPHRINE IN PATIENTS WITH
ASCITES (II) AND WITH HRS (III)
HRS
3000
Norepinephrine (pg/mL)
2000
1500
1000
Ascites
500
0
I
II
III
Arroyo et al.
Conclusions
Following contributes to HRS:
• Hemodynamic Factors
– Renal vasoconstriction
– Systemic vasodilatation causing lowering of blood pressure
• Activation of the sympathetic nervous system
– Abnormal renal autoregulation
• Cirrhotic cardiomyopathy
– Impaired cardiac responses to systemic vasodilatation
• Increased formation of vasoactive mediators
– NO and others…
Figure 1 Mechanisms leading to type 1 HRS and multiorgan failure in patients with SBP
Arroyo, V. & Fernández, J. (2011) Management of hepatorenal syndrome in patients with cirrhosis
Nat. Rev. Nephrol. doi:10.1038/nrneph.2011.96
Prevention of HRS
•
•
•
•
•
•
Prophylaxis against bacterial infections
Volum expansion with 20% albumin
Judicious use of diuretics
Pentoxyfyllin: ani-TNFalfa effect in ALD
”Early” RRT ?
Avoid use of nephrotoxic drugs:
– Aminoglycosides
– NSAID’s
General initial management of
HRS
•
•
•
•
•
•
•
Treatment of upper GI bleeding
Antibiotic therapy of infection/profylaxis
Rehydration
Stop diuretics
Electrolyte correction (K, Mg, Phosfat)
Correct acid-base abnormalities
Treatment of encephalopathy
(laktulose,Rifaximin)
• Treatment of ascites (paracentesis?)
• Optimalization of renal hemodynamics: (MAP
70-75 mmHg ?)
The therapeutic approaches to HRS
• Liver TX (definitive treatment)
• Vasoconstrictors plus albumin
• TIPS
• Extracorporeal liver/renal support
MARS/ Prometheus / Hemodialysis(CVVHD)
Pharmacological treatment of
HRS
•
•
•
•
•
•
•
•
Dopamine +/- albumin
Terlipressin + albumin
Noradrenalin + albumin
Albumin
N-acetylcysteine
Misoprostol (oral PGE1) + albumin
Endothelin antagonists
Aquaretics: Vasopressin V2-receptor antag
Vasoconstrictors + albumin for HRS
• Albumin (20-40 g/day intravenously)
• Terlipressin (0.5-2 mg/4hr intravenously)
J. Uriz, et al. J. Hepatol. 2000 ; 33 : 43-48.
• 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.
P. Sharma, et al. Am. J. Gastroenterol. 2008 ; 103 : 1689-1697.
Recovery of renal function according
to the use of albumin
%
Terlipressin plus albumin
P < 0.05
Terlipressin
2
4
6
8
10
12
R. Ortega, et al. Hepatology 2002 ; 36 : 941-948.
days
TIPS
Transjugular Intrahepatic Porto-systemic Shunt
”Early” RRT in HRS
• Lack of RCT
• Criteria for ”early” RRT are not established
– Metabolic acidosis, electrolyte imbalance,
volume overload
• CVVHD preferred
• Prolonged need for RRT before TX identify
population where Liver-Kidney TX may be
required
N-Acetylcysteine improves renal function in HRS
Mean serun creatinine
( mol/l)
B
250
A
*
*
200
*
*
*
*
**
150
-2
0
2
Days from NAC
4
6
Lancet 1997.
Holt et al.
The two schedules of administration of terlipressin which were compared:
bolus (Group A) vs continuous intravenous infusion (Group B)
GROUP A
GROUP B
0,5 mg/4 hr (3 mg/day)
2 mg/24 hr
1 mg/4 hr (6 mg/day)
4 mg/24 hr
2 mg/4 hr (12 mg/day)
8 mg/24 hr
12 mg/24 hr
The response to terlipressin was evaluated every 48 hr. The dose was increased if serum
creatinine reduced less than 25% of the basal value. Terlipressin was maintained for a
maximum of 14 days in non responders or partial responders.
Both groups of patients received also albumin (1 g/Kg of body weight at the first day followed
by 20-40 g/day).
P. Angeli, et al. AASLD 2008
Patients with response to treatment
%
100
P = N.S.
80
60
40
20
0
Group A (bolus)
Full response
Group B (infusion)
Partial response
P. Angeli, et al. AASLD 2008
Patients with adverse effects (AEs)
%
100
80
P < 0.05
60
40
20
0
Group A (bolus)
Group B (infusion)
P. Angeli, et al. AASLD 2008
Mean effective daily dose of terlipressin
6
mg/24 hr
P < 0.05
4
2
0
Group A (bolus)
Group B (infusion)
P. Angeli, et al. AASLD 2008
Probability of survival in patients treated for Type 1
hepatorenal syndrome according to improvement of renal
function
%
Responders
Non responders
P < 0.005
30
60
90 days
M. Martin-Llhai, et al. Gastroenterology 2008 ; 134 : 1352-1359.
Impact of pre-transplant treatment of hepatorenal
syndrome on the outcome after liver transplantation
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.
• The main mechanism is a progressive splanchnic arterial
vasodilatation due to the overproduction of vasodilator
molecules. During the initial phases of decompensated
cirrhosis, when the activation of vasoconstrictor systems
is moderate, patients develop sodium retention and
ascites. In subsequent stages, activation of ADH leads to
dilutional hyponatremia. Finally, in the most advanced
phase, when circulatory dysfunction is extreme, the renal
vasodilatory systems are overcome and patients develop
severe renal vasoconstriction and type 2 HRS.
Abbreviations: ADH, antidiuretic hormone; HRS,
hepatorenal syndrome; RAAS, renin–angiotensin–
aldosterone system; SNS, sympathetic nervous system.
Permission obtained from Annals of Hepatology ©
Arroyo, V. & Fernandez, J. Ann. Hepatol. 10, S6–S14
(2011).
Table 3 Functional parameters in patients with nonazotemic cirrhosis and ascites, who did and did not develop type 2 HRS
Arroyo, V. & Fernández, J. (2011) Management of hepatorenal syndrome in patients with cirrhosis
Nat. Rev. Nephrol. doi:10.1038/nrneph.2011.96
Arroyo, V. & Fernández, J. (2011) Management of hepatorenal syndrome in patients with cirrhosis
Nat. Rev. Nephrol. doi:10.1038/nrneph.2011.96
Impact of hepatorenal syndrome on the outcome
after liver transplanatation
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 postLT
42  34
27  18
<0.001
Dialysis postLT
35 %
5%
<0.001
T.A. Gonwa, et al. Transplantation 1995 ; 59 : 361-365.