These findings contrast sharply with those of seven
studies in patients with type-1 HRS not receiving specific
treatment or treated with plasma volume expansion alone
or associated with vasodilators (dopamine) or octreotride
or
with
peritoneovenous
shunting.
23,24,56,66,73,76,77
Reversal of HRS was observed in only 4 out of the
137 patients (2.9%) included in these studies. Survival
data were recorded in 13 studies (8 using vasoconstrictors
and 5 using other treatments). Forty (41.6%) and
29 (30%) of the 96 patients with type-1 HRS treated
with vasoconstrictors were alive 1 and 3 months after
treatment, respectively. The corresponding figures in
65 patients receiving other treatments were 2 (3%) and
0 (0%), respectively. Thirty-four patients treated with
vasoconstrictors reached liver transplantation.
A retrospective survey in 99 patients with type-1
HRS admitted to 22 hospitals in France and treated with
terlipressin (all cases) and albumin (70% of cases) showed
a rate of improvement in renal function of 58%.
78
The
probability of survival was 40% at 1 month and 22% at
3 months. Improvement of survival was related to reversal
of HRS. Thirteen patients received a liver transplant.
This study, which reflects what occurs in regular clinical
practice, confirms the results previously described in
several pilot studies including short series of patients.
Two randomized controlled studies finished re-
cently comparing albumin versus albumin plus terlipres-
sin in patients with type-1 HRS (Sanyal et al and
Guevara et al, unpublished results), and they confirm
the results obtained in the pilot studies. Reversal of HRS
was significantly more frequent in patients treated with
terlipressin and albumin. On the other hand, survival of
patients responding to treatment was significantly longer
than that of patients not responding to treatment or
treated with albumin alone.
These studies clearly indicate that vasoconstrictors
associated with I.V. albumin should be recommended
Figure 5 HRS as a part of a multiorgan failure. A-II, angiotensin-II; NE, norepinephrine; ADH, antidiuretic hormone; HRS,
hepatorenal syndrome.
90
SEMINARS IN LIVER DISEASE/VOLUME 28, NUMBER 1
2008
for the management of patients with type-1 HRS since
they normalize serum creatinine in a high proportion of
patients and may improve survival. Terlipressin has been
the most widely used vasoconstrictor agent in type-1
HRS. It is very effective and is associated with a low
incidence of side effects. The efficacy of the association of
oral midodrine and I.V. or subcutaneous octreotide is
probably due exclusively to the vasoconstrictor effect of
midodrine. Noradrenaline has also been shown to be
effective and safe and there is a randomized controlled
trial in a small number of patients with type-1 and type-2
HRS (mainly type-2) indicating that it is as effective as
terlipressin.
75
However, whereas there is much experi-
ence with terlipressin, noradrenaline and midodrine have
been used only in few studies. Based on these consid-
erations, terlipressin should be the drug of choice for the
treatment of type-1 HRS. Reversal of type-1 HRS in two
pilot studies in which terlipressin was given alone (7 out
of 28 patients, 25%)
69,71
was lower than that observed in
the studies in which vasoconstrictors were associated with
I.V. albumin, suggesting that albumin is an important
component in the pharmacological treatment of type-1
HRS. Two recent studies
16,79
suggest that the beneficial
effect of albumin on circulatory and renal function in
patients with type-1 HRS is related not only to the
expansion of the plasma volume but also to a direct vaso-
constrictor effect on the peripheral arterial circulation.
Terlipressin dosage should be progressive, start-
ing with 0.5 to 1 mg/4 to 6 h. If serum creatinine does
not decrease by more than 30% in 3 days, the dose should
be doubled. The maximal dose of terlipressin has not
been defined, although there was consensus that patients
not responding to 12 mg/day will not respond to higher
doses. Albumin should be given starting with a priming
dose of 1 g/kg of body weight followed by 20 to 40 g/day.
It is advisable to monitor central venous pressure.
In patients responding to therapy, treatment should
be continued until normalization of serum creatinine
(< 1.5 mg/dL).
Transjugular Intrahepatic Portosystemic Shunt
Three pilot studies have evaluated TIPS in type-1
HRS.
74,80,81
In the first study,
80
14 patients with type-
1 HRS (12 with alcoholic cirrhosis, 9 with active
alcoholism) and 17 with refractory ascites (some of
them with type-2 HRS) not suitable for liver trans-
plantation were treated with TIPS. Patients with bilir-
ubin > 15 mg/dL, Child-Pugh score > 12 points, or
hepatic encephalopathy were excluded. Eleven out of the
31 patients developed de novo hepatic encephalopathy or
deterioration of previous hepatic encephalopathy. The
3-, 6-, and 12-month survival rates in patients with type-
1 HRS were 64%, 50%, and 20%, respectively. The
second study
81
was performed in 7 patients (4 alcoholics)
with type-1 HRS and a Child-Pugh score < 12 points.
Marked decrease in serum creatinine was observed in
6 patients and reversal of HRS in 4. Five patients
developed episodes of hepatic encephalopathy after
TIPS but they responded satisfactorily to medical treat-
ment. Five patients were alive after 1 month of TIPS but
only 2 after 3 months. The third study
74
was performed
in 14 patients (13 with alcoholic cirrhosis) with type-1
HRS treated initially with vasoconstrictors (midodrine
and octreotide) plus albumin. Reversal of HRS was
obtained in 10 patients. TIPS devices were subsequently
inserted in 5 of these 10 patients who had bilirubin
<
5 mg/dL, international normalized ratio < 2, and
Child-Pugh score < 12 points. Normalization of GFR
was obtained in all cases and patients were alive between
6 to 30 months after TIPS. TIPS, therefore, is effective
in normalizing serum creatinine in a significant propor-
tion of patients with cirrhosis and severe azotemia and is
an alternative treatment to vasoconstrictors in type-1
HRS.
Extracorporeal Albumin Dialysis
Three pilot studies including 29 patients (26 with type-1
HRS and 21 with alcoholic cirrhosis and/or severe
acute alcoholic hepatitis) aimed at assessing molecular
adsorbents recirculating system (MARS) in patients
with type-1 HRS have been reported.
82–84
Since
MARS incorporates a standard dialysis machine or a
continuous veno-venous hemofiltration monitor and
GFR was not measured, it is not possible to know the
effect of this treatment on renal function. The decrease
in serum creatinine observed in most patients could be
related to the dialysis process. However, clear beneficial
effects on systemic hemodynamics and on hepatic ence-
phalopathy were observed. The survival rate 1 and
3 months after treatment was 41% (12 patients) and
34% (10 patients), respectively. A recent randomized
controlled trial in a large series of cirrhotic patients with
hepatic encephalopathy,
85
many of them with HRS, has
demonstrated a clear beneficial effect of MARS on the
rate and time of recovery of encephalopathy. Since the
end point of this trial was encephalopathy, no conclusion
can be obtained in relation to survival.
TREATMENTS FOR TYPE-2 HRS
In patients with type-2 HRS, most of whom may reach a
liver transplant, the main clinical problem is refractory
ascites. Therefore, treatment of type-2 HRS should
consider not only survival but also the control of ascites.
Transjugular Intrahepatic Portosystemic Shunt
Five trials comparing TIPS versus paracentesis in pa-
tients with refractory and/or recidivant ascites have so far
been published.
52,86–89
In total, 172 patients were
PATHOGENESIS AND TREATMENT OF HEPATORENAL SYNDROME/ARROYO ET AL
91
treated by TIPS. Unfortunately, very few of these
patients had HRS. Patients with serum creatinine
>
3 mg/dL were excluded from three studies. Only
two studies gave the number of patients with HRS
included (6 out of 53). Finally, mean serum creatinine
was below 1.5 mg/dL in the groups treated by TIPS in
these five studies. Therefore, data from these five trials
are not valid for the assessment of TIPS in the manage-
ment of patients with type-2 HRS.
There are only two pilot studies specifically
assessing TIPS in type-2 HRS.
80,90
In one study,
90
a
significant reduction of serum creatinine (from 2.1 Æ 0.3
to 1.4 Æ 0.3 mg/dL 1 month after TIPS) was observed in
eight out of nine patients. This was associated with a
significant improvement in the control of ascites. Four of
these patients died, two within the first month and two
12 and 14 months after the procedure. The remaining
five patients had longer survival. No data were given on
the type and rate of complications associated with TIPS.
A second study included 14 patients with type-1 HRS
and 17 with type-2 HRS treated by TIPS.
80
Mean
baseline serum creatinine concentration in patients
with type-2 HRS was only 1.44 Æ 0.3 mg/dL, but
mean creatinine clearance was 28 Æ 14 mL/min. A sig-
nificant improvement in serum creatinine and creatinine
clearance was observed in the whole group of 31 patients
as was as an improvement in the control of ascites in
24 cases. Six patients developed TIPS dysfunction and
11 developed hepatic encephalopathy during follow-up.
The 1-year probability of survival in the 17 patients with
type-2 HRS treated by TIPS was 70%. TIPS is therefore
effective in reversing type-2 HRS, although more data
on complication rate and survival are needed before
advocating a widespread use of this procedure. The
introduction of covered stents should be a stimulus to
re-evaluate the role of TIPS in the management of
refractory ascites and type-2 HRS.
Vasoconstrictors and Albumin
Three pilot studies provided data on the effect of
terlipressin plus albumin in 39 patients with type-2
HRS.
67,71,90
Reversal of HRS was obtained in most
cases (21 cases, 80%). In one of these studies
90
the course
of renal function after stopping treatment was assessed in
11 patients and HRS recurred in all cases. There were no
data on survival. This high prevalence of HRS recur-
rence has been confirmed recently in a second study by
Alessandria et al.
75
In a randomized comparative study
of terlipressin versus noradrenaline in 22 patients with
type-1 and type-2 HRS, reversal of HRS was obtained in
17 patients. HRS recurrence was observed in 8 patients,
5 with type-2 HRS. The current state of knowledge on
vasoconstrictor therapy in type-2 HRS is therefore very
poor. It appears to be not as effective as in type-1 HRS
due to the high rate of HRS recurrence.
PREVENTION OF HRS
Three randomized controlled studies in large series of
patients have shown that HRS can be prevented in
specific clinical settings. In the first study,
56
the admin-
istration of albumin (1.5 g/kg I.V. at infection diagnosis
and 1 g/kg I.V. 48 hours later) to patients with cirrhosis
and SBP markedly reduced the incidence of circulatory
dysfunction and type 1 HRS (10% incidence of type-1
HRS in patients receiving albumin versus 33% in the
control group). Hospital mortality rate (10% versus 29%)
and the 3-month mortality rate (22% versus 41%) were
lower in patients receiving albumin.
The second study was performed in cirrhotic
patients at a high risk of developing SBP and type-1
HRS.
91
Primary prophylaxis of SBP using long-term
oral norfloxacin was given to 35 patients with low
protein ascites (< 15 g/L) and advanced liver failure
(Child-Pugh score ! 9 points with serum bilirubin
! 3 mg/dL) or impaired renal function (serum creatinine
level ! 1.2 mg/dL; blood urea nitrogen level ! 25 mg/
dL, or serum sodium level 130 mEq/L). Thirty-three
patients received placebo. Norfloxacin administration
was associated with a significant decrease in 1-year
probability of development of SBP (7% versus 61%)
and type-1 HRS (28% versus 41%) and with a significant
increase in the 3-month and 1-year probability of sur-
vival (94% versus 62% and 60% versus 48%, respectively).
In this study, patients developing SBP received
I.V. albumin (1.5 g/kg I.V. at infection diagnosis and
1 g/kg I.V. 48 hours later) and only 1 patient developed
HRS associated with SBP. Type-1 HRS, however, was
the principal cause of death in this study. Therefore, oral
norfloxacin prevented type-1 HRS in these patients by
a mechanism different from the prevention of SBP.
Several studies have shown that in patients with cirrhosis
in addition to bacterial translocation there is transloca-
tion of products of bacterial origin (endotoxin, bacterial
DNA) that induce a systemic inflammatory reaction,
activation of nitric oxide, and impairment in circulatory
function.
92–94
The administration of oral norfloxacin in
these patients prevents this translocation of bacterial
products and improves circulatory function with a sig-
nificant increase in arterial pressure and systemic vascular
resistance and suppression of plasma renin activity and
plasma norepinephrine concentration.
92,94
An improve-
ment in circulatory function, which makes patients less
susceptible to type-1 HRS, is, therefore, the most likely
mechanism of the beneficial effect of oral norfloxacin
found in this study.
In the third study,
95
the administration of the
tumor necrosis factor inhibitor pentoxyfilline (400 mg
three times a day) to patients with severe acute alcoholic
hepatitis reduced the occurrence of HRS (8% in the
pentoxyfilline group versus 35% in the placebo group)
and the hospital mortality (24% versus 46%, respec-
tively). Because bacterial infections and acute alcoholic
92
SEMINARS IN LIVER DISEASE/VOLUME 28, NUMBER 1
2008
hepatitis are important precipitating factors of type 1
HRS, these prophylactic measures may decrease the
incidence of this complication.
ABBREVIATIONS
GRF
glomerular filtration rate
HRS
hepatorenal syndrome
MARS
molecular adsorbents recirculating system
SBP
spontaneous bacterial peritonitis
TIPS
transjugular intrahepatic portosystemic shunt
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