are important predictors of type-1 HRS.
24
The second study consisted of a longitudinal
investigation of 66 nonazotemic cirrhotic patients with
ascites.
43
Forty percent of patients developed HRS (type
1 or type 2). These patients were studied at inclusion and
following the development of HRS. In the initial study,
those patients who went on to develop HRS had
significantly lower mean arterial pressure and cardiac
output, and significantly higher plasma renin activity and
norepinephrine concentration compared with those who
did not develop HRS. Moreover, those who developed
HRS had a further decrease in arterial pressure and
cardiac output and an increase in renin and norepinephr-
ine without changes in peripheral vascular resistance
Figure 2 Peripheral arterial vasodilation hypothesis and renal dysfunction in cirrhosis. In initial phases, when cirrhosis is
compensated, the increase in splanchnic arterial vasodilation is compensated by an increase in cardiac output (hyperdynamic
circulation). The effective arterial blood volume and the activity of renin-angiotensin (RAAS), sympathetic nervous system
(SNS), and plasma antidiuretic hormone (ADH) are normal despite a reduction in systemic vascular resistance. With the
progression of liver disease, splanchnic arterial vasodilation increases but the cardiac output does not. An effective arterial
hypovolemia therefore develops, leading to activation of the RAAS and SNS and ADH. Systemic vascular resistance does not
decrease due to vasoconstriction of extrasplanchnic organs. Type-2 HRS could be the extreme expression of renal
vasoconstriction.
PATHOGENESIS AND TREATMENT OF HEPATORENAL SYNDROME/ARROYO ET AL
85
(Table 3). These findings strongly suggest that circula-
tory dysfunction in cirrhosis is due to both an increase in
arterial vasodilation and a decrease in cardiac function
(Fig. 3), and that HRS occurs in the setting of severe
reduction in effective arterial blood volume secondary to
an impairment in cardiovascular function. In this study,
baseline increased plasma renin activity and reduced
cardiac output were found to be the only independent
predictors of HRS.
HRS IN CIRRHOSIS IS A COMPLEX
SYNDROME THAT AFFECTS ORGANS
OTHER THAN THE KIDNEY
Traditionally, patients with HRS were considered to
have mainly two different problems, a terminal and
irreversible liver failure due to advanced cirrhosis and a
functional renal failure secondary to renal vasoconstric-
tion. The link between the diseased liver and the failing
kidney was a deterioration in systemic hemodynamics.
Table 3 Chronological Changes of Vasoactive Systems and Cardiovascular Function from Nonazotemic Cirrhosis
with Ascites (NA) to Type-2 HRS*
NA-1
NA-2
At Diagnosis of
Type-2 HRS
Mean arterial pressure (mm Hg)
y
88
Æ 9
86
Æ 10
79
Æ 7
Plasma renin activity (ng/mL.h)
y
3
Æ 2
7.5
Æ 3.7
11.9
Æ 4.8
Norepinephrine (pg/mL)
y
221
Æ 256
412
Æ 155
628
Æ 320
Systemic vascular resistance (dynes.second/cm
-5
)
962
Æ 256
1058
Æ 265
1014
Æ 276
Cardiac output (L/min)
y
7.2
Æ 1.8
6.2
Æ 1.4
5.8
Æ 1.2
Heart rate (bpm)
87
Æ 15
84
Æ 12
80
Æ 14
Hepatic blood flow (mL/min)
y
1123
Æ 328
1064
Æ 223
824
Æ 180
Hepatic venous pressure gradient (mm Hg)
y
16.5
Æ 3
19
Æ 3
19.5
Æ 2
*Data from Ruiz-del-Arbol L, Monescillo A, Arocena C, et al. Circulatory function and hepatorenal syndrome in cirrhosis. Hepatology
2005;42:439–447.
NA-1, baseline measurement in nonazotemic cirrhotic patients who did not develop hepatorenal syndrome during the follow-up; NA-2, baseline
measurement in nonazotemic cirrhotic patients who developed type-2 hepatorenal syndrome during the follow-up. bpm, beats per minute.
y
p < 0.01.
Figure 3 Peripheral vasodilation hypothesis (top graph) and modified peripheral vasodilation hypothesis (bottom graph).
According to this latter hypothesis, impairment in arterial blood volume in cirrhosis could be the consequence of a progression
of splanchnic arterial vasodilation and a decrease in cardiac output.
86
SEMINARS IN LIVER DISEASE/VOLUME 28, NUMBER 1
2008
During the last decade, however, increasing evidence
suggest that HRS is a much more complex syndrome
affecting organs other than the liver and the kidney.
Moreover, data have been presented suggesting that the
impairment in circulatory function affects the intrahe-
patic circulation and that this may contribute to the
severity of hepatic failure in HRS. Liver failure in HRS
could, therefore, be partially reverted if circulatory dys-
function is improved.
Renal Failure
HRS develops at the last phase of cirrhosis, when
patients already present severe circulatory dysfunction,
arterial hypotension, marked activation of the renin-
angiotensin aldosterone system, sympathetic nervous
system, and antidiuretic hormone, renal sodium and
water retention, ascites, and dilutional hyponatremia.
The mechanism of the renal vasoconstriction that causes
HRS is complex. Since renal perfusion in decompen-
sated cirrhosis correlates inversely with the activity of the
renin-angiotensin
and
sympathetic
nervous
sys-
tems,
36,38,44,45
HRS is thought to be related to the
extreme stimulation of these systems. The urinary ex-
cretion of prostaglandin E2, 6-keto prostaglandin F1a (a
prostacyclin metabolite), and kallikrein is decreased in
patients with HRS, which is compatible with a reduced
renal production of these vasodilatory substances.
46,47
Renal failure in HRS could, therefore, be the conse-
quence of an imbalance between the activity of the
systemic vasoconstrictor systems and the renal produc-
tion of vasodilators. Additionally, once renal hypoperfu-
sion develops, renal vasoconstriction could be amplified
by the stimulation of other intrarenal vasoactive systems.
For example, renal ischemia increases the generation of
angiotensin-II by the juxtagomerular apparatus, the
intrarenal production of adenosine (a renal vasoconstric-
tor which in addition potentiates the vascular effect of
angiotensin-II), and the synthesis of endothelin. Other
intrarenal vasoconstrictors that have been involved in
HRS are leukotrienes and F2-isoprostanes.
48
Renal
vasoconstriction in HRS is, therefore, related to the
simultaneous effect of numerous vasoactive substances
on the intrarenal circulation.
Vasoconstruction of Cutaneous, Muscular, and
Cerebral Circulation in HRS
Brachial and femoral blood flows are markedly reduced
in patients with HRS, indicating a vasoconstriction in
the cutaneous and muscular arterial vascular beds.
36
The
resistive index in the mean cerebral artery is also in-
creased in these patients, indicating cerebral vasocon-
striction
39
(Fig. 4). The degree of vasoconstriction in
these vascular territories in decompensated cirrhosis
(patients with ascites with and without HRS) correlates
directly with the degree of renal vasoconstriction and
with the plasma levels of renin. Impairment in circula-
tory function in cirrhosis is therefore associated with
generalized nonsplanchnic arterial vasoconstriction.
The clinical consequences of the decreased mus-
cular blood flow in advanced cirrhosis have not been
explored. Patients with type-2 HRS and refractory
ascites frequently present muscle cramps. Although
the pathogenesis of this abnormality is unknown, muscle
cramps disappear or improve following plasma volume
expansion with albumin,
49
suggesting that they could be
related to this reduction in muscular blood flow. Hepatic
encephalopathy is common in patients with HRS. There
are many possible mechanisms of this complication,
including the precipitating event of HRS, which can
also cause hepatic encephalopathy, and the deterioration
of hepatic function observed in these patients. Cerebral
vasoconstriction, however, could be an additional factor.
Cardiac Dysfunction
The normal response to arterial hypotension consists of a
stimulation of the renin-angiotensin and sympathetic
nervous systems. Angiotensin-II and the sympathetic
nervous activity produce arterial vasoconstriction and
increase the systemic vascular resistance. Moreover,
these hormones also increase heart rate, ventricular
contractility, and cardiac output. These two mechanisms
increase arterial pressure to normal or near-normal
levels. In patients with type-2 HRS, arterial vasodilation
is followed by an appropriate response of the vasoactive
neurohormonal systems. There is a marked increase
in the plasma levels of renin and norepinephrine and
vasoconstriction in the extrasplanchnic organs that
maintains arterial pressure.
36,39
However, the cardiac
response is clearly abnormal in these patients. Develop-
ment of type-2 HRS is associated with a slight decrease
in cardiac output. Moreover, despite the intense activa-
tion of the sympathetic nervous activity, no change in
heart rate is observed (Table 3).
43
These data clearly
indicate that there is an impairment in cardiac inotropic
and chronotropic functions in patients with type-2 HRS.
In patients with type-1 HRS, the deterioration of cardiac
function is even more evident. Type-1 HRS occurs in
the setting of a severe decrease in cardiac output, which
may reach values below normal. The heart rate remains
unchanged despite a dramatic activation of the renin-
angiotensin and sympathetic nervous systems.
42
The pathogenesis of the impaired cardiac re-
sponse to arterial vasodilation in HRS is unknown. A
specific cardiomiopathy characterized by attenuated sys-
tolic and diastolic responses to stress stimuli, electro-
physiological repolarization changes, and enlargement
and hypertophy of cardiac chambers is common in
patients with advanced cirrhosis.
50
This cirrhotic cardi-
omiopathy has been thought to play a role in the
PATHOGENESIS AND TREATMENT OF HEPATORENAL SYNDROME/ARROYO ET AL
87
pathogenesis of heart failure seen after the insertion
of a transjugular intrahepatic portosystemic shunt
(TIPS),
51,52
major surgery, or liver transplantation,
53,54
and in HRS.
42,43
Other features, however, suggest that
the impairment in the cardiac inotropic function in HRS
is not organic but is mainly functional in nature and
related to a decrease in venous return.
55
First, the
reduced cardiac output in patients with HRS occurs in
the setting of a decrease in cardiopulmonary pressures,
which is compatible with a fall in cardiac preload.
Second, circulatory dysfunction in HRS can be reverted
by the intravenous (I.V.) administration of albumin
associated with vasoconstrictors or after the insertion
of a TIPS. Both treatments increase venous return and
cardiac output. Finally, expansion of plasma volume with
albumin is highly effective in the prevention of type-1
HRS in patients with SBP.
56
The impairment in chro-
notropic cardiac function is probably related to a down-
regulation of b-adrenergic receptors secondary to the
chronic stimulation of the sympathetic nervous system.
Intrahepatic Vasoconstriction
Angiotensin-II, noradrenaline, and vasopressin have
powerful effects on the intrahepatic circulation. They
produce arterial vasoconstriction and increase the intra-
hepatic resistance to the portal venous flow at different
levels (small portal venules, sinusoids, and small hepatic
venules). In patients with cirrhosis these effects are
increased due to a reduced intrahepatic synthesis of
nitric oxide.
57
It is, therefore, not surprising that the
stimulation of the endogenous vasoactive systems in
HRS could be associated with an aggravation of portal
hypertension and a marked reduction in hepatic blood
flow.
42,43
This has been shown recently by Ruiz-del-
Arbol et al.
43
They studied hepatic hemodynamics in a
large series of nonazotemic cirrhotics with tense ascites
when they had normal serum creatinine concentration
and after a follow-up of several months when patients
developed type-1 or type-2 HRS. The hepatic venous
pressure gradient was significantly higher in the follow-
up study than in the baseline study in patients developing
type-1 HRS. Type-1 HRS was also associated with a
dramatic reduction in hepatic blood flow. In patients
developing type-2 HRS, significant differences were
only observed in the hepatic blood flow (Table 3). In a
second investigation from the same group, hepatic he-
modynamics were assessed in patients with SBP at
infection diagnosis and following infection resolution.
42
There was only a 1-week interval between the studies.
Figure 4 Resistive index in the middle cerebral artery in patients with compensated cirrhosis, patients with ascites, and
healthy subjects (upper graph). Relationship between the renal resistive index and the resistive index in the middle cerebral
artery in cirrhotic patients (lower graph). (Reproduced with permission from Guevara M, Bru C, Gine`s P, et al. Increased
cerebrovascular resistance in cirrhotic patients with ascites. Hepatology 1998;28:39–44.)
88
SEMINARS IN LIVER DISEASE/VOLUME 28, NUMBER 1
2008
Hepatic venous pressure gradient increased markedly in
patients who developed type-1 HRS but not in patients
with normal renal function. Changes in intrahepatic
hemodynamics in the two studies correlated significantly
with the increase in plasma renin activity. This finding
suggests that circulatory dysfunction associated with
hepatorenal syndrome adversely influences intrahepatic
hemodynamics. Acute deterioration of hepatic function
is a common event in patients with type-1 HRS. Variceal
bleeding is also frequent in patients with severe bacterial
infections and HRS. The intense reduction in hepatic
blood flow and the increase in portal pressure associated
with type-1 HRS could play a role in the development of
these complications.
Relative Adrenal Insufficiency
Two recent studies indicate that relative adrenal dys-
function is a common problem in patients with cirrhosis
and acute-on-chronic liver failure secondary to severe
sepsis.
58,59
In the first study,
58
adrenal insufficiency was
detected in 80% of patients with HRS but only in 34%
with serum creatinine below 1.5 mg/dL. A close rela-
tionship, therefore, existed between adrenal insufficiency
and HRS in patients with severe infection. Other fea-
tures associated with adrenal insufficiency were severe
liver failure, arterial hypotension and vasopressor de-
pendency, and hospital mortality. Since normal adrenal
function is essential for an adequate response of the
arterial circulation to endogenous vasoconstrictors, adre-
nal insufficiency could be an important contributory
mechanism of circulatory dysfunction associated with
HRS in patients with severe bacterial infections. The
second study
59
recently showed that treatment with
hydrocortisone in cirrhotic patients with severe sepsis
and adrenal insufficiency is associated with a rapid
improvement in systemic hemodynamics, reduction of
vasoconstrictor requirements, and higher hospital sur-
vival. The mechanisms of adrenal dysfunction in cir-
rhosis with severe sepsis have not been explored. Since
adrenal dysfunction is particularly prevalent in patients
with HRS, a reduction in adrenal blood flow secondary
to regional vasoconstriction is a possible mechanism.
Cytokines directly inhibit adrenal cortisol synthesis. The
inflammatory response associated with bacterial infec-
tions is, therefore, another potential pathogenic mech-
anism.
TYPE-1 AND TYPE-2 HRS ARE NOT
DIFFERENT EXPRESSIONS OF A COMMON
SYNDROME BUT RATHER DIFFERENT
ENTITIES
Clinical data suggest that type-1 and type-2 HRS are
different syndromes and not different expressions of a
common underlying disorder. Renal failure in type-1
HRS is severe and progressive whereas in type-2 it is
moderate and steady. As expected, circulatory function is
also stable in type-2 HRS, whereas a rapidly progressive
impairment in circulatory function occurs in type-1
HRS. Type-1 HRS is frequently associated with a
precipitant event, mainly SBP. In contrast, type-2
HRS develops spontaneously in most cases. Finally,
the main clinical consequence of type-1 HRS is severe
hepatorenal failure and death, whereas in type-2 HRS it
is refractory ascites. Type-2 HRS probably represents
the genuine functional renal failure of cirrhosis. It would
be the extreme expression of the impairment in circu-
latory function that spontaneously develops up to the
final stages of the disease (Figs. 2, 3). In contrast, type-1
HRS appears to share similarities with acute renal failure
associated with other conditions such as septic shock or
severe pancreatitis. In fact, as indicated previously,
features of multiorgan failure including acute impair-
ment in cardiovascular, renal, hepatic, and cerebral
function and relative adrenal insufficiency are common
in patients with type-1 HRS but rare in patients with
type-2 HRS (Fig. 5).
TREATMENTS FOR TYPE-1 HRS
Liver Transplantation
Liver transplantation is the treatment of choice for any
patient with advanced cirrhosis, including those with
type-1 and type-2 HRS.
60–63
Immediately after trans-
plantation, a further impairment in GFR may be ob-
served and many patients require hemodialysis (35% of
patients with HRS as compared with 5% of patients
without HRS).
60
Because cyclosporine or tacrolimus
may contribute to this impairment in renal function, it
has been suggested to delay the administration of these
drugs until a recovery of renal function is noted, usually
48 to 96 hours after transplantation. After this initial
impairment in renal function, GFR starts to improve and
reaches an average of 30 to 40 mL/min by 1 to 2 months
postoperatively. This moderate renal failure persists
during follow-up, is more marked than that observed
in transplantation patients without HRS, and is probably
due to a greater nephrotoxicity of cyclosporine or tacro-
limus in patients with renal impairment prior to trans-
plantation. The hemodynamic and neurohormonal
abnormalities associated with HRS disappear within
the first month after the operation and patients regain
a normal ability to excrete sodium and free water.
Patients with HRS who undergo transplantation
have more complications, spend more days in the in-
tensive care unit, and have a higher in-hospital mortality
rate than transplantation patients without HRS. The
long-term survival of patients with HRS who undergo
liver transplantation, however, is good, with a 3-year
probability of survival of 60%. This survival rate is only
PATHOGENESIS AND TREATMENT OF HEPATORENAL SYNDROME/ARROYO ET AL
89
slightly lower than that of patients without HRS (which
ranges between 70% and 80%).
61
The main problem of liver transplantation in
type-1 HRS is its applicability. Due to their extremely
short survival, most patients die before transplantation.
The introduction of the model for end-stage liver disease
score, which includes serum creatinine, bilirubin, and the
international normalized ratio, for listing has partially
solved the problem since patients with HRS are gen-
erally allocated the first places of the waiting list. Treat-
ment of HRS with vasoconstrictors and albumin (see
below) increases survival in a significant proportion of
patients (and, therefore, the number of patients reaching
liver transplantation), decreases early morbidity and
mortality after transplantation, and prolongs long-term
survival.
Vasoconstrictors and Albumin
The I.V. administration of vasoconstrictor agents (vaso-
pressin, ornipressin, terlipressin, noradrenaline) or the
combination of oral midodrine (an a-agonistic agent)
and I.V. or subcutaneous octreotide during 1 to 3 weeks
is an effective treatment of type-1 HRS. Twelve pilot
studies including 176 patients with HRS (141 with type-
1 HRS) have so far been published on this topic.
64–75
In
most patients, I.V. albumin was also given. The overall
rate of positive response was 63.6% (112 patients). In
nine of these studies (including 150 patients) a positive
response was considered when there was reversal of HRS
as defined by a decrease of serum creatinine below
1.5 mg/dL. This feature was observed in 96 patients
(64%). A second important observation was that type-1
HRS does not recur after discontinuation of the treat-
ment in most patients. Six studies including 74 patients
have reported data on this feature. Fifty-two patients
responded to therapy and HRS recurred in only 12. Dostları ilə paylaş: |