Download Renal failure in patients with cirrhosis: hepatorenal syndrome and

Renal failure in patients with cirrhosis: hepatorenal
syndrome and renal support strategies
Current opinion in anaesthesiology [0952-7907] Meltzer Ano:2010 Vol:23 Nr:2
Pág:139 -144
Meltzer, Josepha,b,c; Brentjens, Tricia Ed,e,f
Abstract
Purpose of review: The development of hepatorenal syndrome in liver cirrhosis leads
to an increased morbidity and mortality in patients with cirrhosis. Currently, there are
no proven methods for the treatment or prevention of hepatorenal syndrome except to
maintain adequate hemodynamics and intravascular volume in this patient population.
These patients will frequently require renal replacement therapy when presenting for
hepatic transplantation.
Recent findings: New consensus definitions have been published in order to create
uniform standards for classifying and diagnosing acute kidney injury. Two such
groups are the Acute Dialysis Quality Initiative (ADQI) and the Acute Kidney Injury
Network (AKIN), which have proposed approaches to defining criteria for acute
kidney injury. Recent literature supports not only the role of splanchnic vasodilation
and systemic vasoconstriction but also heart failure in the pathogenesis of hepatorenal
syndrome. The practice of using vasoconstrictor and intravenous albumin therapy for
the treatment of hepatorenal syndrome is ongoing with a growing body of recent data
supporting the use of vasopressin analogs as the first-line therapy in the ICU setting
with knowledge of the possible cardiovascular side-effects.
Summary: Hepatorenal syndrome, HRS, is a diagnosis of exclusion. There are two
forms of hepatorenal syndrome: type 1 hepatorenal syndrome and type 2 hepatorenal
syndrome. Type 1 HRS is rapidly progressive and portends a very poor prognosis and
has a high mortality rate. Type 2 is more indolent while still associated with an overall
poor prognosis. Treatment of HRS is largely still supportive. It is imperative to
maintain euvolemia and hemodynamics in this patient population to optimize renal
perfusion and preserve renal function. Renal replacement therapy may be necessary in
this chronically ill patient population, if renal function deteriorates such that the
kidneys cannot maintain metabolic and volume homeostasis. Further research is still
necessary as to the prevention and effective treatment for hepatorenal syndrome.
Introduction
Acute renal failure (ARF), more recently termed acute kidney injury (AKI) [1], is a
common and major complication of advanced liver cirrhosis. Kidney function, as
evinced by serum creatinine (SCr) and blood urea nitrogen (BUN), is a powerful
predictor of death in patients with decompensated cirrhosis [2]. It is also an important
risk factor when considering orthotopic liver transplantation (OLT), in that it increases
mortality while on the waiting list and increases the frequency of complications after
transplantation [3••,4,5]. In fact, SCr is one of only three variables used in the
calculation of the model of end-stage liver disease (MELD) score, a good predictor of 3-
month mortality in cirrhotic patients without OLT, and is currently used to allocate
organs to patients awaiting transplantation. The other variables are bilirubin and
international normalized ratio. The use of the MELD score in organ allocation has also
increased the number of patients with ARF who present for transplantation [6].
Pretransplant kidney function has been shown to be a predictor of survival post-OLT
[7•]. As there is a powerful interconnection between kidney and liver dysfunction, AKI
in patients with cirrhosis must be identified, understood and treated.
Definitions of acute renal failure and acute kidney injury
Acute kidney injury is a common and complex disorder without a standardized,
accepted definition. Recently, groups of experts have assembled in order to create
uniform standards for classifying and diagnosing AKI. Two such groups are the Acute
Dialysis Quality Initiative (ADQI) and the Acute Kidney Injury Network (AKIN),
which have proposed similar approaches to defining criteria for AKI that are more
specific, sensitive and evidence based than the older ‘gestalt method’ of simply looking
for a rising creatinine [1,8]. These consensus definitions of AKI take into account
reductions in kidney function manifested by absolute elevations in SCr, percentage
increases in SCr or changes in urine output over defined periods of time. Table 1 shows
the AKIN consensus definition of AKI (based upon the ADQI RIFLE criteria for AKI).
A recent study demonstrated the RIFLE classification of AKI as a predictive factor of
mortality in patients with cirrhosis admitted to the ICU [9]. This is an active area of
collaborative clinical and translational research, which needs further validation.
Etiology of acute kidney injury in cirrhosis
Usually, three broad classifications of ARF/AKI are identified. First, AKI resulting
from renal hypoperfusion without glomerular or tubular injury is called prerenal failure
or prerenal azotemia and is rapidly reversible with correction of the underlying etiology.
Second, renal dysfunction related to an obstructed urinary outflow tract is called
postrenal failure, or postrenal azotemia. It is very important to rapidly identify this as
the potential for recovery of renal function is often inversely related to the duration of
obstruction. Third, intrinsic renal failure results from injury to renal tubules (i.e.
ischemic or toxic), interstitium (i.e. autoimmune or allergic), vessels or glomerulus [10].
Patients with cirrhosis are at risk for all types of renal failure; however, they can
uniquely develop hepatorenal syndrome (HRS), a form a prerenal failure that, unlike
most forms of prerenal failure, is unresponsive to fluid resuscitation.
Hepatorenal syndrome is a unique and sometimes reversible form of prerenal failure
that occurs in patients with advanced cirrhosis. Circulatory dysfunction is at the heart of
HRS. Splanchnic vasodilation leads to decreased blood pressure and reduced central
arterial blood volume, which in turn leads to renin–angiotensin release, sympathetic
stimulation and extreme renal vasoconstriction, low glomerular filtration rate (GFR) and
low renal perfusion [11]. Low cardiac output probably exacerbates this hemodynamic
picture [12,13]. Recent data seem to support that renal and cardiac dysfunction are
tightly related in cirrhosis and that this relationship may be the result of chronic
circulatory stress combined with an acute ‘decompensating’ event leading to a systemic
response and even worsened circulatory dysfunction
The diagnosis of hepatorenal syndrome
Differentiating hepatorenal syndrome from acute tubular necrosis (ATN) can be
difficult [15]. The diagnosis of HRS must be based on the exclusion of other disorders
that cause AKI in cirrhosis, as there are no specific tests for the syndrome [16]. HRS is
diagnosed on the basis of a serum creatinine concentration of more than 1.5 mg/dl
which is not reduced with the administration of albumin (1 g/kg of body weight) and
after a minimum of 2 days without diuretic therapy, along with the absence of current or
recent treatment of potentially nephrotoxic drugs, the absence of shock, and the absence
of findings suggestive of renal parenchymal disease (urinary excretion of more than 500
mg of protein/day, more than 50 red cells/high-power field, or abnormal kidneys on
ultrasonography) [3••]. Major diagnostic criteria of HRS [16] are as follows:
1. hepatic failure and ascites,
2. creatinine more than 1.5 mg/dl,
3. no shock, ongoing bacterial infection, nephrotoxic agents or fluid losses,
4. no improvement after diuretic withdrawal and fluid resuscitation,
5. proteinuria less than 500 mg/day, normal renal sonography.
The diagnosis is made after ruling out infection, often spontaneous bacterial peritonitis
(SBP), shock, hypovolemia, parechymal disease, and/or drug-induced renal failure.
The subtypes of hepatorenal syndrome
There are two types of HRS with different characteristics and prognostic implications.
Type 1 is rapidly progressive with SCr doubling to more than 2.5 mg/dl or a 50%
reduction in creatinine clearance to less than 20 ml/min in a period of less than 2 weeks.
This form often occurs in the inpatient setting after a precipitating event. Type 2 is
notable for a steady and slowly progressive rise in SCr in the outpatient setting in the
cirrhotic patient with ascites [14•]. This more ‘chronic’ form does not meet the
definition of ARF/AKI and, therefore, may be considered a form of chronic kidney
disease. Patients with type 1 HRS often have concurrent bacterial infection,
gastrointestinal bleeding, recent surgery, acute hepatitis and signs and symptoms of
severe hepatic insufficiency with jaundice, coagulopathy, encephalopathy and
circulatory dysfunction [17••]. The prognosis for patients with concurrent cirrhosis and
renal failure is poor. The overall survival rate is about 50% at 1 month and 20% at 6
months [3••]. Mortality is higher with type 1 HRS than with type 2 HRS, with a median
survival of 2–4 weeks vs. 5–6 months respectively [18,19].
Management of acute kidney injury in cirrhosis
Treatment of AKI in cirrhosis depends on its cause and severity. Prerenal azotemia
should be treated with isotonic intravenous fluid resuscitation and the discontinuation of
diuretics in order to restore renal blood flow and euvolemia. The cause of hypoperfusion
should be sought and addressed. In patients with gastrointestinal bleeding, red blood
cell transfusion and plasma expanders should be administered aggressively with an eye
towards maintaining hemodynamic stability. All nephrotoxic drugs (i.e. nonsteroidal
anti-inflammatory agents and aminoglycosides) should be discontinued and
radiocontrast agents avoided. Bacterial infections should be prevented and, when
present, treated quickly and aggressively [20]. Some suggest third-generation
cephalosporins as the initial treatment of choice for bacterial infections, but region and
hospital-specific antibiograms may also guide therapy [21•]. Patients should have
ongoing nutritional support. The possibility that sepsis is a causative factor should be
investigated and, if suspected, treated aggressively in an intensive care environment
[21•]. Consideration should be given to early goal-directed therapy [22], the avoidance
of hypoglycemia and hyperglycemia [23], lung-protective ventilation for those with
acute respiratory distress syndrome (ARDS) or at risk for ARDS [24], and steroid
therapy for possible adrenal insufficiency [25,26]. There is little evidence-based data to
support the use of natural/artificial colloids over crystalloids other than that 6%
hydroxyethylstarch (HES) should be avoided in patients with sepsis and/or AKI [27–
29]. There may be a role for vasoconstrictor therapy in AKI secondary to ATN. A
recent study showed a benefit of terlipressin infusion in patients with cirrhosis, ascites
and ATN [30]. The reversal of mesenteric vasodilation with the treatment of
vasopressin analogs and resultant increase in blood pressure, central blood volume and
renal blood flow is the proposed mechanism of action. If hepatorenal syndrome
progresses to frank renal failure, renal replacement therapy will be required.
Renal replacement therapy
Hepatorenal syndrome that has decompensated, resulting in metabolic acidosis,
electrolyte imbalance, metabolic disarray and volume overload should be treated with
renal replacement therapy. There are essentially three usual processes for dialysis:
intermittent hemodialysis, continuous veno-venous hemodialysis (CVVHD), and
peritoneal dialysis. Perintoneal dialysis is contraindicated in the setting of cirrhosis, as
ascites is frequently present. There is a paucity of data in regards to intensity, dose and
timing of renal replacement therapy but continuous veno-venous hemodialysis is
preferable to standard hemodialysis in patients with a tenuous hemodynamic profile.
There are also a number of forms of artificial support systems designed to support the
patient with combined liver and kidney failure. These systems include the molecular
absorbent recirculating system (MARS), the fractioned plasma separation, adsorption
and dialysis system, single-pass albumin dialysis (SPAD) and single-pass albumin
extended dialysis [31••]. These artificial hepatic support systems require further
investigation at this time and are beyond the scope of this review but have been
reviewed elsewhere
Surgical treatment of hepatorenal syndrome
Liver transplantation is the treatment of choice for advanced cirrhosis with or without
HRS. Kidney function often recovers after hepatic transplantation. A liver–kidney
transplant may be necessary for those with severe or prolonged hepatorenal syndrome
[5].
Often there is a further worsening of renal function in the immediate perioperative
period necessitating renal replacement therapy about 35% of the time [34]. Owing to
ongoing AKI, cyclosporine, tacrolimus and other nephrotoxic agents should be avoided
until there is evidence of renal recovery. The hemodynamic and neurohormonal changes
associated with HRS disappear within the first month after hepatic transplantation and
patients regain their ability to handle sodium and water [35]. Liver transplantation in the
face of HRS leads to an increased number of complications, ICU length of stay and
mortality when compared with hepatic transplantation without HRS. Patients who
undergo hepatic transplantation with HRS have a significantly reduced 5-year survival
as compared with patients without HRS [5]. The issue of whether to transplant a kidney
in addition to a liver is also important [36].
Hepatorenal syndrome itself is not an indication for combined liver–kidney
transplantation. Combined transplant is reserved for those with irreversible kidney
injury, requiring hemodialysis for longer than 8 weeks, or progressive primary kidney
disease [37,38]. As hepatic transplantation is a complex, lengthy procedure associated
with major alterations in systemic hemodynamics, metabolic derangements, bleeding
and coagulopathy, intraoperative renal support via CVVHD may be required to
successfully transplant patients with preoperative renal failure [39]. Intraoperative
CVVHD is well tolerated, feasible, associated with neutral or negative fluid balance
during the procedure, and does not require anticoagulation [40].
Transjugular intrahepatic portosystemic shunt (TIPS) lowers portal pressure and may be
useful in treating HRS in patients who are poor transplantation candidates. TIPS, in
these select patients, may improve SCr and GFR [40,41]. Further research is needed in
this area.
Pharmacologic treatment of hepatorenal syndrome
The best approach to the pharmacologic management of HRS is the administration of
vasoconstrictor medications. The physiologic rationale for the administration of
vasoconstrictors is to reverse the splanchnic vasodilation that initiates HRS. Many
vasoconstrictors have been studied in uncontrolled trials in HRS including the
vasopressin analogs terlipressin, ornipressin and vasopressin, somatostatin analogs,
octreotide, and alpha-adrenergic analogs, midodrine and norepinephrine. Of note, in
most of these studies, intravenous albumin therapy was coadministered with the
vasoconstrictor medication and seems to enhance their benefit. It appears that
vasopressin analogs are most effective, probably due to their profound splanchnic
vasoconstrictor effect, and should be considered first-line therapy [3••,42–44,45••,46••].
Two recent randomized controlled trials add to our understanding of vasopressin analog
therapy in type 1 HRS. In the first, Sanyal and the Terlipressin Study Group evaluated
the safety and efficacy of terlipressin plus albumin vs. albumin alone in patients with
HRS type 1 in a multinational study. Although significantly more patients in the
terlipressin group achieved HRS reversal than in the placebo group, there was no
difference in 6-month survival. More patients in the terlipressin group experienced
serious adverse events such as nonfatal myocardial infarction, nonsustained
supraventricular tachycardia and arrhythmias [46••]. In the second study, Martin-Llahi
and the TAHRS investigators used the same drug in both type 1 and type 2 HRS.
Similarly, in this trial, the terlipressin group experienced a significantly higher rate of
improved renal function but a nonsignificant improvement in 3-month survival. There
was, again, an increased rate of cardiovascular complications in the terlipressin group
including myocardial ischemia, intestinal ischemia, arrhythmias and volume overload
[47]. The data supporting the use of oral midodrine and subcutaneous octreotide are
from small nonrandomized and retrospective studies. However, the studies support the
use of these drugs in combination as they have been associated with improved renal
function and survival and may be a more convenient option for less ill patients such as
those with type 2 HRS, as they do not require intravenous administration [38,47].
Attempts at pharmacological renal–arterial vasodilation with fenoldapam, dopamine or
prostaglandins have not been shown to be effective [48].
Prevention of hepatorenal syndrome
The best prevention of hepatorenal syndrome is to maintain normovolemia and
hemodynamics to optimize renal perfusion to preserve renal function. Subacute
bacterial peritonitis (SBP) can cause HRS by inducing proinflammatory cytokines that
lead to vasodilation and hypovolemia [49]. It appears that, when SBP is treated with
cefotaxime and albumin rather than albumin alone, HRS is less likely to develop and
mortality rates are significantly improved [49]. Long-term antibiotic prophylaxis in
certain patients may also reduce the incidence of SBP and HRS [50].
Hepatorenal syndrome is a mortal development in cirrhotic patients with severe alcoholinduced hepatitis. The administration of pentoxifylline, a tumor necrosis factor-[alpha]
synthesis inhibitor, in patients with alcoholic hepatitis appears to reduce mortality [51].
The avoidance of nephrotoxic agents, when possible, may also help prevent HRS.
Prophylaxis should be used in patients with cirrhosis who are at risk for hepatorenal
syndrome when they are to receive radio-contrast dye for imaging studies. These
strategies include isotonic crystalloid prehydration [52], oral or intravenous Nacetylcysteine [53,54], intravenous isotonic sodium bicarbonate infusion [55] as well as
the alteration of volume, dose and type of contrast medium. Intravenous precontrast
hydration is considered the standard of care but multimodal prophylaxis protocols for
high-risk patients, such as those with severe cirrhosis and ascites, may reduce the
incidence of contrast-induced AKI and HRS
Conclusion
The development of hepatorenal syndrome in the presence of cirrhosis is a devastating
complication that affects morbidity and mortality in this pa ient population. There are
currently no effective pharmacologic agents available for the prevention or definitive
treatment of HRS. However, vasopressin analogs and treatment with a combination of
midodrine and octreotide have shown some promise. Further research is desperately
needed in this area. If hepatorenal syndrome progresses to frank renal failure, renal
replacement therapy in the form of intermittent hemodialysis or continuous venovenous hemodialysis in hemodynamically unstable patients is necessary. The definitive
therapy for hepatic cirrhosis with the development of HRS is hepatic transplantation.