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Intensive Care Nephrology 2000 |
* Division of Nephrology, Department of Medicine, University of Rostock,
Rostock, Germany.
Division of Gastroenterology, Department of Medicine, University of
Rostock, Rostock, Germany.
Department of Anesthesiology and Intensive Care Medicine, University of
Rostock, Rostock, Germany.
Correspondence to Dr. Steffen R. Mitzner, Division of Nephrology, Department of Medicine, University of Rostock, E. Heydemann Strasse 6, 18055 Rostock, Germany. Phone and Fax: 49-381-494-7354; E-mail: steffen.mitzner{at}med.uni-rostock.de
Abstract
Abstract. Liver failure resulting from different causes and its concomitant complications represent difficult-to-treat conditions with high mortality rates, despite improved therapeutic modalities in intensive care medicine. The accumulation of albumin-bound metabolites that are normally cleared by the liver, such as bilirubin and bile acids, contributes substantially to the development of multiorgan dysfunction in these clinical situations. The molecular adsorbent recirculating system (MARS) represents a cell-free, extracorporeal, liver assistance method for the selective removal of albumin-bound substances. Moreover, it enables the removal of excess water and water-soluble substances via an inbuilt dialysis step. Since 1993, >400 patients have been treated in 53 centers in Europe, the United States, and Asia. Diseases treated with MARS included acute exacerbation of chronic hepatic failure, hepatorenal syndrome, acute hepatic failure, and primary nonfunction/poor function after liver transplantation and major liver resection. Treatments were well tolerated. No severe adverse events were observed. Six- to 8-h MARS treatments resulted in significant (P < 0.05) removal of bilirubin, bile acids, tryptophan, shortand middle-chain fatty acids, aromatic amino acids, and ammonia. Clearance rates for strongly albumin-bound substances were between 10 and 60 ml/min. The removal of albumin-bound toxins resulted in decreases in hepatic encephalopathy, increases in mean arterial pressure, and improvements in kidney and liver function. In the first randomized clinical trial of the MARS method for treatment of the hepatorenal syndrome, significant prolongation of survival was observed for the MARS-treated group. It is concluded that the MARS method can contribute to the treatment of critically ill patients with liver failure and different underlying diseases.
Mortality rates for acute hepatic failure (AHF) and acute severe decompensation of chronic hepatic failure (AoCHF) resulting from different causes remain high, despite improved therapeutic modalities in modern intensive care medicine (1,2). Liver transplantation (Ltx) has greatly improved survival rates. For elective Ltx, 1-yr survival rates are up to 90% (3). However, mortality rates are much higher in AHF, ranging from 10 to 40% with Ltx and 50 to 90% without Ltx (4,5,6). Patients with AoCHF are normally not eligible for high-urgency Ltx. These patients frequently develop multiorgan failure, placing them at risk for systemic infections, cerebral edema, hemodynamic instability, coagulopathy, and various renal and metabolic complications (7).
The pathophysiologic features of the development of hepatic failure are not fully understood. Although the precipitating event is often well characterized (bacterial or viral infection, bleeding, or intoxication), the mechanisms leading to multiorgan dysfunction/failure have not been completely elucidated. Internal intoxication with metabolites that are normally cleared from the circulation by the healthy liver seems to be one of the single most important mechanisms leading to hepatic encephalopathy (8,9,10,11), kidney failure (12,13,14,15,16), hyperdynamic circulation with systemic hypotension (17,18,19,20), liver insufficiency (detoxification, synthesis, and regulation) (21,22,23,24,25), and eventually death. Therefore, increased serum bilirubin levels are associated with increased mortality rates in AoCHF, as well as in AHF (1,26). Indeed, a number of metabolites accumulate in hepatic failure and are found in increased concentrations in these conditions (Table 1). Almost all of these substances are strongly protein bound. The most important transport protein for liver-bound metabolites is human serum albumin (HSA). Albumin has highly specialized binding sites for these substances (27). Among the substances that bind to albumin are most of the so-called protein-bound drugs, such as benzodiazepines (28). The pathophysiologic hypothesis that formed the basis for the molecular adsorbent recirculating system (MARS) method is the assumption that the accumulation of albumin-bound substances attributable to insufficient clearance by the failing liver results in elevated tissue levels of the subsequently toxic substances. Selective removal of the aforementioned substances from the blood should lead to redistribution and decreases in the plasma and tissue concentrations of the metabolites. In the scope of this hypothesis, the ligands of the HSA molecule are referred to as albumin-bound toxins (ABT). Because ABT such as bilirubin and bile acids have hepatotoxic potential, i.e., induction of hepatocyte apoptosis and necrosis (see above), it seemed reasonable to expect stabilization of liver function with time with sufficiently efficient and prolonged MARS treatments. The same is true for the kidney [in hepatorenal syndrome (HRS)]. It could be shown that the removal of bile acids and bilirubin decreased the degree of tubular necrosis (29).
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Removal rates for single substances during MARS treatments and clinical effects observed in patients with hepatic failure resulting from different causes are presented and discussed in this review.
Materials and Methods
MARS Treatment
MARS is a liver support system developed to support excretory liver
function. It consists of elements from extracorporeal renal replacement
techniques such as hemodialysis and ultrafiltration, as well as adsorption. It
contains no biologic components, such as hepatocytes. The method uses an
albumin-enriched dialysate to facilitate the removal of ABT. It contains three
different fluid compartments ("circuits"), i.e., the
blood circuit, an albumin circuit, and an open-loop, single-pass dialysate
circuit. MARS requires a standard dialysis machine or a continuous venovenous
hemofiltration (CVVH) device (e.g., BM 25; Edwards Life Sciences
GmbH, Munich, Germany) to control the blood and dialysate circuits. An extra
device (MARS monitor; Teraklin AG, Rostock, Germany) is necessary to control
and monitor the closed-loop albumin circuit. The latter circuit connects the
blood and dialysate circuits.
The blood circuit uses a venovenous access (double-lumen catheter) and is driven by the blood roller pump of the dialysis machine and the CVVH monitor. The blood flow rate is 150 to 250 ml/min, depending on the hemodynamic status of the patient. Blood is passed through a non-albumin-permeable high-flux dialysis membrane (MARSFlux; Teraklin) (Figures 1 and 2). The albumin circuit, containing 20% HSA, is driven by a roller pump of the MARS monitor at 150 ml/min. The dialysate HSA is passed through the dialysate compartment of the blood dialyzer (MARSFlux) and subsequently regenerated by dialysis against a bicarbonate-buffered dialysate (dialysate circuit), followed by passage through two sequential columns; the first contains uncoated charcoal, and the second contains an anion exchanger resin (30). Heparin is used as an anticoagulant. The activated clotting time is maintained between 160 and 190 s throughout the treatment.
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Review of Clinical Trials
Clinical trials and pilot studies from different centers using the
technique of albumin dialysis were reviewed.
MARS was normally performed intermittently for 6 to 8 h/d. However, continuous treatment for up to 24 h/d was performed in individual cases. Treatment pauses of 24 h were allowed for hemodialysis or hemofiltration sessions or other diagnostic or therapeutic interventions. The number of single treatment days ranged between 1 and 24 d, with an average of 5 to 6 d/patient.
In Vivo Removal Capacities of Hemodiafiltration and MARS
To compare the efficacy of MARS with that of hemodiafiltration with respect
to single-substance clearance, we determined the pre- and post-treatment
concentrations of different albumin-bound substances (bilirubin, bile acids,
fatty acids, tryptophan, and aromatic amino acids). No branched-chain amino
acids were administered during the assessment period. The same type of
dialysis membrane was used throughout the experiments. Flow rates,
ultrafiltration rates, and dialysate flow rates were kept at the
aforementioned levels. The Fischer ratio (branched-chain/aromatic amino acid
ratio) was calculated for evaluation of the course of the amino acids.
Statistical Analyses
All results were expressed as means ± SD. Because the data were
normally distributed, the t test was used to analyze differences
between mean values for each variable before and after treatment (paired
t test) and between the groups (unpaired t test). The 5%
probability level was regarded as statistically significant.
Results
Substance Clearance
Significant removal of water-soluble and albumin-bound substances was
observed during MARS therapy, by our group and by other groups. An overview of
single substances measured and found to be significantly removed during
treatment using the albumin dialysis concept is presented in
Table 2. Clearance rates for
ABT ranged between 10 and 60 ml/min.
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Clinical Comparison of the Removal Efficacy of Hemodiafiltration
versus MARS
Under comparable conditions (flow rates, membrane, and treatment times),
significantly higher removal rates for bilirubin (P < 0.001), bile
acids (P < 0.001), middle- and short-chain fatty acids (P
< 0.05), and tryptophan (P < 0.05) were found for MARS,
compared with hemodiafiltration. The difference in Fischer ratios missed the
level of significance (P = 0.05). Figures
3,4,5,6,7
provide the results obtained from the pretreatment/post-treatment comparison
of blood concentrations of different albumin-bound substances.
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Clinical Effects
Summary of Effects. Various clinical effects were observed primarily
for patients with AoCHF. However, the first reports of data for patients with
AHF and primary nonfunction also demonstrated favorable clinical effects.
These included improvements in mental status, liver detoxification and
synthesis functions, hemodynamic status (increase in mean arterial pressure),
and kidney function (Table 3).
Additional effects not listed in Table
3 included the marked regression of pruritus in patients with
AoCHF (Huster D, Berr F, unpublished observations)
(39) and increases in serum
sodium levels during a series of MARS treatments for patients with HRS
(34).
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Cerebral Function. The degree of hepatic encephalopathy was decreased in patients with AHF, as well as in patients with AoCHF (31,35,37,39).
Hemodynamic Function. The mean arterial pressure was increased in patients with AoCHF (34,36). This was probably attributable to increases in systemic vascular resistance (36).
Kidney Function. MARS treatment improved kidney function for patients with AoCHF and HRS (34,36,39).
Liver Function. Protein synthesis improved during the treatment phase, and plasma antithrombin III levels, prothrombin activity, and Factor VII levels were increased. Cholinesterase levels were also increased (31,32,33,34,35,39).
Child-Turcotte-Pugh (CTP) scores decreased because of improved liver synthesis, decreased encephalopathy grades, and decrease in degree of ascites. The significant decrease in bilirubin concentrations did not contribute to changes in CTP scores, because plasma concentrations after the MARS treatments were still elevated (>3 mg/dl = 3 points). Interestingly, the CTP scores remained low and even exhibited additional decreases after the end of the MARS treatments (35).
In cell culture experiments performed with primary rat hepatocytes, the cytotoxicity of plasma from patients with AoCHF was markedly decreased (increases in viability and cytochrome P450 activity) after the patients were treated with MARS (35).
Adverse Events
Almost all groups reported smooth safe performance of the MARS technique
(31,32,34,35,37,38,39).
No adverse events attributable to MARS treatments were documented.
Discussion
Different approaches to supportive liver therapy have been used in the past
decade, including extracorporeal whole-liver perfusion
(43), hepatocyte
transplantation (44), and
extracorporeal artificial and bioartificial devices
(45,46,47,48).
Potential problems arising from the use of bioartificial liver systems include
antibody formation and complement activation after repeated treatments with
bioartificial liver systems using xenogenic cells
(49), viral transfer to
patients (50), and induction
of proinflammatory cytokines such as tumor necrosis factor-
and
interleukin-6 (51).
Results obtained to date with the albumin dialysis MARS indicate that the hypothesis made in the beginning holds true. The removal of ABT seems to contribute to improvement in organ function and survival rates in different forms of liver failure.
However, no comprehensive pathophysiologic explanation can now be provided for the clinical and biochemical effects observed during the course of MARS treatment. Current knowledge regarding the removal kinetics of albumin-bound substances and some clinical effects of the MARS method give rise to different hypotheses that attempt to elucidate the mechanism of action of the MARS method in HRS. Possible mechanisms include the following.
Removal of Nitric Oxide
Nitric oxide (NO) is thought to be one of the factors responsible for the
vasodilation and hyperdynamic status observed in hepatic failure and HRS.
Plasma NO can act as a potent vasodilator
(17,18,20).
It is transported primarily bound to serum albumin as an
S-nitrosothiol (19).
Therefore, a possible mechanism of action of the MARS method could involve the
removal of plasma NO. The increase in systemic vascular resistance and mean
arterial pressure observed in the MARS-treated patients with AoCHF and HRS
(34,36)
might be explained by such a mechanism.
Increase in Binding Capacity for Toxic Metabolites
ABT were found to compete with tryptophan for free binding capacity at the
receptor sites of the albumin molecule in uremic patients
(52). The MARS concept of
albumin dialysis was shown to facilitate the in vivo removal of
strongly albumin-bound uremic compounds such as
3-carboxy-4-methyl-5-propyl-2-furanpropionic acid
(53). Therefore, the increase
in free binding capacity at the surface of the albumin molecule by MARS
treatment could decrease the concentration of free toxic metabolites via
binding to serum albumin. This again may lead to decreased tissue
concentrations of these substances, facilitating organ recovery. The
intravenous infusion of HSA was shown to have beneficial effects on the course
and outcome of spontaneous bacterial peritonitis
(54) and resulted in improved
response rates and prevention of recurrence of ascites
(55). This again may indicate
that the increase in the total binding capacity of the serum albumin pool of
the patient can have beneficial effects for patients with ascites and
hepatorenal failure.
Removal of Bilirubin, Bile Salts, and Bile Acids
Bilirubin, bile salts, and bile acids have toxic potential and can impair
liver and kidney function. Bile salts were shown to cause lactate
dehydrogenase leakage from human endothelial cells in vitro.
Prostacyclin release from the cells was decreased
(56). Moreover, bile salts can
cause hepatocyte death by inducing mitochondrial permeability transition
(25) and apoptosis in rodent
hepatocytes (22). In the
kidney, bile acids disturb renal water and electrolyte handling by blocking
the Na+/H+-antiporter in the tubule and thus impairing
intracellular pH regulation. Bile acids induce damage to tubular cell
membranes by stimulating oxygen radical generation
(12,13).
High bilirubin levels are a predictor of death in acute renal failure, because
of acute tubular necrosis
(14). Although serum
concentrations of up to 15 mg/dl did not induce changes in renal function in
patients with obstructive jaundice, higher concentrations in patients with
hypoalbuminemia were associated with decreased urinary sodium excretion, free
water clearance, negative water clearance, renal blood flow, and creatinine
clearance (15). Bilirubin can
also cause tubular damage. Kamisako et al.
(16) demonstrated a positive
effect of (enzyme-triggered) bilirubin removal on hepatic and renal function
in a rat model of obstructive jaundice. Those authors concluded that the
systemic reduction of serum bilirubin concentrations might contribute to
normalization of the urinary levels of prostaglandins and thromboxane
B2, to decreases in serum bile acid levels, and to improvement of
the hepatic energy charge in obstructive jaundice. Moreover, they concluded
that preoperative improvement of jaundice might be beneficial for patients
with obstructive jaundice
(16).
The removal of bilirubin and bile acids/salts during MARS treatment could therefore decrease the toxic effects that higher concentrations of these compounds exert on liver and kidney function and could thus contribute to improvements in organ function, as observed by different groups (31,32,33,34,35,36,39).
Removal of Aldosterone and Other Vasoactive Hormones
The renin-angiotensin-aldosterone system, the sympathetic nervous system,
and arginine vasopressin are responsible for sodium and water retention in
patients with cirrhosis (57).
Except for plasma renin analysis
(36), no hormone
determinations were performed in the trials reviewed. However, we started to
analyze plasma aldosterone concentrations and plasma renin activity in
patients treated with MARS. Preliminary data obtained in a single case of a
patient with type I HRS who was treated with MARS indicated that single-pass
reductions of plasma aldosterone levels of 40% and plasma renin activity of
11% in the extracorporeal circulation could be achieved. These reductions may
lead to substantial decreases in the systemic concentrations and activities of
these hormones with treatment times of 6 to 8 h. For eight patients with AoCHF
who were treated once with MARS for 10 h, significant reductions in plasma
renin concentrations were observed
(36). These data provide an
initial indication of possible effects of MARS treatments on plasma
concentrations of the aforementioned hormones, which may in part explain the
clinical improvements observed (e.g., in HRS).
The parallel removal of water-soluble and albumin-bound substances seems to be one of the major advantages of the MARS approach, because both groups can substantially contribute to the clinical situation in advanced AHF/AoCHF. Probably the most important water-soluble substance is ammonia, because it plays a pivotal role in the development of cerebral edema and hepatic encephalopathy (58). Approximately 55% of all patients referred to specialized centers with AHF develop some type of renal failure (hepatorenal failure or drug-induced renal failure) (59). In cases that need renal replacement therapy it might be reasonable to use the albumin dialysis MARS as a first choice for extracorporeal treatment rather than hemodialysis or CVVH, as (1) MARS allows the removal of ABT in addition to the clearance of water-soluble factors and ultrafiltration, and (2) the risk/benefit ratio of the procedure is in favor of the MARS method.
In summary, we conclude that MARS treatment can substantially contribute to the treatment of patients with liver failure. However, more multicenter, randomized, clinical trials, with well defined patient groups and standardized outcome measures, will be essential for proper evaluation of the clinical value of this system and other artificial or bioartificial devices.
References
This article has been cited by other articles:
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 R Jalan, S Sen, and R Williams PROSPECTS FOR EXTRACORPOREAL LIVER SUPPORT Gut, June 1, 2004; 53(6): 890 - 898. [Full Text] [PDF]
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