Aliment Pharmacol Ther 2002; 16 (Suppl. 5): 3238.

doi: 10.1046/j.1365-2036.2002.00193.x

Review article: the Molecular Adsorbents Recirculating System

(MARS) in liver failure
S. SEN, R. P. MOOK ERJEE, N. A. DA VIES, R. WILLIAM S & R. JALAN
Institute of Hepatology, University College London Medical School and University College London Hospitals

SUMMARY

In recent years different artificial liver support systems

are being developed for use in patients with acute
decompensation of chronic liver disease or acute liver
failure. The molecular adsorbents recirculating system
(MARS), a device in which patients blood is dialysed
across an albumin-impregnated membrane against a
recirculated albumin-containing solution, seems to be
effective in removing albumin-bound toxins, such as
fatty acids, bile acids and bilirubin. Although the

BACKGROUND

Liver failure can occur either as an acute liver failure

without any pre-existing liver disease, an acute
decompensation of chronic liver disease (acute-onchronic liver failure; ACLF) or as a chronic decompensation in end-stage liver disease. They have different
causes or precipitating factors, and the underlying
pathophysiological mechanisms may also differ. However, they manifest clinically in fairly similar fashions,
with hepatic encephalopathy, hepatorenal syndrome
and circulatory changes.1, 2 This is probably because
they are all ultimately associated with the accumulation
of a variety of toxins, due to the loss of the detoxifying
function of the liver. The effects of endotoxaemia and
sepsis, which occur frequently in the setting of liver
failure3, 4 may also represent a common pathway,

Correspondence to: Dr R. Jalan, Institute of Hepatology and University

College London Hospitals and Medical School, 6975 Chenies Mews,
London WC1E 6HX, UK.
E-mail: r.jalan@ucl.ac.uk

32

clinical experience with MARS is scarce, some pilot

studies have reported its effectiveness at improving liver
function and hepatic encephalopathy in patients with
acute decompensation of chronic liver disease, and
renal function in patients with hepatorenal syndrome
type I. Data regarding MARS experience in acute liver
failure and in primary graft dysfunction are encouraging but limited. Its real usefulness in these settings is,
at present, under evaluation in randomized controlled
clinical trials.

leading ultimately to end-organ dysfunction, affecting

the brain,59 the kidney1013 and the circulation.1418
This is probably the reason why an increased serum
bilirubin, acting as a surrogate marker for the other
toxins, is associated with increased mortality in both
ACLF and acute liver failure.1, 19
While chronic decompensation in end-stage liver
disease usually results in an irreversible deterioration,
with liver transplantation being the only realistic
therapeutic option, both acute liver failure and ACLF
result in acute episodes, which are potentially reversible.
In these situations if the liver can be adequately
supported for a short period (anything between a few
days to a few weeks), there is a good chance of
spontaneous recovery, or in some cases (especially acute
liver failure) the patient can successfully be bridged to
liver transplantation (where an organ is not immediately available or the patients initial condition does not
allow immediate liver transplantation). Therefore, the
availability of a device for removal of the accumulated
toxins in liver failure could be of considerable clinical
value.

2002 Blackwell Publishing Ltd

REVIEW: MARS IN LIVER FAILURE

33

THE MOLECULAR ADSORBENTS RECIRCULATING

SYSTEM (MARS)

Table 1. Some of the endogenous albumin-bound toxins that

accumulate in liver failure

The design of such a device is not as simple as it may

appear, because the majority of the potential toxins
(apart from a few like ammonia and lactate, which
are water soluble) are protein-bound, usually to
albumin (Table 1).2022 They cannot be removed by
simple haemodialysis or haemofiltration (in contrast
to renal failure), but are potentially removable by
albumin dialysis, whereby blood is dialysed against an
albumin-containing solution across a suitable membrane.2325 The albumin-bound toxins should be
taken up by the binding sites of the albumin in the
dialysate and thus removed from blood. However, the
cost involved in using a volume of albumin comparable to the volume of dialysate used in conventional
haemodialysis haemodiafiltration (i.e. as a single pass
albumin dialysis system) would be prohibitive.
To circumvent this problem, Stange and Mitzner from
the University of Rostock, Germany, designed a device
in 1993 where the albumin dialysate, after removing
the toxins from the blood, was cleansed by a three-step
process and reutilized.26, 27 Thus the albumin circuit
was converted into a closed circuit, where a fixed
volume of albumin dialysate was recirculated again
and again. This is what has been named the Molecular
Adsorbents Recirculating System or MARS (Figure 1).
This system consists of a hollow fibre dialysis module
in which the patients blood is dialysed across an
albumin-impregnated high-flux polysulphone membrane, i.e. a hybrid membrane (MARSFlux),28 while

Aromatic amino acids

Bile acids
Bilirubin
Copper (Wilsons disease)
Digoxin-like substances
Endogenous benzodiazepines
Indols
Mercaptans
Middle- and short-chain fatty acids
Nitric oxide
Phenols
Prostacyclins
Tryptophan

at the same time maintaining a constant flow of

albumin-rich (usually 20%) dialysate in the extracapillary compartment (Figure 2). The adsorbed toxins
from the binding sites on the membrane pass to the
albumin-binding sites in the dialysate. The dialysate is
then passed through a column through which conventional dialysis filtration is performed (to remove
water-soluble toxins), and then perfused successively
over an activated charcoal and an anion exchange
resin column to remove the albumin-bound toxins,
and thus regenerate the dialysate. Substances with a
molecular weight of more than 50 kDa such as
essential hormones bound to carrier proteins, growth
factors and albumin are not removed from the perfused
plasma because of the pore size of the MARSFlux
membrane.

Figure 1. A schematic diagram showing

the MARS circuit.

2002 Blackwell Publishing Ltd, Aliment Pharmacol Ther 16 (Suppl. 5), 3238

34

S. SEN et al.

Figure 2. Passage of albumin-bound toxins through the membrane consisting of an active de-ligandization of plasma albumin,
transport of the ligands across the membrane, and ligandization of
dialysate albumin.

THE EARLY YEARS: THE ROSTOCK EXPERIENCE

While the MARS system was an excellent idea in

principle, it actually had to be shown that it worked as
predicted. Most of the early work in this respect was
done at Rostock. Early in vitro studies showed that this
method resulted in effective removal of unconjugated
bilirubin, drugs with a high protein-binding ratio
(sulfobromophthalein, theophylline), and a proteinbound toxin (phenol).27 Further studies demonstrated
that the system effectively removed strongly albumin
bound toxins like unconjugated bilirubin or free fatty
acids from plasma and blood in vivo as well.26
Next, they tried to determine how the hybrid membrane functioned and what was the effect of MARS on
toxins, as well as other physiologically important
molecules in the body.28 Working with Texas Redlabelled albumin, they showed that during the precoating procedure (priming), as a pure albumin solution
was passed repeatedly over the dialysate side of the
polysulphone membrane, penetration of a substantial
amount of albumin occurred throughout the pores in
the membrane (50 kDa size), followed by an internal blood surface coating. Subsequently, during the dialysis period, passage of albumin-bound toxins through
the membrane consists of an active de-ligandization of
plasma albumin, transport of the ligands across the
membrane, and ligandization of dialysate albumin
(Figure 2). It has been shown that albumin, when
attached to polymers, have a higher affinity for albuminbound toxins.29 This is a possible reason why the toxins
should detach from plasma albumin, and then attach to

the binding sites on the albumin impregnated on the

membrane. This mechanism of membrane transport was
supported by the observation that tightly albuminbound molecules (unconjugated bilirubin and sulfobromophthalein) were: (i) transported much better by a
hybrid membrane, compared to a conventional highflux polysulphone membrane, and (ii) that the transport
was also improved by an albumin-containing dialysate,
compared to an albumin-free one. Studies with labelled
albumin showed that the transported toxins were not
accompanied by the passage of albumin across the
membrane. This is an interesting observation, because
albumin does seem to pass through the pores during
priming. A possible explanation is that the sieve
coefficient for large molecules like albumin is higher in
pure aqueous solutions (as during precoating priming)
than in whole plasma (as during treatment) because no
deposition of a mixed protein layer occurs.30
In the same study28 the Rostock group also looked at
the in vivo effect of MARS on:
(a) the amino acid profile,
(b) (i) physiologically important high molecular weight
proteins(albumin,a-1-glycoprotein,a-1-antitrypsine,
a-2-macroglobulin, transferrin), (ii) hormonebinding proteins (thyroxine binding globulin) and
(iii) hormone systems (thyroxine and thyroid stimulating hormone) to evaluate the relative selectivity
of the albumin-mediated detoxification, and
(c) albumin-bound toxic substances (bilirubin, bile
acids, free fatty acids, tryptophan).
Their results showed that there was an improvement
of the amino acid profile, with relative clearance of the
aromatic amino acids (which accumulate in hepatic
insufficiency) and an improved ratio of branched chain
amino acids to aromatic amino acids. There was no
significant removal of the physiologically important
proteins or thyroxine binding globulin, nor was there a
significant change of the thyroid hormone profile. There
was, however, a significant removal of all the albuminbound toxins, which was most effective for fatty acids,
followed by bile acids, tryptophan and bilirubin.
THE LAST 5 YEARS: CLINICAL EXPERIENCE
WITH MARS

After the initial reports from Rostock, more and more

clinical experience was gained with MARS, and over the
last few years it has been used in over 50 centres in

2002 Blackwell Publishing Ltd, Aliment Pharmacol Ther 16 (Suppl. 5), 3238

REVIEW: MARS IN LIVER FAILURE

Europe, the USA and Asia for indications like ACLF,

acute liver failure, hepatorenal syndrome and primary
nonfunction poor function after liver transplantation
and major liver resection.20
Acute-on-chronic liver failure
Several studies have looked at what MARS can do to
this group of patients.3137 Twenty-three out of 38
patients (61%) with ACLF studied in four of these
studies survived the acute episode and could be
discharged from hospital.3133, 37 This improvement in
survival was accompanied by a significant improvement
in serum bilirubin3133 and an improvement of the
ChildTurcottePugh score.31, 33
There was a significant improvement in the level of
hepatic encephalopathy as well,3133 with some degree
of improvement in all patients seen in at least one of the
studies.32 This was accompanied by a significant reduction of serum ammonia levels,3133 which might possibly
contribute to this improvement.5, 7, 8 Another possible
explanation might be a favourable alteration of the
amino acids profile, with relative clearance of aromatic
amino acids, as had been observed in the early in vivo
studies.28 An associated finding was an improvement of
cerebral blood flow. In three patients, intracranial
pressure and jugular bulb oxygen saturation decreased
and cerebral perfusion pressure increased after treatment initiation.32 This was supported by a study on eight
patients with ACLF treated with a single 10-h session of
MARS,35 where cerebral perfusion, determined by
transcranial Doppler as mean flow velocity in the
middle cerebral artery, increased from 42 cm s (range,
2659) to 72 cm s, (52106) (P < 0.05, n 6).
An improvement of renal function was also observed,
as demonstrated by an improvement of serum urea and
creatinine3133 as well as improvement of oliguria.33
This was supported by a randomized controlled study on
13 ACLF patients with type I hepatorenal syndrome
performed in Rostock and Tublingen, Germany.34 Eight
patients received MARS in addition to haemodiafiltration and standard medical treatment, while the
remaining five had only haemodiafiltration and standard medical treatment. A significant decrease in serum
bilirubin and creatinine levels (P < 0.01) and increase
in serum sodium level and prothrombin activity
(P < 0.01) were observed in the MARS group, but not
in the control group. Mortality rates were 100% in the
control group at day 7, and 62.5% in the MARS group

35

at day 7 and 75% at day 30, respectively (P < 0.01).

Presumably it is the removal of albumin-bound toxins
that is responsible for the improvement in the renal
function. Another factor might be the associated
improvement of the circulatory status, which was
observed in the form of improved mean arterial
pressure3234 along with a decrease in cardiac output
and an increase in systemic vascular resistance
observed in three patients.32 This was again supported
by another study on eight patients with ACLF treated
with a single session of MARS.36 Mean arterial pressure
increased from 67 9 to 76 6 mmHg (P < 0.05).
Systemic vascular resistance index increased from
757 134
to
884 183
dyne s cm5 m2
(P < 0.05), whereas cardiac index remained constant
(5.9 0.7 vs. 6.0 1.1 L min m2).
The largest series of patients with ACLF (n 26), with
intrahepatic cholestasis (bilirubin level > 20 mg dL),
treated with MARS has been reported from Rostock.38
Twenty-three had hepatic encephalopathy, 14 had
hepatorenal syndrome, 11 had refractory ascites and
23 had detectable infection. The series included 10
patients with a United Network Organ Sharing (UNOS)
status 2b, all of whom survived, and 16 patients with a
UNOS status 2a, of whom seven survived. There was a
reduction of serum bilirubin and bile acids, associated
with an improvement of hepatic encephalopathy and
ChildTurcottePugh score (which was sustained even
after withdrawal of MARS treatment in all long-term
survivors). An interesting observation demonstrating
the detoxifying capacity of MARS was that toxicity
testing of patient plasma on to primary rat hepatocytes
by live dead fluorescence microscopy showed celldamaging effects of jaundiced plasma that were not
observed after treatment.
Acute liver failure
There is considerably less data regarding the use of
MARS in acute liver failure. One study described four
such patients treated with MARS39 where improvement
of serum bilirubin and ammonia was observed. All four
were bridged to liver transplantation, but only one
survived and could be discharged from hospital.
Another study described three patients of acute liver
failure with grade IV hepatic encephalopathy and
cerebral oedema40 who were treated with MARS. After
the first treatment session, hepatic encephalopathy
improved to grade I in all three, with improvement of

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S. SEN et al.

cerebral oedema (as evidenced by computerized cerebral

tomography). Individual intracranial pressures decreased from 18 to 11 mmHg in patient 1, from 22 to
13 mmHg in patient 2, and from 12 to 10 mmHg in
patient 3. Cerebral perfusion pressure increased from 42
to 58 mmHg in patient 1, from 58 to 67 mmHg in
patient 2, and from 61 to 87 mmHg in patient 3.
Jugular venous saturation decreased from 86 to 68 in
patient 1, from 89 to 70 in patient 2, and from 85 to 73
in patient 3. There was associated reduction of blood
ammonia and serum bilirubin levels. The patients were
treated with further sessions of MARS. However, two
died due to multi-organ failure following sepsis, while
one could be discharged and was awaiting liver
transplantation at the time of publication.
Interestingly, a phase I trial from the USA25 has
evaluated the role of an extra-corporeal hepatic support
device utilizing continuous haemodiafiltration with
continuous albumin dialysis in nine patients with acute
liver failure (UNOS status I: n 5, status IIA: n 4).
There was significant improvement of serum bilirubin,
factor VII levels, blood ammonia, hepatic encephalopathy scores, intracranial pressure, without changes in the
systemic haemodynamics or venous oxygenation. Of five
UNOS status I patients, one recovered native hepatic
function and three were bridged to liver transplantation.
There have been individual case reports of the use of
MARS (n 3)37, 41, 42 or albumin dialysis (n 1)43 in
the treatment of Wilsons disease presenting with acute
liver failure, all of whom could be successfully bridged to
liver transplantation. MARS has also been used to treat
acute liver failure due to paracetamol overdose
(n 3)37, 44, 45 and mushroom intoxication (n 1)37
where liver transplantation was ultimately not required
and all survived, and in one case of acute BuddChiari
syndrome,37 who ultimately died in spite of liver
transplantation. However, no definite conclusions can
be drawn on the basis of these data.
Primary graft dysfunction
Results with MARS in the treatment of primary graft
dysfunction following liver transplantation are also
limited. One study39 reported six such patients (primary
nonfunction: n 4, delayed nonfunction: n 2), all of
whom had serum bilirubin > 15 mg dL and high blood
ammonia levels, where MARS treatment led to a
recovery in five cases, eliminating the need for
re-transplantation. The sixth patient died. Another

study37 reported two patients of liver failure following

liver transplantation, one due to primary nonfunction
and the other due to severe graft dysfunction, both of
whom were bridged to re-transplantation with MARS.
The former died following sepsis, while the latter
survived. The same study also described two cases of
liver failure following hepatic resection, who were
treated with MARS, one of whom survived. Data
available from four other centres describe eight cases
of primary graft dysfunction treated with MARS, of
whom three recovered and four were successfully
bridged to re-transplantation.46
Other conditions
There is anecdotal evidence only of the benefit of MARS
in recurrent intrahepatic cholestasis (n 1), leading to
the improvement of pruritus47 in progressive intrahepatic cholestasis due to chronic graft vs. host disease
(n 1),48 and in patients with heart failure, complicated by liver failure, awaiting heart transplantation.49
Adverse effects
The safety profile of MARS is remarkable for an extracorporeal circuit. Most studies have not reported any
significant adverse effects, except for mild thrombocytopenia, which did not have any clinical implications.20, 33 Transient arrhythmia had been observed in
one patient, which was probably not as a consequence
of MARS therapy.50
CONCLUSIONS

MARS appears to have provided a very exciting tool to

the hepatologist for the treatment of liver failure. It
seems to be consistently effective at improving liver
function and hepatic encephalopathy, with probably
some improvement in renal function as well. Most
importantly, it apparently improves survival, especially
in cases of ACLF, as has been borne out by a randomized
controlled trial in patients with hepatorenal syndrome.
However, it is important to remember that almost all
the studies existing in the literature are pilot studies
with a small sample size and without a control arm.
The trial with hepatorenal syndrome patients, although
with a control arm, is quite small in size. The importance of performing randomized controlled trials before
coming to a firm conclusion is emphasized by the fact

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REVIEW: MARS IN LIVER FAILURE

that a recent study looking retrospectively at 99

patients of type I hepatorenal syndrome in 24 centres
found a 40% survival rate at 1 month following treatment with terlipressin.51 Therefore, a high standard of
medical therapy might actually achieve the sort of
survival advantage that has been attributed to MARS.
Hopefully, this question can be satisfactorily answered
by a multicentric randomized controlled trial, which is
at present ongoing.
What about the future? From the current evidence,
MARS appears to be good, but certainly not the ultimate
extra-corporeal liver support device. Other such devices,
mostly bio-artificial, have been studied over the past
decade.52, 53 However, concern has been expressed
regarding the safety of these devices. Porcine hepatocytes54 are seen as a potential source of retroviral
infection, and those using hepatoma cells55 raise
concerns over cancer seeding. The hybrid membrane
of MARS was initially developed as a safety barrier
between a patients blood and a bioartificial liver.28 It
can be envisaged that a combination of these systems
will lead to a total liver support system.
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