Ann Transplant, 2013: 18: 205-217

DOI: 10.12659/AOT.889188

Received: 2013.02.20
Accepted: 2013.03.20
Published: 2013.05.10

WWW.annalsoftransplantation.COM

Review Paper

Human albumin: old, new, and emerging applications

Jacek Rozga, Tomasz Pitek, Piotr Makowski
Department of Surgical and Transplantation Nursing, Medical University of Warsaw, Warsaw, Poland

Summary

Human serum albumin has been widely used in an array of clinical settings for nearly 7 decades. Although there is no evidence to support the use of albumin rather
than crystalloid in acute volume resuscitation, many clinicians continue to use albumin because it has other important physiologic effects besides the oncotic function.
In keeping with the improved understanding of albumin physiology and pathophysiology of many acute and chronic diseases, use of albumin for medical applications
has increased in recent years. This, along with increased costs of manufacturing and
lower production volume of medical-grade albumin, has lead to an ongoing shortage and rapid increase in albumin prices.

This review is based on the analysis of major publications, related to albumin chemistry, physiology, and medical uses including guidelines developed by professional
and governmental organizations. Results reflect current knowledge about the role
of albumin in health and disease and relevance of albumin therapy in specific clinical settings.

Albumin therapy is currently recommended in spontaneous bacterial peritonitis

with ascites, refractory ascites not responsive to diuretics, large-volume paracentesis, post-paracentesis syndrome, and the treatment of hepatorenal syndrome as an
adjunct to vasoconstrictors. New indications for albumin therapy are linked to the
antioxidant activity of albumin and its effects on capillary integrity. In recent years,
large-pore hemofiltration and albumin exchange have emerged as promising liver
support therapies for liver failure and other toxic syndromes. They are designed to
remove a broad range of blood-borne toxins and to restore normal functions of the
circulating albumin by replacing defective forms of albumin and albumin molecules
saturated with toxins with normal albumin. In view of the ongoing worldwide shortage and high cost of human albumin (native and recombinant), new usage criteria,
protocols, and guidelines for appropriate utilization of albumin are needed.

Key words:

albumin hypoalbuminaemia albumin binding capacity fluid resuscitation albumin

supplementation blood detoxification liver failure

Full-text PDF: http://www.annalsoftransplantation.com/download/index/idArt/889188

Word count: 3988
Tables: 2
Figures: 2
References: 100

Authors address:

Jacek Rozga, Department of Surgical & Transplantation Nursing, Medical University of Warsaw, Oczki 4 St.,
02-007 Warsaw, Poland, e-mail: jrozga@dslextreme.com

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Background
Human albumin has many important physiologic
effects and has been used in various clinical settings for 7 decades [14]. For example, it is commonly used in patients with a volume or oncotic
deficit, despite the fact that a large number of studies comparing albumin solution with other agents
for fluid resuscitation have failed to demonstrate
a beneficial effect of albumin [2]. Furthermore,
the safety record of albumin has been challenged
by Cochrane meta-analysis, where the risk of death
in patients receiving albumin solutions was found
to be greater than in patients who received no albumin [5]. Although this analysis received much
criticism and the authors conclusions about albumin were not confirmed in subsequent studies,
controversy about certain uses of albumin persist
to this day. Further focused clinical trials to evaluate the effectiveness and safety of albumin in critically ill patients are warranted [2,59].
The use of albumin solution in other clinical settings, such as decompensated cirrhosis, cirrhosis complicated by ascites, renal failure or spontaneous bacterial peritonitis, is less controversial
(1013]. Furthermore, over time, licensed indications for medical use of albumin have expanded (e.g., albumin dialysis). This, along with increased costs of manufacturing and decreased
production of albumin for medical uses, has
lead to an ongoing shortage and rapid increase
in the price of albumin (as high as $75/gram for
human recombinant product). In this situation,
it is reasonable to develop usage criteria, protocols, and guidelines for appropriate utilization
of albumin. This review aims to highlight the
relevance of albumin therapy in the context of
old, new, and emerging indications in the critically ill and in patients with failing liver, kidneys,
and other organs.

Human Albumin Physiology

Properties
Human albumin belongs to the evolutionarily linked family of transport proteins, which includes alpha-fetoprotein, vitamin D-binding protein and alpha-albumin (afamin) [14,15]. The
molecule is a single peptide chain composed of
585 amino acids with an abundance of lysine, arginine, glutamate, and aspartate residues, relatively
few tryptophane and methionine molecules, and
no carbohydrate moiety. The molecular weight of
albumin is 66 500 Da [16]. At physiological pH,

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albumin is negatively charged and binds to the

cell surface receptor, albondin [17]. The polypeptide chain is arranged in alpha-helices, folded and held by disulphide bridges, which create
3 homologous domains that are movable relative to one another [18,19]. On crystallography,
the molecule is heart-shaped [14,20], but in solution (plasma) it assumes an ellipsoid configuration [21]. Because of this flexibility, albumin
may change shape, which facilitates its ability to
bind many endogenous and exogenous ligands
(e.g., blood-borne toxins) and even to bury some
of them within its structure [15].
Synthesis
Albumin is produced by hepatocytes in circular
polysomes on the rough endoplasmic reticulum.
In healthy adults, albumin is synthesized at a rate
between 12 and 25 g per day [15]. The majority of the protein is immediately released into the
blood circulation, where approximately 60% of
it escapes into the extravascular interstitial compartment, either passively via sinusoids (liver, bone
marrow) and fenestrated capillaries (e.g., the small
intestine and pancreas), or via an active transport
mechanism through the continuous capillaries
[22]. Some of the albumin lost into the extravascular space is tissue-bound (e.g., in skin, muscle,
and kidneys). Only small amounts of albumin (2
g) are stored in the liver; therefore, the interstitial
pool is the principal source of albumin in situations of increased albumin loss or requirements.
In addition the half-life of albumin is approximately 15 days, and synthesis can increase on demand
in healthy livers by as much as 300% [4,16,21].
Synthesis is regulated chiefly by a change in interstitial colloid osmotic pressure [20]. Other important regulatory factors and stimuli (positive or
negative) include the nutritional state (adequate
supply of amino acids), energy supply (ATP and/
or GTP), changes in hormonal environment (insulin, steroids, growth hormone), and presence
of the systemic inflammatory response.
In a normal 70 kg adult, the total body albumin
content is 250300 g (45 g/kg body weight), of
which approximately 40% is held in the intravascular compartment and the other 60% is in the interstitial space. The normal range of human serum
albumin in adults is 3.55.0 g/dl. Concentration
in the tissue spaces is much lower (1.4 g/dl). For
children younger than 3 years of age, the normal
range is wider (2.95.5 g/dl). Total daily degradation of albumin is around 14 g, of which 4060%
occurs in muscle and skin [21].

Ann Transplant, 2013: 18: 205-217

Rozga J. et al. Albumin therapy

Table 1. Known physiological and pathophysiological effects of human albumin.

Maintenance of colloid osmotic pressure
a. Because of its low molecular weight relative to immunoglobulins and other major intravascular proteins, albumin accounts for up to 80%
of plasma oncotic pressure. Sixty percent of this contribution is due to the direct osmotic effect of albumin and the other 40% due to water
retention via attraction of sodium ions and other active cations (Gibbs-Donnan effect).
b. Interstitial oedema in critically ill patients caused by hypoalbuminaemia due to vasodilation, leaky capillaries, malnutrition, liver failure,
catabolism, renal losses, haemorrhage, exudative losses in burns, or a combination thereof [9].
Binding and transport properties with implications for circulating depot (reservoir) of ligands, metabolite and drug delivery to tissue
sites, detoxification, drug inactivation, stabilization of other molecules, involvement in the metabolism of endogenous and exogenous
substances (e.g., lipids, eicosanoids, drugs), anti-oxidant protection, and other functions.
a. Endogenous substances [haematin, fatty acids, bile salts, metabolites, bilirubin, certain hormones and inflammatory mediators, enzymes,
arachidonic acid metabolites, essential metals (Cu, Zn), divalent cations (Ca, Mg), amino acids, steroids including derivatives such as vitamin D
and thyroxine, nitric oxide, etc.].
b. Exogenous substances (basic drugs, antibiotics, sulfonamides, anti-epileptic drugs, anti-coagulants, sedatives, salicylates, furosemide,
indomethacin, tacrolimus, etc.).
Acid-base function
a. Plasma buffering due to the presence of many positively and negatively charged residues on albumin molecules [23,24].
Anti-oxidant and free radical scavenging
a. Inhibiting oxygen free radicals production by polymorphonuclear leukocytes [25].
b. Binding of Fe and Cu making them less likely to form reactive oxygen species [26].
c. Scavenging of reactive oxygen and nitrogen species by sulfhydryl groups (thiols) present on the albumins only free cysteine residue [4].
d. Anti-oxidant properties demonstrated in inflammatory reaction, carbon tetrachloride poisoning and uraemia [2729].
Anti-apoptotic effects
a. Albumin is a specific inhibitor of apoptosis in cultured endothelial cells [30].
Effects on vascular integrity (positive and negative)
a. Increasing microvascular permeability during inflammation, sepsis and trauma [31].
b. Reducing microvascular permeability to large molecules by repelling negatively charged molecules or by narrowing the channels by binding to
the endothelial cells [31].
c. Reducing vascular permability by its anti-oxidant and anti-inflammatory effects (e.g., by binding of the leukotoxin in the setting of sepsis and
shock).
d. Reducing stress-induced leakage from capillary beds [32].
Anti-coagulant and anti-thrombotic effects
a. Heparin-like effects via neutralization of factor Xa by anti-thrombin III [33].
b. Platelet function inhibition through platelet activating factor [34] and cyclo-oxygenase pathway [35].

Functions
Albumin is a major multifunctional protein. It accounts for 5560% of all plasma proteins and is
regarded as a negative acute-phase protein [15].
The physiological and pathophysiological functions of albumin in humans are relatively well
known, although the exact role in critical illnesses and certain chronic diseases is not fully understood and some authors believe they may differ
significantly from those seen in healthy subjects
[21]. Table 1 describes in an abbreviated form
the principal functions of albumin.

Human Albumin Pathophysiology

In many pathological states, the properties and
physiological functions of albumin are altered.
The most frequent, and perhaps best studied,
abnormality is hypoalbuminaemia. Indeed, an

array of critical illnesses can result in and/or become exacerbated by low serum albumin. The
pathomechanism of hypoalbuminaemia is always
ascribed to one or more factors, such as malnutrition, changes in the rates of synthesis and
degradation of albumin, altered distribution between the intravascular and extravascular compartments, translocation of albumin molecules
into the extravascular compartment, changes
in albumin kinetics (transcapillary flow vs. lymphatic return), and external losses (e.g., burns
or hemorrhage) (Table 2).

Albumin Therapy
The first clinical use of human albumin dates
back to the attack on Pearl Harbor during World
War II, when it was used in several burned sailors
[4]. Three years later, Janeway et al reported using albumin in patients with decompensated liver

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Table 2. Common clinical settings and mechanisms involved in hypoalbuminaemia.

Clinical setting

Mechanisms

Chronic liver disease

(cirrhosis, portal hypertension, ascites)

Malnutrition (inadequate supply of amino acids, reduced protein

intake, reduced energy supply, disintegration of polysomes any and
all of these factors may cause diminished rate of albumin synthesis).
Reduced synthesis.
Accumulation in ascitic fluid.
Increased plasma volume.

Chronic renal failure

Inflammation (reduced synthesis, increased catabolism, transcapillary

leakage).
Undernutrition.
Direct loss of albumin in nephrotic syndrome and during peritoneal
dialysis and high-flux hemodialysis.
In dialysis patients, dilutional effect due to plasma volume expansion.

Sepsis

Increased catabolic rate.

Decreased liver synthesis due to preferential synthesis of acute
reactant proteins and inhibition of the albumin gene transcription by
inflammatory mediators [36,37].
Transcapillary leakage [37].

Cancer

Hypoalbuminaemia despite increased rate of albumin synthesis due to

nutritional and energy deficits and increased catabolism.

Burns

Cutaneous (exudative) losses.

Hemorrhage

Blood losses (e.g., gastrointestinal bleeding).

Severe head trauma

Hypoalbuminaemia despite increased synthesis due to an increase in

the fractional catabolic rate [38].

The critical illnesses

Any of the above associated with the acute-phase response, systemic
(severe trauma, sepsis, systemic inflammatory response syndrome,
inflammation and other pathological events [10,3946].
multiorgan dysfunction syndrome, acute respiratory distress syndrome,
acute hepatic failure, type-1 hepato-renal syndrome, spontaneous
bacterial peritonitis, cardiac surgery).

cirrhosis [1]. However, even though the rationale

for albumin therapy was always rooted in knowledge of albumin properties, its physiological characteristics and etiology of the underlying disease,
there were always controversies in relation to its
use in human patients [47,48]. Fortunately, the
results of the Cochrane meta-analysis, which implied that albumin therapy increases patient morbidity and mortality, were not confirmed in subsequent appropriately designed studies [2,5,49].
For nearly 7 decades, albumin has been widely
used for volume replacement and correction of
hypoalbuminaemia and continues to be used for
these indications.
Volume replacement
In critical care patients, no significant beneficial
effects of fluid resuscitation using albumin solution have been demonstrated with respect to
either morbidity or mortality when compared
to crystalloid substitues or alternative colloids

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[42,50,51]. Such therapy is perhaps best suited

for management of hypovolaemia (hypotension)
in patients who do not respond to pressors, inotropes, or other colloids. Patients who may also
benefit from albumin therapy include trauma
and burn patients, especially those with burns
on more than 50% of the body surface [7,52].
However, in the subgroup analysis of the Saline
vs. Albumin Fluid Evaluation (SAFE) study, patients with traumatic brain injury who received
4% albumin had increased 28-day mortality compared to subjects who received saline (24.5% vs.
15.1) (P=0.009) [2]. In a follow-up analysis, at
24 months 33.2% of the albumin recipients had
died compared to 20.4% of the patients who received saline (P=0.003) [53] and it was concluded that albumin therapy should be avoided in
patients with traumatic brain injury.
Recently, the Italian Society of Transfusion
Medicine and Immunohematology (SIMTI)
Working Group defined recommendations for
the use of albumin in acute conditions from the

Ann Transplant, 2013: 18: 205-217

evidence-based medicine standpoint [54]. They

are as follows:
A. In patients with hemorrhagic shock, albumin
should be used as a second choice (Grade 1A
recommendation) when crystalloids or non-protein colloids (first choice treatment) have already been used at maximum doses without
clinically adequate response.
B. In patients undergoing major surgery, albumin solution may be used after normalization
of blood volume, when serum albumin is lower than 2.0 g.dl (Grade 2C+ recommendation).
C. In patients with burns, albumin therapy is recommended after the first 24 hours, with the
dose of albumin during the 24-hour period of
transcapilarry leakage calculated according to
the burned body surface area (BSA) (Grade
2C+ recommendation):
BSA 3050%: 0.3 mL kg % of burned BSA,
BSA 5070%: 0.4 mL kg % of burned BSA,
BSA 70100%: 0.5 mL kg % of burned BSA.
In the post-resuscitation period, the dose of albumin used to correct severe hypoalbuminaemia
should be calculated based on the serum albumin level (end-point of 2.0 g/dl).
A. In patients undergoing heart surgery, albumin
can be used as a last choice plasma expander
after crystalloids or other colloids (Grade 2C+
recommendation).
B. After liver transplantation, albumin may be
indicated for treating ascites and peripheral oedema (Grade 1C recommendation) [7,55].
Otherwise, albumin therapy during the peritransplant period offers no additional therapeutic benefits [5658].
Treatment of hypoalbuminaemia
Serum albumin is an independent predictor of
morbidity and mortality in a wide range of clinical settings [3946,5961].
Hypoalbuminaemia is associated with poor clinical outcome [49,62], yet correction of low serum
albumin levels in critically ill patients does not
improve outcome measures such as mortality, duration of ICU and hospital stay, or mechanical
ventilation, to name but a few [63]. In 2 randomized controlled studies, correction of hypoalbuminaemia improved respiratory, cardiovascular, and central nervous system function [64,65].
With respect to patients with chronic liver disease (cirrhosis), there is some evidence in the

Rozga J. et al. Albumin therapy

literature that correction of hypoalbuminaemia

leads to a reduction in morbidity and mortality
[10,66]. Albumin therapy may be indicated in patients with liver cirrhosis and refractory ascites,
who cannot be treated with transjugular intrahepatic portosystemic shunt (TIPS; [67]), and
in those requiring large volume paracentesis. In
the latter case, albumin was found to be more effective than other colloids in preventing delayed
circulatory dysfunction [68]. The International
Ascites Club has recently established recommendations for albumin therapy in these groups of
patients [4,13,69].
Additional indications for albumin therapy in
cirrhotic patients include spontaneous bacterial peritonitis (SBP), hepato-renal syndrome, and
post-paracentesis syndrome. The clinical results
of albumin administration in these settings are
conflicting and the interested reader is referred
to excellent reviews by Vincent [3] and Boldt
[70]. In SBP, albumin in association with antibiotics was found to reduce mortality and probability of the development of hepato-renal syndrome [10,11,71,72].
According to the above-mentioned recommendations of the Italian Society of Transfusion
Medicine and Immunohematology (SIMTI)
Working Party [54], the uses of albumin in chronic states of hypoalbuminaemia include:
A. Ascites not responsive to diuretics (occasionally appropriate indication; Grade 2C
recommendation).
B. Large volume paracentesis (appropriate indication; Grade 1C+ recommendation).
C. Hepato-renal syndrome type 1 and type 2 (occasionally appropriate indication; Grade 2B
recommendation) (73).
D. Spontaneous bacterial peritonitis (appropriate indication; Grade 1C+ recommendation).
Other indications
Serum albumin has been shown to be a free radical scavenger. Because of this function some authors have recommended it as an adjuvant therapy in patients with sepsis [74]. However, to date,
there are no confirmed data on the benefits of
albumin therapy in this patient population, and
International Surviving Sepsis Campaign guidelines do not recommend the use of human albumin for volume replacement in severe sepsis and
septic shock [75]. On the other hand, in other
conditions associated with systemic inflammation

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such as acute lung injury or acute respiratory distress syndrome, albumin therapy was found to improve oxygenation and hemodynamic status [64].
Surprisingly, there is only limited evidence to justify the use of human albumin in patients with
malnutrition, protein-losing entheropaties, and
malabsorption. Accordingly, albumin therapy is
not recommended in these patient populations
[54]. However, patients with severe diarrhea
who cannot tolerate enteral nutrition and do
not respond to short-chain peptides and mineral formulas, may benefit from albumin therapy
(Grade 2C recommendation). The effects of correcting hypoalbuminaemia in nephrotic syndrome
are short-lived, as most of the administered albumin is quickly eliminated by the kidneys.
Nonetheless, short-term infusion of 2025% albumin can be used in hypoalbuminemic patients
with hypovolemia and/or secondary complications (e.g., pulmonary oedema, acute pulmonary oedema, and/or acute renal failure (Grade
2C recommendation) [76].
Emerging medical uses of albumin
In keeping with the increasing knowledge about
albumin as the key blood component that binds,
inactivates, and transports blood-borne toxins to
other organs for metabolism and/or excretion,
albumin dialysis, large-pore hemofiltration, and
albumin exchange have emerged as liver support therapies [7784]. One of the key engineering features of some of these technologies (e.g.,
Prometheus, SEPET, Evaclio, SeptX) is
the use of a membrane permeable to albumin,
albumin-bound toxins, inflammatory mediators,
and other middle molecules [7880,83].
Albumin filtration and dialysis
Currently, there is no direct, satisfactory treatment for hepatic failure and patients must receive a transplant or endure prolonged hospitalization with significant morbidity and mortality.
Because of the scarcity of donor organs, many
liver failure patients will die awaiting a transplant. In addition, many patients do not qualify
for transplantation due to medical and socio-psychological reasons. Thus, liver support strategies
are being developed with the aim of either supporting patients until an appropriate organ becomes available for transplantation or until their
livers recover from injury (regenerate). Until the
1990s, hepatic failure was thought to be caused
by small water-soluble molecules and most liver

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Figure 1. Schematic depiction of the MARS system. Blood from the

patient is pumped through the intrafiber space of high-flux
dialyzer made of the membrane which is impermeable to
albumin. Albumin solution is recirculated at 250 ml/min
through an extrafiber space of dialyzer, 2 adsorber cartridges filled with vapor-activated carbon and an anionexchanger resin, respectively, and an intrafiber space of
the second dialyzer. Additionally, the dialysate enriched
with human serum albumin (20%) undergoes conventional dialysis to remove water-soluble toxins (ammonia,
urea, creatinine).
assist techniques relied on detoxification using
dialysis and chemical sorbents (charcoal, resin).
Today, the repertoire of substances that accumulate in the blood in hepatic failure and cause encephalopathy (coma) and damage of the liver and
other organs also includes albumin-bound toxins, mediators of inflammation (e.g., cytokines,
chemokines), vasoactive substances, inhibitors
of cell/tissue repair, endotoxin, and other small
and middle molecules. In addition, many noxious plasma components exist as complex molecules (multimers). It is difficult to remove these
compounds from the blood stream using chemical sorbents or dialysis/filtration devices utilizing membranes that have only limited (if any)
permeability to albumin [80,81].
The concept of albumin dialysis (a rather imprecise term) was developed in the early 1990s by
a group of investigators from Rostock University
(Germany) [77]. The MARS system (an acronym for molecular adsorbent recirculating system) was designed to facilitate removal from the
blood of not only small dialyzable molecules, but
also albumin-bound toxins (Figure 1). The first
circuit consists of human serum albumin, which
is in contact with the patients blood through a
semipermeable membrane. It has 2 sorbent columns loaded with vapor-activated carbon and an
ion exchanger resin, respectively, to clean the

Ann Transplant, 2013: 18: 205-217

Figure 2. Schematic depiction of the Prometheus system. Blood

from the patient is pumped through a large-pore hemofilter. A 250-kDa plasma fraction enters a circuit that includes 2 columns loaded with adsorbents (exchange resins). Purified plasma fraction is reconstituted with blood,
which is subjected to high-flux hemodialysis.
albumin after it has absorbed toxins that diffused
across the albumin-tight membrane into the circuit from the patients blood. The second circuit
consists of a hemodialysis system and is used to
remove water-soluble toxins (e.g., ammonia, creatinine, urea) from the first circuit.
The Prometheus liver support system is a direct
competitor of the MARS system [78]. During
treatment, which involves fractionated plasma
filtration (FPF) using an albumin-leaking membrane, a large MW fraction of the separated plasma undergoes regeneration (purification) using 2 sorbent columns before it is returned to the
patient via back filtration through the same FPFfilter. In addition, conventional HD is performed
downstream of FPF to increase clearance of small
water-soluble toxins (Figure 2). During therapy,
the fractionated plasma filtrate is thought to be
cleared of albumin-bound toxins. However, valuable proteins, including protein C, blood coagulation factor VIII, antithrombin III, and other
beneficial incidental molecules are also removed
from the filtrate, which may cause coagulation
problems and other adverse effects [85].
Over the years, the MARS system has been used
in many thousands of patients worldwide, mostly as an extracoporeal liver assist therapy in patients with acute exacerbation of chronic liver
disease (cirrhosis) [8688]. The Prometheus
system was tested principally in Europe and in a
much smaller number of patients [89]. Published

Rozga J. et al. Albumin therapy

data indicate that these therapeutic modalities

are safe and capable of improving blood chemistries, hepatic encephalopathy, and long-term
relief of pruritus in patients with chronic liver
failure [89,9093]. Additionally, MARS therapy leads to improvement in systemic circulatory
dysfunction. Despite these encouraging data, no
evidence of improvement in patient survival has
been noted in large-scale prospective controlled
trials conducted in patients with acute-on-chronic hepatic failure and severe hepatic ecephalopathy (RELIEF and HELIOS studies of the MARS
and Prometheus, respectively) [94,95]. Thus,
after nearly 2 decades of steadily growing clinical
experience with these therapies, it is reasonable
to postulate that indications for their use should
be re-defined; perhaps narrowed to treatment of
severe hepatic encephalopathy, hepatorenal syndrome, and cholestatic liver disease. In establishing indications for MARS or Prometheus, it is
also important to realize that the costs involved
in treating patients with these liver assist devices are substantial.
An example of an unorthodox use of HD is the
so-called single-pass albumin dialysis (SPAD) [82].
During this form of dialysis, the patients blood
flows through a circuit with a high-flux hollow
fiber hemodiafilter, identical to that used in the
MARS system. The other side of this membrane
is cleansed with an albumin solution in counterdirectional flow, which is subsequently discarded after passing through the filter. Hemodialysis
can be performed in the first circuit via the same
high-flux hollow fibers [82]. The clinical efficacy
of this therapeutic measure is expected to be limited, because only the water-soluble toxins and
toxins that only weakly bind to albumin can be removed from the blood using SPAD. Additionally,
similarly to MARS, SPAD is not effective in removing pro-inflammatory mediators (cytokines,
chemokines, anaphylatoxins, leukotriens) and endotoxins. In direct in vitro comparison, the detoxification capacity of SPAD was similar to or even
greater than that of the MARS system (e.g., a significantly greater reduction in bilirubin levels)
[82]. However, performing SPAD requires 1000
ml of human albumin solution (20%).
Albumin exchange
Conventional dialysis and hemofiltration devices have a molecular weight (MW) cutoff of up
to 5 kDa to 10 kDa and are designed to avoid
sieving of albumin. While high-flux dialyzers
may have a MW cutoff of greater than 66 kDa

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(MW of albumin), the sieving of albumin and inflammatory mediators that have a MW between
15 and 50 kDa is minimal because many filtration membranes are hydrophobic and prone to
clogging and cake formation by plasma proteins. For these reasons, currently available dialyzers and hemofilters are useless for performing blood purification in hepatic failure where
large quantities of circulating albumin-bound
and unbound toxins, inflammatory mediators,
and other harmful molecules must be removed.
These observations have prompted the development of blood filtration devices with albuminleaking membranes [79,80]. The concept of selective large-pore hemofiltration, gains further
support from the knowledge of the role of albumin in blood detoxification. In this capacity, albumin inactivates numerous toxins and other ligands through binding and transports them to
the liver for chemical transformation and excretion, or to the kidney for excretion. In hepatic
failure, there is a rapid and significant accumulation of albumin bound toxins, including bile
acids, phenols, bilirubin, mercaptans, dioxin-like
substances, tryptophan, and many other noxious
molecules. When the binding capacity of albumin is exhausted, the effects of circulating toxins and harmful mediators become more pronounced. Accumulation of these components in
the blood may even become life- threatening, affecting not only the liver, but also the brain, kidneys, lungs, and immune system. Additionally,
it was demonstrated that during hepatic failure,
sepsis, and other pathological conditions associated with severe toxemia and systemic inflammation, circulating albumin undergoes structural
and functional modifications that negatively affect its ability to bind toxins [96,97]. In the recent study by Jalan et al. [98], all parameters estimating albumin function (functional capacity
of the binding sites, transport efficiency, and detoxification efficiency) were found to be severely compromised in patients with acute decompensation of cirrhosis.
From the medical standpoint, these data have
2 potential implicatations. First, albumin-binding capacity (ABC) alone or in combination with
other measures of hepatic function may emerge
as a valuable prognostic test in patients with liver failure. Second, hemofiltration using an albumin-leaking membrane may be a simple and
effective method for purifying blood from albumin-bound toxins and restoring normal functions of the circulating albumin by replacing defective forms of albumin and albumin molecules

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saturated with toxins with normal albumin and

incidental molecules lost during therapy (e.g.,
water, electrolytes, hormones, vitamins, amino acids, and certain blood clotting factors). Indeed,
removal of the circulating albumin is also advocated by the Jalan group, University College
London (London, UK). Accordingly, the latest version of their liver support device (UCLARSeNEL) consists of 3 components: a plasma
separation filter, an endotoxin ligation component, and a high cut-off (100 kDa) plasma filter. The device was found to improve survival in
pigs with paracetamol-induced acute liver failure and this technology is expected to be tested in human patients [83].

Final Remarks & Conclusions

The term critical illness is vague and is not used
to describe any specific disease. In the context
of albumin therapy, it may apply to severe plasma volume deficit of any etiology, fulminant or
subfulminant hepatic failure, advanced cirrhosis requiring large-volume paracenthesis, spontaneous bacterial peritonitis, and other conditions that can result in or become exacerbated
by hypoalbuminaemia (e.g., pancreatitis, sepsis, crush injury, and extensive burns). Each of
these illnesses has a unique pathophysiology,
blood chemistry profile, and clinical course,
and requires complex therapeutic measures.
Additionally, because of the heterogeneity of
each patient population, the goals of albumin
therapy may be different, and in many instances albumin supplementation is not indispensable. Even if there is good reason to believe that
it is, it is difficult to demonstrate because in control subjects, albumin would have to be ommited or replaced with another colloid. For these
reasons it is difficult (and sometimes impossible) to design clinical trials in which the relevance of albumin administration in the critical
care setting can be discerned in an objective,
unbiased manner [73]. From the standpoint of
evidence-based medicine, it is crucial to pay attention to the methodology used in the studies included in any systematic review and to be
careful when defining its end-points and outcomes. The infamous Cochrane meta-analysis
published in 1998 [5] is a good example of a
study that violated these rules. Indeed, its key
finding that albumin supplementation may increase the overall risk of death and morbidity in
critically ill patients was not confirmed in later
randomized controlled trials and meta-analyses
[2,7,10,42,49,62]. When reviewing the literature

Ann Transplant, 2013: 18: 205-217

for this review it was noted that studies, in which

administration of albumin produced measurable therapeutic effects were those in which 2 or
more of the known functions of albumin worked
in concert (e.g., maintenance of colloid osmotic pressure in combination with the ability of
albumin molecules to seal leaky blood vessels
preventing escape of proteins) [99]. Not surprising, due to its long half-life, albumin is effective in diseases in which hypoalbuminaemia
results from decreased albumin synthesis [100].
In conclusion, based on the published data, the
use of albumin in modern critical care medicine
remains controversial. Although albumin supplementation for fluid resuscitation does not increase the relative risk of death or morbidity, it
offers no measurable benefits when compared
to crystalloids and other colloids. In acute conditions and chronic states of hypoalbuminaemia, albumin therapy is recommended in the
following settings.
After major surgery;
Hemorrhagic shock with an inadequate response to crystalloids and non-protein colloids;
Extensive burns during the period of transcapillary leakage;
Ascites and peripheral oedema during the posttransplant (liver) period;
Spontaneous bacterial peritonitis with ascites;
Refractory ascites not responsive to diuretics;
Large-volume paracentesis;
Post-paracentesis syndrome;
Treatment of hepatorenal syndrome as an adjunct to vasoconstrictors.
New emerging indications for albumin therapy
are linked to the anti-oxidant activity of albumin
and its effects on capillary integrity (e.g., sepsis,
acute lung injury, or acute respiratory distress
syndrome). In recent years, large-pore hemofiltration and albumin exchange have emerged as
promising liver support therapies for liver failure
and other toxic syndromes. They are designed
to remove a broad range of blood-borne toxins
and to restore normal functions of the circulating albumin by replacing defective forms of albumin and albumin molecules saturated with
toxins with normal albumin.
In view of the ongoing worldwide shortage and
high cost of human albumin (both native and recombinant), new usage criteria, protocols, and
guidelines for appropriate utilization of albumin are needed.

Rozga J. et al. Albumin therapy

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