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Abstract

Being one of the most abundant proteins in human and other mammals, albumin plays a crucial role in transporting various endogenous and exogenous molecules and maintaining of colloid osmotic pressure of the blood. It is not only the passive but also the active participant of the pharmacokinetic and toxicokinetic processes possessing a number of enzymatic activities. A free thiol group of the albumin molecule determines the participation of the protein in redox reactions. Its activity is not limited to interaction with other molecules entering the blood: of great physiological importance is its interaction with the cells of blood, blood vessels and also outside the vascular bed. This topic review contains data on the enzymatic, inflammatory and antioxidant properties of serum albumin.
Entry
Serum Albumin
Daria A. Belinskaia 1, *, Polina A. Voronina 1, Anastasia A. Batalova 1and Nikolay V. Goncharov 1,2


Citation: Belinskaia, D.A.; Voronina,
P.A.; Batalova, A.A.; Goncharov, N.V.
Serum Albumin. Encyclopedia 2021,1,
65–75. https://dx.doi.org/10.3390/
encyclopedia1010009
Received: 23 November 2020
Accepted: 24 December 2020
Published: 27 December 2020
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1
Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, pr. Torez 44,
194223 St. Petersburg, Russia; paulina291731@gmail.com (P.A.V.); batalova.phys@gmail.com (A.A.B.);
ngoncharov@gmail.com (N.V.G.)
2Research Institute of Hygiene, Occupational Pathology and Human Ecology, p/o Kuzmolovsky,
188663 Leningrad Region, Russia
*Correspondence: daria.belinskaya@iephb.ru
Definition: Being one of the most abundant proteins in human and other mammals, albumin plays
a crucial role in transporting various endogenous and exogenous molecules and maintaining of
colloid osmotic pressure of the blood. It is not only the passive but also the active participant
of the pharmacokinetic and toxicokinetic processes possessing a number of enzymatic activities.
A free thiol group of the albumin molecule determines the participation of the protein in redox
reactions. Its activity is not limited to interaction with other molecules entering the blood: of great
physiological importance is its interaction with the cells of blood, blood vessels and also outside the
vascular bed. This entry contains data on the enzymatic, inflammatory and antioxidant properties of
serum albumin.
Keywords: albumin; blood plasma; enzymatic activities; oxidative stress
1. Introduction: Physico-Chemical, Evolutionary and Genetic Aspects
Albumin is a family of globular proteins, the most common of which are the serum
albumins. All the proteins of the albumin family are water-soluble and moderately soluble
in concentrated salt solutions. The key qualities of albumin are those of an acidic, highly
soluble and very stable protein, able to withstand temperatures of 60
C for 10 h [
1
].
Human serum albumin (HSA) has a total of 83 positively charged residues (Arg + Lys) and
98 negatively charged residues (Asp + Glu), with a theoretical pI of 5.12. Albumins are
commonly found in blood plasma and differ from other blood proteins in that they are not
glycosylated. Several other blood transport proteins are evolutionarily related to serum
albumin, including alpha-fetoprotein, vitamin D-binding protein and afamin [
2
,
3
]. This
family is only found in vertebrates [
4
]. The four canonical human albumins are arranged
on chromosome 4 region 4q13.3 in a tandem manner [
5
]. The human albumin gene is 16,961
nucleotides long from the putative ‘cap’ site to the first poly(A) addition site. It is split into
15 exons that are symmetrically placed within the three domains thought to have arisen by
triplication of a single primordial domain.
Humans are not the only organisms for which serum albumin plays a critical role;
albumin has also been characterised in an extensive number of species, including (but not
limited to) canines, chickens, several species of frogs, lampreys, pigs and salamanders
(an exhaustive list can be found at albumin.org [
6
]). Albumin-like proteins, which were
sequenced from a sea urchin, were found to have a cysteine binding pattern similar to that
seen amongst other proteins in the albumin family [7].
The precursor of serum albumin (preproalbumin) has the N-terminal peptide, which
is cut off before the protein leaves the rough endoplasmic reticulum. The product of this
removal (proalbumin) is transported to the Golgi apparatus. In secretory granules, the
limited proteolysis occurs and the mature non-glycosylated albumin is secreted into the
extracellular environment [
1
]. Synthesis occurs in the polysomes of hepatocytes, and in
healthy adults, 10–15 g/day of albumin can be produced; this accounts for nearly 10% of
Encyclopedia 2021,1, 65–75. https://dx.doi.org/10.3390/encyclopedia1010009 https://www.mdpi.com/journal/encyclopedia
Encyclopedia 2021,166
total protein synthesis in the liver [
8
]. While 30% of albumin is maintained in the plasma,
the remaining pool is found predominantly in skin and muscle tissue.
The molecule of HSA consists of 585 amino acids forming one polypeptide chain. The
length of the primary sequence can be different in albumins of other species; for example,
584 amino acids in bovine serum albumin (BSA) and 583 residues in rat serum albumin
(RSA). The amino acid compositions of HSA and RSA are 73.0% identical, of BSA and
RSA—69.9%. Molecular weight of HSA based on amino acid composition is 66.439 kDa,
BSA—66.267 kDa, RSA—65.871 kDa; however, the values of molecular weight can vary
because of post-translational modifications and genetic variants. The secondary structure
of the protein contains about 67% helical structures next to 33% of turn and extended
chain configurations without any β-sheets [9] (Figure 1). The three-dimensional structure
of HSA was resolved rather late, only in the 1990s [
10
]. A similar structure of BSA was
obtained in 2012 [
11
], but the three-dimensional structure of albumin of rats, the principal
animals used in pharmacological and toxicological experiments, has not been obtained
yet. Three homologous domains (I, II, III), consisting of two subdomains (A, B) form a
three-dimensional structure of the protein, which is rather labile (Figure 1).
Encyclopedia 2021, 1, FOR PEER REVIEW 2
and in healthy adults, 1015 g/day of albumin can be produced; this accounts for nearly
10% of total protein synthesis in the liver [8]. While 30% of albumin is maintained in the
plasma, the remaining pool is found predominantly in skin and muscle tissue.
The molecule of HSA consists of 585 amino acids forming one polypeptide chain.
The length of the primary sequence can be different in albumins of other species; for
example, 584 amino acids in bovine serum albumin (BSA) and 583 residues in rat serum
albumin (RSA). The amino acid compositions of HSA and RSA are 73.0% identical, of
BSA and RSA69.9%. Molecular weight of HSA based on amino acid composition is
66.439 kDa, BSA66.267 kDa, RSA65.871 kDa; however, the values of molecular
weight can vary because of post-translational modifications and genetic variants. The
secondary structure of the protein contains about 67% helical structures next to 33% of
turn and extended chain configurations without any β-sheets [9] (Figure 1). The
three-dimensional structure of HSA was resolved rather late, only in the 1990s [10]. A
similar structure of BSA was obtained in 2012 [11], but the three-dimensional structure of
albumin of rats, the principal animals used in pharmacological and toxicological exper-
iments, has not been obtained yet. Three homologous domains (I, II, III), consisting of
two subdomains (A, B) form a three-dimensional structure of the protein, which is rather
labile (Figure 1).
Figure 1. The structure of serum albumin. Domains I, II and III are shown in purple, blue and
green, respectively; each domain consists of two subdomains A and B. The albumin molecule does
not contain β-sheets, α-helices are presented as cylinders. To create the figure, a three-dimensional
structure of human serum albumin from the PDB database, code 3JQZ [12], was used.
There are dozens of genetic variants of HSA (for exhaustive list see [6]). Possible ef-
fects of some single point mutations on the ligand-binding capabilities of HSA were in-
vestigated by studying the interactions between the strongly bound drugs warfarin, sa-
Figure 1.
The structure of serum albumin. Domains I, II and III are shown in purple, blue and
green, respectively; each domain consists of two subdomains A and B. The albumin molecule does
not contain
β
-sheets,
α
-helices are presented as cylinders. To create the figure, a three-dimensional
structure of human serum albumin from the PDB database, code 3JQZ [12], was used.
There are dozens of genetic variants of HSA (for exhaustive list see [
6
]). Possible
effects of some single point mutations on the ligand-binding capabilities of HSA were
investigated by studying the interactions between the strongly bound drugs warfarin, sali-
cylate and diazepam, and five structurally characterised genetic variants of the protein [
13
].
Equilibrium dialysis data revealed pronounced reductions in high affinity binding of all
Encyclopedia 2021,167
three ligands to HSA Canterbury (313 Lys
Asn) and to HSA Parklands (365 Asp
His).
By contrast, unchanged binding of the drugs was found in the case of HSA Verona (570
Glu
Lys). Salicylate was the only drug bound with a lower affinity to HSA Niigata (269
Asp
Gly), whereas binding of both salicylate and diazepam to HSA Roma (321 Glu
Lys)
were moderately reduced. In about half of the cases of diminished binding, the primary
association constant was reduced by 1 order of magnitude, giving rise to an increase in the
unbound fraction of the drugs of 500% or more at therapeutically relevant molar ratios of
drug and protein. Changes in protein charge play minor importance for reduced binding,
though conformational changes in the 313–365 region of the proteins seem to be the main
cause for diminished binding of these ligands [13].
Albumin normally is not covered with hydrocarbons and can bind different endoge-
nous and exogenous ligands: water and metal cations, fatty acids, hormones, bilirubin,
transferrin, nitric oxide, aspirin, warfarin, ibuprofen, phenylbutazone, etc. [
14
]. Ligand
binding occurs at two primary sites (Sudlow site I in subdomain IIA and Sudlow site II
in subdomain IIIA) and several secondary ones. When albumin interacts with different
substances, the effects of cooperativity and allosteric modulation occurs, which is usually
inherent to multimeric macromolecules [
15
,
16
]. The albumin molecule contains 17 disulfide
bonds and one free thiol group in Cys34, which determines the participation of albumin in
redox reactions.
2. Enzymatic Properties
Albumin is not only the passive but also the active participant of the pharmacokinetic
and toxicokinetic processes. Numerous experiments showed the esterase or pseudoesterase
activity of albumin against
α
-naphtylacetate and p-nitrophenylacetate (NPA), fatty acid
esters, aspirin, ketoprofene glucuronide, cyclophosphamide, nicotinic acid esters, octanoyl
ghrelin, nitroacetanilide, nitrofluoroacetanilide and organophosphorus pesticides [
17
19
].
Acetylation is a typical example of the pseudoesterase activity of albumin when the con-
sumption of the substrate is due to the formation of covalent bonds with the participation
of many amino acid residues of the albumin molecule. Acetylation of albumin by NPA was
found to occur at 82 amino acids (aa) including lysine (59 aa), serine (10 aa), threonine (8 aa),
tyrosine (4 aa) and aspartate (1 aa) residues [
20
], with adducts at the lysine residues being
the most stable.
Of special interest is the phosphatase activity of albumin, i.e., the phosphomonoesterase
(EC 3.1.3
. . .
?) [
21
], RNA-hydrolase or phosphodiesterase (EC 3.1.4.16 ?) [
22
] and phos-
photriesterase (EC 3.1.8.1 and 3.1.8.2) [
23
,
24
] activities. The subclass 3.1.8 (hydrolases
of phosphotriesters) contains aryldialkylphosphatase (EC 3.1.8.1) and diisopropylfluo-
rophosphatase (EC 3.1.8.2) [
25
,
26
]. Aryldialkylphosphatase is known as paraoxonase,
which hydrolyses esters of tribasic phosphoric acid, of dibasic phosphonic acid and of
monobasic phosphinic acid. Divalent cations (mainly Ca
2+
) are required for activity of
paraoxonase [
27
]; the fundamental difference of albumin is the lack of dependence on
Ca
2+
, that is used for the differential analysis of the activities of these enzymes [
24
,
28
]. In
toxicology, understanding the mechanistic interactions of organophosphates (OPs) with
albumin could help in the development of new types of antidotes [
29
]. Among the other
activities of serum albumin, one should note its prostaglandin D synthase and other activi-
ties associated with prostanoid metabolism [
30
32
]. Quite exotic activities for albumin are
glucuronidase activity [
33
,
34
] and the enolase activity [
35
]; the latter can be used for the
differential diagnostics of benign and malignant tumors.
Bovine and human serum albumins catalyse the aldol reaction of aromatic aldehydes
and acetone, with saturation kinetics and moderate and opposite enantioselectivity; the
reaction occurs at the binding site in domain IIa and is inhibited by warfarin [
36
]. A
101-amino-acid polypeptide derived from the sequence of the IIA binding site of HSA was
identified, containing eight cysteine residues to form disulfide bridges that stabilise the
polypeptide structure [
37
]. This protein retains the IIA fragment’s capacity to bind typical
ligands such as warfarin and efavirenz and other albumin’s functional properties such as
Encyclopedia 2021,168
aldolase activity and the ability to direct the stereochemical outcome of a diketone reduction.
It was suggested that some simple reactions that were catalysed by the serum albumin
with Michaelis-Menten kinetics involve nonspecific substrate binding and catalysis by
local functional groups [
38
]. These different active sites can bind promiscuously an array
of hydrophobic negatively charged ligands, with a lysine residue acting as a primitive
active site allowing these promiscuous activities to take place [
39
]. A method for predicting
catalytic and substrate promiscuity using a graph-based representation known as molecular
signature was suggested and enolase activity was among the first promiscuous activities
described [
40
]. However, the binding mechanism via hydrophobic interaction with the
binding site can be entirely different in presence of protein denaturing agent like urea, with
electrostatic interaction playing a major role [41].
Most, if not all, enzymes are capable of catalysing physiologically irrelevant secondary
promiscuous reactions in addition to the reactions that they have evolved to catalyse, and
the universe of promiscuous activities available in nature was found to be enormous [
42
,
43
].
Nevertheless, we suggest that the promiscuity of albumin is principally different from that
of the specialised enzymes, in that it was evolved as a result of not acquiring but a loss of
some specialised activities, such as esterase (hydrolase) activities with digestive functions.
The Kemp elimination is regarded to be a prototypical reaction used to study proton
abstraction from carbon. The reaction takes place at the so-called Stern layer, the interface
between a micellar head or protein surface and water, and a significant rate acceleration
can be achieved regardless of the precise positioning of substrates [
44
,
45
]. It is interesting
to note that the reaction rate is decreased in protic solvents such as water as compared
with aprotic organic solvents, the electrostatic term of the hydrogen bonds being the main
factor for the large inhibitory effect of water; the presence of an external electric field
oriented in the direction of the charge transfer increases the reaction rate [
46
]. On the
other hand, the mechanism of the Kemp elimination in protein molecules was strongly
associated with the presence of a catalytic base (Trp, Tyr, Phe) and a hydrogen bond donor
(Lys, Arg, Ser, Tyr, His, water molecule) [
47
]. To this end, we were the first who explained
the albumin mediated hydrolysis of some substrates by existence of catalytic dyads (as
compared with catalytic triads in cholinesterases) His-Tyr or Lys-Tyr, where the histidine
or lysine residues function as the acidic residues and hydrogen bond donors, whereas Tyr
residue is a catalytic base [17].
In 1986, concern was expressed over the fact that the current classification of esterases
did not reflect the real state of things. Albumin was just used as an example of the protein
that exhibits the esterase activity but has no place in the classification [
48
]. The broad
substrate specificity and no dependence on Ca
2+
do not allow for the identification of
albumin as any of the enzymes with their numbers in the enzyme nomenclature. The place
of albumin in the nomenclature of enzymes remains yet to be determined.
3. Effect of Molecular Crowding on the Functional Properties of Albumin
In live systems, in contrast to
in vitro
experiments, biochemical processes take place in
an environment containing high concentrations of macromolecules (50–400 mg/mL). Such
conditions are called molecular crowding. Due to the dense environment, the volume of
available solvent decreases, which might affect protein structure, folding, shape, conforma-
tional stability, binding of small molecules, enzymatic activity, protein-protein interactions,
protein-nucleic acid interactions and pathological aggregation [
49
]. In blood plasma, the
density of macromolecules reaches 80 mg/mL, which causes noticeable crowding effects
and affects the conformation and functional characteristics of plasma proteins. Crowding
effects have been proved for albumin too.
Ota and Takano, with the help of by Raman spectroscopy, showed that crowded milieu
influenced the strength of intramolecular hydrogen bonds of BSA molecule. This effect, in
turn, led to the BSA molecule adopting a more compact structure [50].
Zhu et al. studied the effect of molecular crowding on the binding of saturated
medium-chain FAs and unsaturated long-chain FAs to BSA [
51
]. Polyethylene glycol
Encyclopedia 2021,169
PEG2000 was used to simulate the conditions of crowded milieu. Adding of the polymer
to the medium improved the binding of medium-chained FAs but weakened the binding
of the long-chain FAs. Having analysed the secondary structure of BSA, the authors have
concluded that gradual increase of the medium density makes the albumin molecule more
friable. Thus, taking into account the literature data available, it can be assumed that
the constants of esterase and binding and esterase activity of albumin in the bloodstream
will differ from the constants measured in the “ideal solution” of
in vitro
and in silico
experiments. Definitely, it is necessary to develop the test systems that simulate the activity
of albumin under conditions of molecular crowding.
4. Albumin and Redox Modulation
In healthy human organism, about 80% of all detected plasma thiols are those of
albumin [
52
]. The Cys34 residue is able to neutralise hydrogen peroxide, peroxynitrite,
superoxide anion and hypochlorous acid, being oxidised to sulfenic acid (HSA-SOH) [
53
,
54
].
A list of the albumin activities associated with redox modulation of blood plasma and
intercellular liquid consists of the thioesterase [
55
,
56
], glutathione peroxidase and cysteine
peroxidase activities, as well as the peroxidase activity towards lipid hydroperoxides [
57
59
].
The important role of two cysteine residues of albumin, Cys392 and Cys438 should be noted,
which form redox active disulfide in the complex of albumin with palmitoyl-CoA [
59
]. Al-
bumin is a trap of radicals due to six methionine residues, but Cys34 is the most important
for this function [
53
,
60
]. The N-terminal region of human albumin, Asp-Ala-His-Lys, in the
complex with cuprum ions has the superoxide dismutase activity [
61
]. Albumin can stoi-
chiometrically inactivate hydrogen peroxide and peroxynitrite due to reversible oxidation of
the Cys34 residue to the sulfenic acid derivative [
53
]. This group of activities may probably
be supplemented by the cyanide detoxification reaction with the formation of thiocyanate,
which is catalysed by the regions of subdomain IIIA without the involvement of Tyr411 [
62
].
In addition, the prooxidant properties of albumin should be noted: the albumin-bound Cu
2+
ions strengthen the formation of ascorbate radical, followed by oxidation of the formed Cu
+
ions by molecular oxygen and protons again to Cu
2+
[
63
]. Albumin is more exposed to the
reactive oxygen species (ROS) than other proteins, and the percentage of oxidised albumin
serves as a biomarker of the severity of oxidative stress accompanying various diseases. The
level of Cys34-cysteinylated albumin is significantly increased in patients suffering from
diabetes mellitus, liver and kidney diseases [
64
]. Oxidised albumin has been proved to be
a biomarker of the heaviness of such pathologies as Duchenne muscular dystrophy [
65
],
Alzheimer’s and Parkinson’s diseases [
66
,
67
], hyperparathyroidism [
68
], acute ischemic
stroke [
69
], etc. An extensive study of Japanese residents revealed that the risk of atheroscle-
rosis is inversely correlated with the percentage of oxidised form of serum albumin [
70
]. In
2020, Violi et al. demonstrated that there is an independent direct correlation of mortality in
COVID-19 with HSA level. The author suggested that this association might be connected
with anticoagulant and antioxidant properties of albumin [71].
Glycation (covalent binding of monosaccharides to the side chains of arginines and
lysines) is another possible chemical modification that can affect the structural and func-
tional features of albumin [
72
]. More than 60 albumin glycation sites have been identified
so far, and Lys525 is considered to be the most reactive one [
73
,
74
]. As in the case of the
effect of Cys34 oxidation on the binding activity of Sudlow sites, the data on the effect
of glycation on the antioxidant properties of albumin are contradictory [
75
78
]. The con-
troversial behavior of glycosylated albumin in biochemical experiments might be due
to interspecies differences, the nature and concentration of the involved carbohydrates
(glucose, methylglyoxal), and the conditions of incubation with monosaccharides [
72
]. The
differences between human and bovine albumin are of particular interest: glycation of
HSA sharply decreases its antioxidant activity, while glycation of BSA tends to enhance its
antioxidant properties. These data correlate with the results of computational experiments
aimed at studying the effect of the redox status of HSA and BSA on their binding and
Encyclopedia 2021,170
esterase activity towards paraoxon [
79
,
80
]. According to the data, human and bovine
albumins react differently to the oxidation of Cys34 to sulfenic and sulfinic acids.
Fatty acids (FAs) appear to play the main role in the regulation of the antioxidant
properties of albumin. For the first time, this conclusion was made by Gryzunov and
co-authors [
63
]. Binding of FAs changed the conformations of Sudlow sites I and II and
increased the fluorescence quantum yield of the probes dansylamide (ligand of Sudlow site
I) and dansylsarcosine (ligand of Sudlow site II); further, FAs increased the steric availability
of Cys34 thiol group and strengthened its reactivity towards 5,5’-dithiobis-2-nitrobenzoic
acid (DTNB). Thus, the binding of FAs by albumin makes possible a finely regulated
conjugation of two important activities of the protein: ligand transport and antioxidant
defense [
63
]. Additionally, albumin is able to enhance the antioxidant protection of the
body by binding bilirubin (a ligand of Site III [
81
]) and polyunsaturated fatty acids, which
interact with residues Arg117, Lys351 and Lys475 [53].
5. Albumin Interaction with Endothelial Cells Is a Basis for Its Diagnostic and
Therapeutic Application
The level of albumin in blood plasma or serum, as well as in urine, from the point
of view of diagnostics is the level of not just a major, but an integrative protein of the
whole organism, which depends on two fundamental properties: the protein-synthesising
function of the liver (hence its role as a negative acute phase protein [
82
]) and the functional
state of the vascular endothelium, which determines the integrity of the blood-tissue
barriers. The relationship between endothelial integrity and the level of albumin in urine
is the most studied phenomenon in medical practice, indicating primarily the pathology
of the kidneys, but also the state of other components of the blood and cardiovascular
system [8385].
Endothelial glycocalyx is a membrane-bound covering of the endothelial cells that
is found on the intraluminal surfaces of all blood vessels and organs and is composed
of glycoproteins that hold between 700 and 1000 mL of non-circulating plasma volume.
This intraluminal layer maintains its own colloidal-osmotic pressure (COP) because of its
plasma protein content (primarily albumin) that is trapped within the endothelial glyco-
calyx layer (EGL). Subsequently, it also has a higher COP than that of circulating plasma
because of its retention of plasma proteins [
86
]. For this reason, the EGL is thought to
contribute to approximately 60% of the intravascular COP [
87
]. Structurally, the EGL is a
negatively charged gel-like layer that is composed of an intricate array of oligosaccharide
and polysaccharide chains called glycosaminoglycans (e.g., heparan sulfate, hyaluronic
acid, chondroitin sulfate, dermatan sulfate and keratan sulfate), which are covalently
bonded to glycosylated membrane proteins called proteoglycans (antithrombin III, inte-
grins and selectins) and membrane bound proteoglycans such as syndecans, glypicans
and perlecans, and other plasma proteins. The EGL ranges in thickness between 0.1 and
4.5
µ
m, depending on the location/size of the vessel, and maintains an active reservoir
of proteins and polysaccharides, such as antithrombin III and heparan sulfate [
86
]. An
intact EGL maintains a separation between circulating plasma and vascular endothelial
cells, creating an “exclusion zone”, which keeps the formed elements of the blood (red
cells, white cells and platelets) from actually contacting the surface of the endothelial cells.
In the presence of an intact EGL, water and electrolytes will pass freely across this layer
and then beyond the endothelial cells through the intercellular clefts. With the exception of
albumin, this exclusion zone also prevents high molecular weight colloids that are >70 kDa
from contacting the endothelial cells. Albumin is the only major plasma protein that moves
easily between the plasma and the EGL because of the selectively permeability nature of
the EGL to natural colloids with molecular weights < 70 kDa [
88
]. A detailed schematic
illustration of the space between the plasma and the EGL with albumin molecules moving
through the cleft is shown in Figure 1b of the work of Kundra et al. [89].
A large-scale search for new diagnostic indicators using modern metabolomics tech-
nologies made it possible to identify from a huge set of only four simple indicators of
blood plasma, including the level of albumin, which with high accuracy allows us to
Encyclopedia 2021,171
assess the severity of a person’s health condition and predict the likelihood of mortality
for patients, regardless of their age, gender and nature of the disease [
90
]. In patients of
intensive care units, the use of a simple ratio of positive (C-reactive protein) and negative
(albumin) acute phase proteins can significantly increase the accuracy of the assessment of
the risk of death [
91
]. Urine albumin/creatinine ratio is one the most sensitive indicators of
glomerular renal dysfunction and hypertension in patient with high-risk neuroblastoma
treated with myeloablative regimens [92].
A compromised blood-brain barrier leads to leakage of plasma components across
the endothelial cell monolayer. Increased levels of K
+
and Glu enhance neuron excitability.
Extravasated albumin is taken up by astrocytes via TGF-
β
R and leads to Smad2-mediated
downregulation of the K
+
channel Kir4.1; decreased expression of Glu transporter EAAT-2
is initiated by astrocytic TNF-α. Both mechanisms exacerbate neuronal hyperactivity due
to impaired K+and Glu buffering by astrocytes [93].
Competent application of regression analysis methods makes it possible to increase
the sensitivity and specificity of the diagnosis of diabetic complications due to the use of
“internal” albumin indices, such as the ratio of its reduced and oxidised forms [
94
]. The
rate of oxidised albumin to total albumin can be enhanced in liver, diabetes plus fatigue
and coronary artery diseases, leading to bacterial/viral infections and eventually death in
severe conditions. Due to the induction of cytokine storm, the level of oxidised albumin in
serum of COVID-19 patients may be a positive predictor of mortality [95].
Albumin can serve not only as a biomarker of severity of different pathologies, but as
a therapeutic substance, too. It was demonstrated that albumin can be used for delivering
of reactive sulfur species (RSS) to melanoma cells enhancing the inhibition of melanin
synthesis [
96
]. Schneider et al. showed that continuous infusion of 4% albumin in patients
of intensive care unit (ICU) decreased the risk of nosocomial infections [
97
]. According to
the data obtained, albumin reduces the oxidised form of vasostatin-1 and thus restored its
antimicrobial properties.
The ability of albumin to bind water can be used to treat OPs poisoning. A decrease of
glycocalyx leads to a decrease of oncotic pressure and to hypovolemia, so that appropriate
compensation could become one of the therapeutic factors in acute poisoning with OPs
in order to reduce the risk of death and prevent the delayed pathology. Indeed, there are
described cases of successful use of fresh frosen plasma in the treatment of the so-called
“intermediate syndrome”, one of the possible consequences of OPs poisoning [98].
6. Conclusions
Serum albumin is able to bind almost all known drugs, nutraceuticals and toxic sub-
stances. The protein largely determines their pharmaco- and toxicokinetics, transporting
them to target tissues or sites of their biotransformation. Simultaneously, the albumin
molecule can bind up to ten ligand molecules, and for this reason, many substances com-
pete with each other for binding sites. In addition to direct competition, the protein is
susceptible to allosteric modulation: binding of a ligand in one site can affect the efficiency
of binding in another. Due to the thiol group within Cys34, albumin can serve as a trap for
reactive oxygen and nitrogen species and participate in redox processes in the body. More-
over, this protein has a number of enzymatic activities: (pseudo) esterase, paraoxonase,
phosphotriesterase, thioesterase, glutathione peroxidase and some others. The environ-
ment of the bloodstream can significantly affect the functional properties of albumin; the
major fatty acids and molecular crowding display the most pronounced influence. This
effect should be taken into account when studying the interaction of pharmaceuticals and
xenobiotics with albumin in
in vitro
and in silico experiments. Interaction with EGL largely
determines the integrative role of both albumin and endothelium. All these features suggest
that a targeted influence on albumin to modulate its binding, enzymatic and antioxidant
properties can become a kind of adjuvant therapy for pathological conditions.
Encyclopedia 2021,172
Author Contributions:
Conceptualisation, D.A.B. and N.V.G.; writing—original draft preparation,
D.A.B., P.A.V. and A.A.B.; writing—review and editing, D.A.B. and N.V.G.; supervision, N.V.G. All
authors have read and agreed to the published version of the manuscript.
Funding: These studies were carried out within the State assignment AAAA-A18-118012290142-9.
Conflicts of Interest:
The authors declare no conflict of interest. The funders had no role in the design
of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or
in the decision to publish the results.
Entry Link on the Encyclopedia Platform: https://encyclopedia.pub/3592.
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... Human serum albumin (HSA) is the most abundant protein in human blood: with a normal concentration ranging from 3 to 5 g/dL, it accounts for approximately 60% of serum proteins [44,57]. It is composed of a single, 585 amino acids-long polypeptidic chain with a molecular weight of 66.5 kDa [58,59], and its three-dimensional structure is reported in Figure 2. HSA has a half-life of approximately three weeks [60], during which the exposure to blood glucose induces glycation processes primarily at its lysine and arginine residues [15] that modify its spatial arrangement as well as the N-terminal region [16]; glycation of albumin also leads to a slight increase in the polarity of the molecule [46]. Clinically, GA has some clear advantages over HbA1c. ...
... Three-dimensional structure of human serum albumin. The three domains I, II, and III are highlighted in purple, blue and green, respectively, and for each domain the two subdomains A and B are shown-from Belinskaia et al.[59]. ...
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Diabetes mellitus is a worldwide-spread chronic metabolic disease that occurs when the pancreas fails to produce enough insulin levels or when the body fails to effectively use the secreted pancreatic insulin, eventually resulting in hyperglycemia. Systematic glycemic control is the only procedure at our disposal to prevent diabetes long-term complications such as cardiovascular disorders, kidney diseases, nephropathy, neuropathy, and retinopathy. Glycated albumin (GA) has recently gained more and more attention as a control biomarker thanks to its shorter lifespan and wider reliability compared to glycated hemoglobin (HbA1c), currently the “gold standard” for diabetes screening and monitoring in clinics. Various techniques such as ion exchange, liquid or affinity-based chromatography and immunoassay can be employed to accurately measure GA levels in serum samples; nevertheless, due to the cost of the lab equipment and complexity of the procedures, these methods are not commonly available at clinical sites and are not suitable to home monitoring. The present review describes the most up-to-date advances in the field of glycemic control biomarkers, exploring in particular the GA with a special focus on the recent experimental analysis techniques, using enzymatic and affinity methods. Finally, analysis steps and fundamental reading technologies are integrated into a processing pipeline, paving the way for future point-of-care testing (POCT). In this view, we highlight how this setup might be employed outside a laboratory environment to reduce the time from measurement to clinical decision, and to provide diabetic patients with a brand-new set of tools for glycemic self-monitoring.
... Thus, the main factors behind alterations in nutrition and inflammation, mucositis toxicity, and treatment interruption could be substances with antioxidative, anti-inflammatory, and metal-ion-chelating effects in the blood. Serum albumin has multiple ligand-binding capacities and free-radical-scavenging properties; thus, it exerts antioxidant and anti-inflammatory functions, accounting for over 80% of the antioxidant activity in the blood [80,81]. Compared to other blood proteins, it is primarily exposed to reactive oxygen species (ROS) because of its free thiol group of the Cys34 residue [80,81]; it is the main extracellular molecule responsible for modulating the plasma redox state, augmenting intracellular glutathione levels, and regulating cell signaling through the ubiquitous transcription factor nuclear factor kappa B (NF-κB), which mediates pro-inflammatory stress [82][83][84]. ...
... Serum albumin has multiple ligand-binding capacities and free-radical-scavenging properties; thus, it exerts antioxidant and anti-inflammatory functions, accounting for over 80% of the antioxidant activity in the blood [80,81]. Compared to other blood proteins, it is primarily exposed to reactive oxygen species (ROS) because of its free thiol group of the Cys34 residue [80,81]; it is the main extracellular molecule responsible for modulating the plasma redox state, augmenting intracellular glutathione levels, and regulating cell signaling through the ubiquitous transcription factor nuclear factor kappa B (NF-κB), which mediates pro-inflammatory stress [82][83][84]. The antioxidative and anti-inflammatory functions of serum albumin explain the pathological process, and the albumin supply improves the clinical condition in certain critical and chronically ill patients [84][85][86][87][88][89][90]. ...
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We investigated risk factors for treatment interruption (TI) in patients with locally advanced head and neck squamous-cell carcinoma (LAHNSCC) following concurrent chemoradiotherapy (CCRT), under the provision of recommended calorie and protein intake; we also evaluated the associations between clinicopathological variables, calorie and protein supply, nutrition–inflammation biomarkers (NIBs), total body composition change (TBC), and a four-serum-amino-acid metabolite panel (histidine, leucine, ornithine, and phenylalanine) among these patients. Patients with LAHNSCC who completed the entire planned CCRT course and received at least 25 kcal/kg/day and 1 g of protein/kg/day during CCRT were prospectively recruited. Clinicopathological variables, anthropometric data, blood NIBs, CCRT-related factors, TBC data, and metabolite panels before and after treatment were collected; 44 patients with LAHNSCC were enrolled. Nine patients (20.4%) experienced TIs. Patients with TIs experienced greater reductions in hemoglobin, serum levels of albumin, uric acid, histidine, and appendicular skeletal mass, and suffered from more grade 3/4 toxicities than those with no TI. Neither increased daily calorie supply (≥30 kcal/kg/day) nor feeding tube placement was correlated with TI. Multivariate analysis showed that treatment-interval changes in serum albumin and histidine levels, but not treatment toxicity, were independently associated with TI. Thus, changes in serum levels of albumin and histidine over the treatment course could cause TI in patients with LAHNSCC following CCRT.
... From this we can conclude that the effect on the conformation of protein molecules is determined mainly by generation of the dendrons, and thus their branching and size of the hydrophobic part. It is likely that hydrophobic interactions make the greatest contribution to the interaction of the dendrons with the proteins, which means that the hydrophobic part of amphiphilic dendrons interacts with hydrophobic pockets of albumin molecules [21,22]. The smaller effect of the studied dendrons on conformation of thrombin compared to albumin is probably due to the more rigid structure of thrombin, rich in beta-barrel-based domains [23]. ...
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Amphiphilic dendrons are highly branched synthetic polymeric soft nanoparticles that possess properties of both dendrimers and micelles. Such properties allow dendrons to become promising delivery systems for targeted delivery. While much attention is focused on the design and biological effect of a drug-delivery system, the nature of its interaction with surrounding tissues—their biocompatibility—is crucial for further optimization. The biocompatibility and biological effects of some amphiphilic phosphorus dendrons on human serum albumin and thrombin are investigated in this report. The results from protein fluorescence, circular dichroism, and zeta potential experiments showed that the dendrons of the first generation have a lesser impact on protein molecules than the dendrons of the second generation and therefore tend to be more biocompatible.
... Specifically, BSA has a single polypeptide chain composed of 583 amino acids that contain 15 main types of amino acids (Table S1). 36,37 The molecular weight of BSA is ∼66.267 kDa. ...
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... kDa), amino acid sequence length (585 vs. 583 residues), and amino acid composition (73.0% identical), including the number of lysine residues (59 vs. 53) [15,16]. We believe it is unlikely that these differences in albumin composition would have a measurable effect on the observed stability of AFB1-lys, but future stability testing of human sera with endogenous AFB1-lys concentrations would be prudent to confirm AFB1-lys measurement stability. ...
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Aflatoxin exposure is endemic in developing countries with warm, humid climates that promote toxigenic mold growth on crops and foodstuffs. Estimating human aflatoxin exposure is key to identifying and abating contamination sources. Serum aflatoxin B1 bound to albumin lysine (AFB1-lys) is a preferred exposure biomarker, but field sample collection, processing, transportation, and storage logistics are challenging. We validated an improved LC-MS/MS method for serum AFB1-lys and applied it to three field sampling challenges: transportation/storage (elevated temperature); collection/processing (hemolysis); and sample type substitution (heparinized plasma). Our new LC-MS/MS method had a LOD of 0.03 ng/mL, accuracy (mean spike recovery) of 112%, total imprecision (replicate pool measurements) ≤5% at ≥0.2 ng/mL, and results that were 95.1% similar (mean percentage similarity) to an established method. AFB1-lys in human serum spiked with serum from aflatoxin-dosed rats was stable for 14 days at both ambient (22.5 °C) and elevated (38 °C) temperatures. Simulated hemolysis (adding 0.25–3 mg hemoglobin) did not affect AFB1-lys accuracy at ≥0.5 ng/mL but caused 10–25% signal suppression. Heparinized plasma AFB1-lys was 99.0% similar to serum but interfered with albumin measurements (bromocresol green) causing spurious low bias. Further investigation is warranted, but our findings suggest that AFB1-lys is pre-analytically robust.
... CRP production has been shown to be strongly associated with pro-inflammatory cytokines in patients with HNC [72,73]. Histidine is also one of the major amino acids and is involved in the modulation of redox and inflammation of albumin [74]. Thus, the observed negative correlation between histidine and GPS is clear. ...
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Few prospective cohort trials have investigted the effect of pretreatment nutritional and inflammatory status on the clinical outcome of patients with cancer and optimal performance status and assessed the interplay between nutrition, inflammation, body composition, and circulating metabolites before treatment. Here, 50 patients with locally advanced head and neck squamous cell carcinoma (LAHNSCC) and Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 2 were prospectively recruited along with 43 healthy participants. Before concurrent chemoradiotherapy, compared with healthy controls, the cancer group showed lower levels of histidine, leucine, and phenylalanine and had low values in anthropometric and body composition measurements; however, the group displayed higher ornithine levels, more malnutrition, and severe inflammation. Pretreatment advanced Glasgow prognostic score (1 and 2) status was the sole prognostic factor for 3-year mortality rate and was associated with age and serum histidine levels in patients with cancer. Thus, even at the same tumor stage and ECOG PS, patients with LAHNSCC, poor nutrition, and high inflammation severity at baseline may have inferior survival outcomes than those with adequate nutrition and low inflammation severity. Assessment of pretreatment nutritional and inflammatory status should be included in the enrollment criteria in future studies.
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Biotechnology has revolutionized science and health care by providing new biomolecules with biological and medical applications. However, the low stability of several life-saving bioproducts still hinders their transport, storage, and application. Hence, protein-based bioproducts instability and high costs are the main bottlenecks limiting access to biopharmaceuticals in low-income countries and communities. Aiming to improve the stability of protein-based products, researchers have studied ionic liquids (ILs) as protein stabilizers due to their unique properties and ability to enhance the solubility and stability of a wide range of biomolecules. Although different classes of ILs have the potential to improve protein stability, their effects are dependent on several variables, such as the complex and intrinsic properties of proteins, the nature and concentration of ILs, and environmental conditions (e.g., temperature, pH). For medical applications, the biocompatibility of ILs can also limit their biological use. Therefore, the current state-of-the-art on ILs applications for non-enzymatic protein stabilization was carefully analyzed and discussed, considering protein properties, ILs classes, and IL solutions concentrations. Lastly, a critical perspective regarding ILs applications as protein stabilizers was presented, highlighting the current lacunas in the field while guiding future studies to answer the existing paradigms.
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Protein-based nanoparticles (NPs) are biodegradable, biocompatible, and easily amenable to chemical modifications to allow for the incorporation of bioactive compounds. In the current study, we adopted a full factorial design to optimize dexamethasone disodium phosphate (Dex) encapsulation within NPs formed with bovine serum albumin (BSA) and stabilized using polyethylenimine (PEI). The optimized NP size (<200 nm dia.), zeta potential (−23.3 mV), and entrapment efficiency (67.4%) were occurred at 0.652 mg, 0.04, 5%, and 8.3 for solution concentration of Dex, PEI/BSA molar ratio, BSA solution concentration, and solution pH, respectively. Incorporation of Dex resulted in a decrease in alpha helix content of BSA indicating a change in its secondary structure. Dex loaded NPs yielded a bimodal release of Dex over an extended period of time via a quasi-Fickian diffusion mechanism. The in vivo anti-inflammatory activity of BSA/PEI Dex NPs surpassed that of free Dex in carrageenan-induced hind paw edema in rats as evidenced by enhanced suppression of oxidative stress, abrogation of NF-κB-p65 expression, as well as reduced myositis and inflammatory cell infiltration. The extended-release profile of BSA/PEI Dex NPs is crucial for achieving a significantly significant anti-inflammatory activity.
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Duchenne muscular dystrophy (DMD) is a lethal, X-linked disease that causes severe loss of muscle mass and function in young children. Promising therapies for DMD are being developed, but the long lead times required when using clinical outcome measures are hindering progress. This progress would be facilitated by robust molecular biomarkers in biofluids, such as blood and urine, which could be used to monitor disease progression and severity, as well as to determine optimal drug dosing before a full clinical trial. Many candidate DMD biomarkers have been identified, but there have been few follow-up studies to validate them. This Review describes the promising biomarkers for dystrophic muscle that have been identified in muscle, mainly using animal models. We strongly focus on myonecrosis and the associated inflammation and oxidative stress in DMD muscle, as the lack of dystrophin causes repeated bouts of myonecrosis, which are the key events that initiate the resultant severe dystropathology. We discuss the early events of intrinsic myonecrosis, along with early regeneration in the context of histological and other measures that are used to quantify its incidence. Molecular biomarkers linked to the closely associated events of inflammation and oxidative damage are discussed, with a focus on research related to protein thiol oxidation and to neutrophils. We summarise data linked to myonecrosis in muscle, blood and urine of dystrophic animal species, and discuss the challenge of translating such biomarkers to the clinic for DMD patients, especially to enhance the success of clinical trials.
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Long-term hyperglycemia in diabetic patients leads to human serum albumin (HSA) glycation, which may impair HSA function as a transport protein and affect the therapeutic efficacy of anticoagulants in diabetic patients. In this study, a novel mass spectrometry (MS) approach was developed to reveal the differences in the profiles of HSA glycation sites between diabetic and healthy subjects. K199 was the glycation site most significantly changed in diabetic patients, contributing to different interactions of glycated HSA (gHSA) and normal HSA with two types of anticoagulant drugs, heparin and warfarin. In vitro experiment showed that the binding affinity to warfarin became stronger when HSA was glycated, while HSA binding to heparin was not significantly influenced by glycation. A pharmacokinetic study showed a decreased level of free warfarin in the plasma of diabetic rats. A preliminary retrospective clinical study also revealed that there was a statistically significant difference in the anticoagulant efficacy between diabetic and non-diabetic patients who had been treated with warfarin. Our work suggests that larger studies are needed to provide additional specific guidance for patients with diabetes when administered anticoagulant drugs or drugs for treating other chronic diseases.
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Objective Elevated microalbuminuria (MAU) levels have been demonstrated in patients with heart failure with reduced ejection fraction (HFrEF). However, nothing is known about MAU levels in patients with heart failure with preserved ejection fraction (HFpEF). Therefore, the aim of our study was to explore the relationship between MAU levels and HFpEF.Methods The MAU and N‑terminal B‑type natriuretic peptide (NT-proBNP) concentrations were examined in 260 participants, including 160 patients with HFpEF and 100 control subjects without HF. Echocardiography was performed on all study participants. The patients with HFpEF were divided into class II, III, or IV according to the New York Heart Association (NYHA) classification.ResultsThe MAU levels in the HFpEF group were significantly higher than those in the non-HF group (58.97 ± 89.84 vs. 19.56 ± 29.34, p > 0.05). However, there was no significant difference in the levels of MAU among NYHA class II–IV patients in the HFpEF group (p > 0.05). In Pearson linear correlation analysis, MAU levels in the HFpEF group were positively correlated with left atrial diameter (LAD; r = 0.344, p < 0.05), but negatively correlated with hemoglobin (r = − 0.233, p < 0.05). The area under the ROC curve (AUC) of MAU for the diagnosis of HFpEF was 0.83 (95% CI [0.76, 0.90], p < 0.05), the sensitivity was 72.50%, and the specificity was 82.0%. The AUC of NT-proBNP was 0.88 (95% CI [0.83, 0.94], p < 0.05), the sensitivity was 82%, and the specificity was 73.8%. The AUC of MAU combined with NT-proBNP was 0.91 (95% CI [0.86, 0.96], p < 0.05).Conclusion Our results show that MAU can be used as a biomarker for the diagnosis of HFpEF. Combined detection of MAU with NT-proBNP has clinical value in improving the accuracy of diagnosis of HFpEF. However, there is no significant correlation between MAU levels and the severity of HFpEF.
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Human serum albumin (HSA) as the most abundant protein in human blood plasma, can be a good indicator for evaluating severity of some diseases in the clinic. HSA can be find in two forms: reduced albumin (human mercaptalbumin (HMA)) and oxidized albumin (human non-mercaptalbumin (HNA)). The rate of oxidized albumin to total albumin can be enhanced in multiple diseases. Increase in HNA level have been demonstrated in liver, diabetes plus fatigue and coronary artery diseases. In liver patients, this enhancement can reach to 50–200 percent which can then lead to bacterial/viral infections and eventually death in severe conditions. Due to the induction of cytokine storm, we can say that the level of HNA in serum of coronavirus disease 2019 (COVID-19) patients may be a positive predictor of mortality, especially in patients with underlying diseases such as cardiovascular disease (CVD), diabetes, aging and other inflammatory diseases. We suggest that checking oxidized albumin in COVID-19 patients may provide new therapeutic and diagnostic opportunities to better combat COVID-19.
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New enzyme functions often evolve through the recruitment and optimization of latent promiscuous activities. How do mutations alter the molecular architecture of enzymes to enhance their activities? Can we infer general mechanisms that are common to most enzymes, or does each enzyme require a unique optimization process? The ability to predict the location and type of mutations necessary to enhance an enzyme's activity is critical to protein engineering and rational design. In this review, via the detailed examination of recent studies that have shed new light on the molecular changes underlying the optimization of enzyme function, we provide a mechanistic perspective of enzyme evolution. We first present a global survey of the prevalence of activity‐enhancing mutations and their distribution within protein structures. We then delve into the molecular solutions that mediate functional optimization, specifically highlighting several common mechanisms that have been observed across multiple examples. As distinct protein sequences encounter different evolutionary bottlenecks, different mechanisms are likely to emerge along evolutionary trajectories toward improved function. Identifying the specific mechanism(s) that need to be improved upon, and tailoring our engineering efforts to each sequence, may considerably improve our chances to succeed in generating highly efficient catalysts in the future. This article is protected by copyright. All rights reserved.
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Background: Patients with high-risk neuroblastoma (HR NBL) treated with myeloablative regimens are reported to be at risk for cardiovascular morbidity, and this risk may be increased by impaired renal function. Procedure: Long-term renal function was assessed in a national cohort of 18 (age 22.4 ± 4.9 years) HR NBL survivors by plasma creatinine (P-Cr), urea, and cystatin C (P-Cys C) concentrations, urine albumin/creatinine ratio (ACR), and estimated glomerular filtration rate (eGFR). Ambulatory blood pressure was monitored, and common carotid intima-media thickness (CIMT) and left ventricular mass index (LVMI) were evaluated. Results: No significant difference in P-Cr, P-Cys C, or eGFR was found between the NBL survivors and the age- and sex-matched 20 controls. P-Cys C-based eGFR (eGFRcysc) was significantly lower than the P-Cr-based eGFRcr (97 ± 17 mL/min/1.73 m2 vs 111 ± 19 mL/min/1.73 m2 , P < 0.001) among the NBL survivors. The eGFRcysc was below normal in 28%, and ACR was above normal in 22% of the NBL survivors. Abnormal blood pressure was found in 56% of the survivors, and an additional 17% were normotensive at daytime but had significant nocturnal hypertension. Both ACR and P-Cys C were associated with nighttime diastolic hypertension. Conclusions: Long-term survivors of childhood HR NBL showed signs of only mild renal dysfunction associated with diastolic hypertension. Elevated ACR and P-Cys C were the most sensitive indicators of glomerular renal dysfunction and hypertension in this patient cohort.