Paraoxonase-1 and ischemia-modified

albumin in patients with end-stage renal

disease

Kazuhiko Kotani, Satoshi Kimura &

Alejandro Gugliucci

Journal of Physiology and

Biochemistry
Official Journal of the University of
Navarra, Spain
ISSN 1138-7548
Volume 67
Number 3
J Physiol Biochem (2011) 67:437-441
DOI 10.1007/s13105-011-0092-4

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J Physiol Biochem (2011) 67:437441
DOI 10.1007/s13105-011-0092-4

MINI REVIEW

Paraoxonase-1 and ischemia-modified albumin in patients

with end-stage renal disease
Kazuhiko Kotani & Satoshi Kimura &
Alejandro Gugliucci

Received: 5 October 2010 / Accepted: 24 March 2011 / Published online: 12 April 2011
# University of Navarra 2011

Abstract End-stage renal disease (ESRD) with and/

or without treatment by hemodialysis (HD) is associated
with accelerated atherosclerosis, leading to cardiovascular disease (CVD) including acute coronary syndromes. Therefore, the regulation of CVD is a crucial
issue for ESRD patients. Given the recent reports that
paraoxonase-1 (PON-1) and ischemia-modified albumin (IMA) could predict CVD-related mortality in
ESRD, the two recent biomarkers may be useful for
preventive strategies for CVD. This review paper
presents current data on the relationships between
PON-1, IMA, and ESRD. Many studies have shown
that circulating PON-1 activity is lower in ESRD
patients, and we have shown that its levels increase
after HD. Although circulating IMA levels can increase

K. Kotani (*)
Department of Clinical Laboratory Medicine,
Jichi Medical University,
3311-1 Yakushiji,
Shimotsuke City, Tochigi 329-0498, Japan
e-mail: kazukotani@jichi.ac.jp
K. Kotani : A. Gugliucci
Glycation, Oxidation and Disease Laboratory,
Touro UniversityCalifornia,
Vallejo, CA, USA
S. Kimura
Department of Laboratory Medicine and Central Clinical
Laboratory, Showa University Northern
Yokohama Hospital,
Yokohama, Japan

before HD in ESRD patients, there remains to be little

data. Our pilot study has shown a significant inverse
correlation between PON-1 and IMA in ESRD patients.
Although the pathogenic link between PON-1 and IMA
remains speculative, considering both biomarkers may
provide new insights into the prevention of CVD in
ESRD patients.
Keywords Oxidative stress . Oxidation . Renal
failure . Atherosclerosis . Cardiovascular disease

Introduction
End-stage renal disease (ESRD) with and/or without
treatment on hemodialysis (HD) is associated with
accelerated atherosclerosis, leading to cardiovascular
disease (CVD) including coronary artery disease [9,
30]. This constitutes an important medical problem, in
view of the mounting prevalence of ESRD as well as
the life span increase of these patients due to
treatment [39]. Although classical atherosclerotic risk
factors, such as hypertension and diabetes mellitus,
are involved in the increased incidence of atherosclerosis seen among ESRD patients, these only partially
explain the excess in risk, namely, the precise
mechanisms for the pathogenesis of CVD in ESRD
patients is not fully understood [9, 30]. A form of
complex dyslipidemia/dyslipoproteinemia consisting
of both quantitative and qualitative abnormalities,
such as dysfunctional high-density lipoprotein (HDL)

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438

K. Kotani et al.

and increased intermediate density lipoprotein levels,

plays a key role in CVD prevalence in ESRD [5, 29,
40]. Moreover, increased oxidative stress is a feature
in ESRD patients, independently of the other conventional atherosclerotic risk factors [19, 41]. In order to
prevent CVD in ESRD, it is therefore crucial to better
understand the pathophysiology of CVD development
and to monitor the subjects with biomarkers that are
tailored for this population and that may turn to be
more predictive of CVD in ESRD patients.
Recently, prospective studies on CVD outcomes in
ESRD using the new biomarkers of HDL dysfunction
and/or oxidative stress, paraoxonase-1 (PON-1) and
ischemia-modified albumin (IMA), have appeared in
the literature. These studies show that serum PON-1
activity as well as IMA could predict CVD-related
mortality in ESRD [15, 33]. The application of the
two biomarkers may provide new insights into the
prevention of CVD among ESRD patients. In this
brief report, we present the existing current findings
on the relationships between PON-1, IMA, and
ESRD.

Paraoxonase-1 (PON-1) is an enzyme (calciumdependent esterase) associated with HDL subfractions

that contain apo A-I and clusterin, and confers
protection against oxidative damage of various cells
and lipoproteins (i.e., low-density lipoprotein) [11, 21,
36]. Its main physiological activity appears to be
lactonizing/lactonase action on oxidized phospholipids
or homocysteine thiolactone [36]. Changes in HDL
subfractions observed in various diseases under oxidative stress conditions can be a cause of reduction of
PON-1 activity [11, 21, 36]. In fact, low levels of
serum PON-1 have been reportedly associated with
obesity-related disorders and CVD [1, 4, 22, 34,
36]. Interestingly, many studies have shown significantly lower levels of PON-1 (measured by phenylacetate and/or paraoxon as substrate in all studies) in
ESRD patients with and without HD treatment
compared to controls [6, 7, 10, 1214, 1618, 24,
26, 27, 31, 32, 35]. These results suggest that ESRD
patients may suffer from chronic oxidative stress and

Fig. 1 Possible interaction between PON-1 and IMA in endstage renal disease. The figure schematically (and speculatively
in part) summarizes a possible interaction between PON-1 and
IMA, described in the text. As seen on the upper part of the
illustration, cardiac ischemia (possibly by free radical attack)
produces IMA from albumin. Earlier studies have reported
IMA to be a biomarker of cardiac ischemia. Even though there

is no apparent cardiac ischemia, the decreased PON-1 state as

observed in patients with end-stage renal failure may produce
IMA via an increase in oxidative stress. A significant inverse
correlation between PON-1 and IMA may partly be explained
in this mechanism, and the two biomarkers may reflect
oxidative stress condition levels in end-stage renal failure.
LDL: low-density lipoprotein, HDL: high-density lipoprotein

Paraoxonase-1 in ESRD

Author's personal copy

PON-1 and IMA in end-stage renal disease

have less antioxidant capacity, leading to an increased incidence of CVD. Of note, we have also
shown that PON-1 levels in ESRD patients significantly increase after HD [12, 13].

Ischemia-modified albumin in ESRD

While the amino-terminal end of a circulating
albumin binds transitional metals such as cobalt,
copper and nickel, various changes of circulating
albumin can occur in the terminal end under certain
conditions [2, 3, 25]. When the specific motif (DAKK
motif) in the N-terminus is damaged, this results in a
reduced binding capacity for transitional metals [2, 3,
25]. The effect is related to albumin circulating
through ischemic capillary beds as found in CVD,
especially in the acute coronary syndromes [2, 3, 25].
IMA is thus considered as a CVD-related biomarker
that is sensitive to cardiac ischemia [25]. Furthermore,
the modification of albumin, leading to higher IMA
levels, has also been recently documented in patients
with diabetes mellitus, hyperlipidemia, and metabolic
syndrome [8, 28, 38]. These results suggest that IMA
formation may occur not only under acute but also
chronic oxidative stress conditions and also at extra
cardiac sites [8, 28, 38]. Unfortunately, little information about circulating IMA in ESRD is presently
available. Recent studies have shown significantly
higher IMA levels in ESRD patients compared to
controls and its increased levels after HD [23, 37],
while we have not found remarkably increased IMA
levels after HD [13]. Although differences in study
populations and methodologies including HD procedures may partly influence the inconsistencies of
results, more studies are warranted to resolve this
controversy.

439

correlated with IMA levels in these patients (correlation coefficient=0.522) while such a clear correlation was not found in non-ESRD controls [20]. An
inverse correlation between PON-1 and IMA levels
may partially be explained by the speculation that a
low PON-1 activity in these patients produces
increased oxidative stress, leading to IMA formation
(Fig. 1). Monitoring serum PON-1 and IMA simultaneously might thus provide another useful tool for the
clinical pathologists as a prognostic biomarker of CVD
in ESRD patients.

Conclusions
This article describes the current status of our
knowledge on serum PON-1 and IMA in ESRD.
PON-1 activity is lower in ESRD patients and this is
corrected by HD. While some reports show higher
IMA levels in ESRD patients and either no changes or
an increase after HD, the data are scarce and
inconclusive. Especially, PON-1 and IMA have been
respectively shown to be predictors of CVD-related
outcomes in ESRD. Our pilot study shows an inverse
correlation between PON-1 and IMA in ESRD
patients, although the pathologic link between both
biomarkers remains unclear. To clarify whether the
simultaneous monitoring of serum PON-1 and IMA
can be helpful for the CVD control in ESRD, more
studies with experimental and clinical designs are
needed.

Conflict of interest
interest.

The authors declared no conflicts of

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data on this relationship in a small cohort of HD
patients with ESRD [20]. Of note, this study showed
that PON-1 levels were significantly and inversely

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