Download patients on non-dialytic therapy (Group 2a)

Pentraxins

Pentraxins are a superfamily of
proteins highly conserved during
evolution from non-vertebrates to
vertebrates and characterized by
specific pattern recognition proteins.
is subdivided
Pentraxin family
into two subclasses:
short pentraxins
&
long pentraxins
that depend on the length and
structure of the molecules.
Short pentraxins

 such as:
 C-reactive
protein(CRP)
in
humans that produced in the
liver.
 and serum amyloid P (SAP) in
mice.
Long pentraxins

The first cloned long pentraxin is
Pentraxin 3 (tumor necrosis factor
stimulated gene 14).
Other long pentraxins in human are:
 Pentraxin 4
Neuronal pentraxin 1
Neuronal pentraxin 2.
The human PTX3 gene has been
localized on chromosome 3 band
q25 and is organized in three
exons separated by two introns.
Pentraxin
molecular
3
has
size
a
(40.6
bigger
KDa)
compared to CRP (21.5 KDa).
Long pentraxins are characterized by an
unrelated N-terminal domain (amino
acids 18-178) coupled to a short PTXlike C-terminal domain (amino acids
179-381).

Carboxy-terminal domain contains the
canonical pentraxin signature of eight
amino acids sequence (HxCxS/TWxS),
where X is any amino acid.
Release of PTX3
The long PTX3 is rapidly produced and
released by diverse cell types :
mononuclear phagocytes
dendritic cells,
endothelial cells &
epithelial cells in response to primary
inflammatory signals .
while it is synthesized de novo in a variety
of cells, specific neutrophil granules store
PTX3 .

Pentraxin 3 production is induced by

lipopolysaccharide (LPS), interleukin-1
(IL-1), and tumor necrosis factor-alpha
(TNF-α) but not by Interleukin-6 (IL-6)
which induce CRP.
PTX3 in neutrophils

PTX3 in neutrophil granules is mainly
in the monomer form and mature
glycosylated
multimeric
forms
(pentamers, octamers or decamers) are
detected
in
the
supernatants
activated neutrophils.
of

 Pentraxin 3 is produced locally in response to
proinflammatory stimuli. During inflammation,
by matrix metalloprotease, there is production
of mediators such as cytokines, lipid
mediators, pattern recognition molecules and
matrix metalloproteins .
 Different microorganisms(fungi- bacteriaeviruses) may activate macrophages and
dendritic cells through Toll-like receptors.
These cells can produce PTX3.
PTX3 mRNA is expressed at a late
stage of promyelocyte differentiation.

Most PTX3 is synthesized at the
myelocytes/metamyelocytes stages.
However, the source of PTX3
production or release depends on the
kind of inflammatory stimulus.
Pentraxin 3 is a key component of
the humoral arm of the innate
immune system and influences the
adaptive immunity.
1.Invading pathogens are controlled by both innate and
adaptive immune system.
2.Binding of pathogen to TLRs on antigen-presenting cells
activate the components of adaptive immunity.
3.Pentraxin 3 bind with high affinity to the complement
component C1q thus activating the complement system
through the classical pathway.
4.it may protects against unwanted complement activation.
5.The selective recognition of fibroblast growth factor by
PTX3 inhibits FGF-2 angiogenic activity.
6.Pentraxin 3 participates in the clearance of apoptotic cells
and several microorganisms.
PTX3 and pregnancy
Pentraxin 3 plays
an essential role in
female fertility by acting as a nodal
point in the extracellular matrix
architecture, and its involvement in
tissue remodeling.
 Pentraxin 3 was expressed
placentas
from
pregnancies
uncomplicated subjects.
in
of
PTX3 in asthma
Pentraxin 3 expression is increased

in asthmatic airways.
 PTX3 cause inhibition of human
airway
smooth
muscle
cells
migration induced by FGF-2.
 Thus, PTX3 may play a dual role in
allergic asthma.
1. Unlike CRP, PTX3 appears to be more specific for vascular
inflammation.
2. Rolph et al (2002) showed a strong expression of PTX3 in
human advanced atherosclerotic lesions.
3. PTX3 level has been proposed as a risk predictor for
acute myocardial infarction and biomarker of adverse
outcome in patients with unstable angina pectoris,
myocardial infarction and heart failure.
4. In acute myocardial infarction, PTX3 reaches peak values
after 6-8 hours compared to 24 hours for CRP.
 Pentraxin 3 mRNA is expressed in
cortex,medulla and glomeruli of the normal
human kidney. Stimulation with IL-1, TNFα, interleukin-17 (IL-17) and CD40 Ligand
(CD40L) increases the expression and
production of PTX3 by renal epithelial cells.
 There is a gradual increase of PTX3
concomitent to the decline in glomerular
filteration rate (GFR) .
Serum levels of PTX3 are elevated in a
number of human diseases, such as:
1. myocardial infarction
2. rheumatoid arthritis
3. sepsis and tuberculosis
4. vasculitis
5. inflammatory reaction in the kidney.
Therefore,
Pentraxin
3
may

represent a diagnostic
approach
unrelated to CRP to the study of
inflammatory
disease.
and
autoimmune
Chronic kidney disease (CKD) is defined as the
presence of kidney damage, manifested by
abnormal albumin excretion or decreased kidney
function that persist for more than three months.
During recent years, the prevalence of CKD has
markedly increased and is expected to double
continuously every 8 to 10 years.
 The first task in evaluating the patient with an
elevated creatinine level is to categorize the
patient's presentation as 1 of 3 possible types of
renal failure: post renal failure, prerenal azotemia
or intrinsic renal failure.
 Chronic kidney disease is a complex disease, its
progression is associated with a number of
serious
complications
including
increased
incidence
of
cardiovascular
disease,
hyperlipidemia, anemia and metabolic bone
disease.
STAGE
1
2
GFR, ml/min/1.73 m2
DESCRIPTION
Kidney damage with normal or
increased
GFR.
Mostly
recognized by albuminuria or
structural renal abnormalities.
Kidney damage
decreased GFR.
with
≥90
midly
60-89
3
Moderately decreased GFR.
30-59
4
Severely decreased GFR.
15-29
5
Kidney failure.
‹15 or dialysis

Stage5 kidney failure(ESRD)
GFR<15 ml/min/1.73m2.
is
defined
as
 Chronic kidney disease promotes hypertension
and dyslipidemia, which in turn can contribute to
the progression of renal failure.
 Approximately 50% of individuals with ESRD die
from a cardiovascular cause.

In dialysed chronic renal failure patients we can
encounter dialysis pericarditis and endocarditis.
 Pentraxin 3 levels are increased in patients with
impaired renal functions. The bigger molecular
size for PTX3 (40.6KD) may suggest increased
retention in uremia.
 The Pentraxin 3 may amplify the inflammatory
response after being produced both in peripheral
tissues and in the kidney.
 PTX3 may also play a role in the atherogenic
process present in chronic kidney disease.
 PTX3 levels may provide more information on the
development and progression of atherosclerosis than
non-specific markers like CRP and IL-6.
 PTX3 is induced in vascular smooth muscle cells by
atherogenic modified low-denisty lipoprotein and is
present in human atherosclerotic lesions.
 Pentraxin 3 levels increase rapidly in acute myocardial
infarction, reaching a peak ~7 hours after the onset of
symptoms.
 CRP is an acute phase protein and a member of the family
of pentraxins.
 The major part of the CRP present in the plasma comes
from the liver and small amount of CRP can be produced
locally.
 CRP may be involved in
atherosclerosis by direct
influencing
process
like
complement
activation,
apoptosis, vascular cell activation, monocyte recruitment,
lipid accumulation and thrombosis.
 PTX3 is thought to be more specific to endovascular injury
than C-reactive protein.

75subjects were included in this study. They were divided into
Control group (Group 1)
Patients group (Group 2)
50patients with chronic
kidney disease (CKD ) .
subdivided into 2
subgroups:
25apparently healthy
volunteers
Group 2a
Group 2b
25 patients with CKD on
conservative non dialytic
therapy
25 patients with endstage renal disease on
maintenance
hemodialysis therapy.
Exclusion Criteria:

Patients with lung disease, rheumatoid arthritis, psoriasis, vasculitis or using
immunosuppressive drugs and pregnant females were not included in the
present study.
To all the studied subjects, the following was done
Detailed history taking.
Thorough physical examination.
12-lead electrocardiography.
Measurment of carotid intima media thickness
(CIMT) by ultrasound.
Laboratory investigations
Serum Glucose
Serum Creatinine
Serum Albumin
High density lipoprotein
cholesterol (HDL-C)
Serum Triglycerides
Serum Urea
Serum Uric acid
Total serum Cholesterol
Low density lipoprotein
cholesterol (LDL-C)
Serum Alanine
aminotransferase(ALT)
Determination of high sensitivity
C-reactive protein (hs-CRP) by ELISA
Estimation of Pentraxin 3 by ELISA
80
70
r = 0.624*
p = 0.001
Age
60
50
40
30
20
10
0
0.50
0.55
0.60
0.65
CIMT
0.70
0.75
0.80
70
r = 0.693*
p <0.001
60
Age
50
40
30
20
10
0
0.50
0.55
0.60
0.65
CIMT
0.70
0.75
0.80
160
r = 0.412*
p = 0.041
140
120
TG
100
80
60
40
20
0
0
5
10
15
CRP
20
25
30
35
120
r = -0.537*
p = 0.006
100
LDL-C
80
60
40
20
0
0
5
10
15
CRP
20
25
30
35
15
> 8.46
0
10
≤ 22.36
9
3
> 22.36
13
22
Efficiency
100.0
62.50
70.0
88.0
40.91
62.86
75.0
65.96
%
100.0
%
40.0
%
NPV %
PTX3
25
PPV %
CRP
≤ 8.46
Specificity
(Group1)
patients on
non-dialytic
therapy
(Group 2a)
Sensitivity
Control
group
25
10
> 8.46
0
15
≤ 23.62
16
7
> 23.62
6
18
Efficiency
100.0
71.43
72.0
72.73
75.0
69.57 72.34
%
100.0
%
60.0
%
NPV %
PTX3
≤ 8.46
PPV %
CRP
(Group2b)
Specificity
(Group1)
patients on
hemodialysi
s
Sensitivity
Control
group
80.0
1. There was a significant decrease
in the mean levels of albumin in all
the studied chronic renal failure
patients when compared to
controls.
Hypoalbuminemia is due to
malnutrition and inflammation in
CKD patients.
2.There was a significant increase in
hsCRP in patients on hemodialysis
therapy when compared to both
controls and patients on non-dialytic
therapy.

The circulating value of CRP reflects
ongoing inflammation and/or tissue
damage.
3.There was a significant increase in PTX3 in
patients on hemodialysis therapy
as
compared to controls. PTX3 levels may
directly reflect the inflammatory status.
Since a state of persistant low-grade
inflammation is a common feature in
hemodialysis patients so PTX3 increased
in such patients.
4.There was no correlations between PTX3
and hsCRP in the studied groups.
5. By drawing the ROC curve for hsCRP
and PTX3 in patients on non-dialytic
therapy (Group 2a), the area under
the curve was 0.545 ( p = 0.594) and
0.653 ( p = 0.073) respectively. In
patients on hemodialysis therapy
(Group 2b), the area under the curve
was 0.735 ( p = 0.006) for hsCRP and
0.765 ( p = 0.002) for PTX3.
6.By using the best cut off values, it was found
that high sensitivity C-reactive protein showed
a better specificity and positive predictive
value than PTX3 while PTX3 showed a better
sensitivity than hsCRP in the studied two
groups of patients.
 It could be concluded that using both hsCRP
and PTX3 complement each other to give
better specificity and sensitivity as predictors
of inflammation in chronic kidney disease
patients.