INVESTIGATION OF TLR4 POLYMORPHISM IN CHILDREN WITH VESICOURETERAL REFLUX AND RENAL SCARRING
Sav NM1*, Eroz R2, Kalay Duran N3, Kilicaslan O4, Erisen Karaca S5
*Corresponding Author: *Corresponding Author: Nadide Melike SAV, Address: Duzce Universitesi Araştırma Uygulama Hastanesi, Pediatrik Nefroloji B.D, Merkez, DUZCE, TURKEY; Phone: +905378683281; Fax:+903805421390; e-mail address: savmelike@gmail.com
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DISCUSSION
One of the mechanisms in the body that resist disease
agents and develop resistance is the recognition and identi-
fication of the pathogen. TLRs play an important role in the
healthy progress of this process. The coordinated activity of
TLRs on the cell surface or inside the phagosomes enables
the release of cytokines, recruitment of neutrophils, and
release of free radicals and phagocytosis in the immune
system, [8]. These responses determine the severity of the
disease. Signaling disorders in the immune system resulting
from polymorphisms in receptors and cytokines affect the
susceptibility to infectious pathogens and the development
of complications [9]. In this study, it has been shown that
VUR increases the susceptibility to scar formation with the
effect of TLR4 gene variations. These variations were deter-
mined by the NGS method [10]. To our knowledge, this is
the first study in which the associations of TLR4 gene poly-
morphisms with UTI were investigated by NGS screening.
Pyelonephritis is an important risk factor for CKD in
children. Although anatomical anomalies such as VUR are
associated with recurrent UTIs in the majority of patients, the urinary system is usually normal both anatomically
and functionally in patients with recurrent UTIs [11]. This
suggests that some other factors related to host defense may
also be involved in pyelonephritis and scar formation [12].
Successful defense against bacterial infection requires coor-
dinated work of the innate and adaptive immune responses.
TLRs are important for the recognition of microorganisms
by the innate immune system as well as for laying a bridge
between innate and adaptive immune responses [8]. These
receptors act as critical sensors of microbial attack and also
serve as effectors of the innate defense that ensures the
elimination of pathogens [13]. It was suggested that TLR
gene polymorphisms may affect an individual’s ability to
respond to TLR ligands, resulting in altered susceptibility to
infections or inflammation [14]. This altered susceptibility
may clinically emerge as decreased inflammatory response,
protection against pyelonephritis, as in asymptomatic bac-
teriuria, or, conversely, recurrent UTIs [9, 12].
On the other hand, the effects of the TLR4 gene on
kidney damage were addressed through different mecha-
nisms. It is thought that endogenous molecules that ac-
cumulate at non-physiological amounts or sites during
cellular damage can bind to TLR4 and trigger inflammation
[15]. It was reported that there is a relationship between
the TLR4 expression and the degree of kidney damage in
progressive CKD due to inflammation-induced fibrosis
[6]. Cellular debris which is a product of the degradation
of extracellular matrix as a result of cellular damage and
increased matrix cycle and endogenous ligands such as
heat shock proteins could be activated TLR4 [16]. Endog-
enous TLR4 ligands such as fibrinogens, heparan sulfate,
hyaluronan, and fibronectins are overproduced during pro-
gressive renal fibrosis and tubulointerstitial damage and
bind to TLR4 on macrophages. Then, with the activation
of antigen-producing cells, NF-ĸB dependent gene expres-
sion occurs [17]. Interstitial inflammation and fibrosis
occur continuously in the process [6].
In this study, carriage of compound heterozygous
variation in the TLR4 gene was much more common in the
group with kidney scarring than in the group without scar-
ring. Some studies showed that TLR4 gene polymorphism
affects cellular immune response and cytokine production
in vitro and that this paves the way for the deterioration
of resistance against microorganisms. It was also noted
that each polymorphism has different effects in defense
against different microorganisms [18]. In a study conducted
by Svanborg et al., it was found that C3H/Hej mice in-
oculated with virulent Escherichia coli strains could not
eliminate Escherichia coli infection and developed UTI.
The researchers stated that the response of these animals
to bacteria was weakened and the resistance to infection
decreased because of impaired neutrophil migration due
to the defective TLR4 gene [19]. In another study, it was
shown that some TLR4 gene polymorphisms increased the
prevalence of Gram-negative infections and that these poly-
morphisms facilitated the progression to sepsis and septic
shock [20]. The fact that TLR4 polymorphism decreases
resistance, especially against Gram-negative bacteria and
that UTIs occur frequently due to Gram-negative micro-
organisms may explain the increase in the frequency of
kidney scar tissue development in these patients. Scar de-
velopment is more common in the presence of frequent and
complicated UTIs. Therefore, the higher incidence of TLR4
polymorphism in patients with scar tissue suggests that this
group of patients more frequently have complicated UTIs.
One of the variations detected in the study group was
c.942A>G. This variation was not detected in the group
without scarring whereas it was determined at a rate of
6.9% in the group with scarring. Torices et al. reported
that this variation can be seen at a low rate in patients
with rheumatoid arthritis; however, there is no informa-
tion about its clinical significance in the literature [21].
On the other hand, the relationship between kidney scar
development and the same variation has not yet been de-
fined. The absence of this variation in the control group
was suggested that c.942A>G variation may be a factor
that increases the susceptibility to scar development. Fur-
thermore, another variation found at a rate of 10.3% in the
patient group, but not seen in the control group, was the
c.776A>G variation. It was reported that this variation
reduces TLR4 response to lipopolysaccharides and leads to
less inflammatory cytokine production. As a result, it was
stated that an adequate inflammatory response could not
be given and that the resistance to infections decreased in
the presence of this variation [22]. It could be concluded
that the risk of permanent damage increases with the de-
creased inflammatory response and insufficient clearance
of infectious agents from the environment. However, why
this condition resulted in scarring in some patients has not
been clarified yet. Perhaps, the infection may be difficult to
eliminate and scarring may be easier due to multiple poly-
morphisms. However, some inflammatory cytokines are
known to be associated with the development of scar tissue
and resistance to infections. One of the most important
cytokines is TNF-alpha. It was reported that TNF-alpha
causes tissue damage. This damage could also be seen in
the kidneys; however, TLR4-mediated blockade of TNF-
alpha production is also associated with improvement in
kidney functions in experimental models [23]. On the other
hand, it is known that different doses of cytokines have
different effects. Although the release of low-dose cytokine
is an important factor in resistance to infections, high-dose
releases can cause kidney damage. Therefore, the varia-
tions found in this study may trigger the development of scar tissue by reducing the block in TNF-alpha production.
However, we thought that further detailed experimental
studies are required to reveal the effects of cytokines on
permanent kidney damage since they are released locally
as well as systemically.
Some genetic polymorphisms identified might be
directly associated with the increased frequency of certain
infections in the body. In particular, the decrease in the
resistance of the urinary system to infections was associ-
ated with the presence of these polymorphisms. One of the
reasons for the susceptibility to UTIs might be c.896AT
variation detected in this study was shown to increase
susceptibility to invasive Gram-negative bacterial infec-
tions [25]. Karoly et al. reported the frequency of TLR4
c.896AT. The rate of
this variation was 13.8% in the patient group and 5% in
the control group. Although some studies in the literature
showed that this variation increased the susceptibility to
UTI, there were no data regarding its effects on scar tissue
development. In a meta-analysis conducted by Huang et
al., many data were evaluated showing that the rs4986791
variation increases the susceptibility to UTI. The research-
ers stated that this variation is unlikely to be associated
with the frequency of UTIs since the current studies have
been carried out with a small number of patients [27]. Al-
though there is no clear information about this variation,
we thought that it may possibly increase the development
of scar tissue in the presence of recurrent UTIs.
The c.958T>T gene encodes the T6SS protein. T6SS
protein is one of the main contact-dependent delivery sys-
tem proteins responsible for interactions between bacterial
cells. At least one type of this protein was found in gram
negative bacteria [28]. Gene mutations are also thought to
play a role in the etiology of chronic damage due to infec-
tious agents. Therefore, c.958T>T polymorphism may con-
tribute to the development of scar tissue. However, the fact
that this mutation was demonstrated in both groups in our
study suggests that gram-negative infections, although fre-
quent, do not contribute to the development of scar tissue.
c.315C>T is a polymorphism shown in some parasitic
infections and some bacterial infections that might be as-
sociated with cancer [29, 30]. However, there is no data
in the literature related with scar tissue development. We
think that it is coincidental that this polymorphism was
found in only one patient in our study.
Moalem et al. identified a mutation, suggesting that
the c.1078>T polymorphism may be associated with cili-
ary dysgenesis [31]. Ciliary functions play an important
role in the elimination of infectious agents. Disruption of
these functions may trigger scar development secondary to
infections. In our study, this polymorphism was detected
in only one patient who developed scar tissue. Therefore,
based on this result, it is difficult to claim that c.1078>T
polymorphism may be associated with scar tissue.
It should not be ignored that genetic predisposition
combined with environmental effects is an important factor
in the development of scar tissue. It could not be stated that
scar tissue develops based on genetic factors alone. This
may explain the lack of scarring in some patients, even
in the presence of genetic variation. Additionally, kidney
scar tissue could develop without genetic variation. On the
other hand, vesicoureteral reflux could also be genetically
transmitted on its own. The prevalence of VUR has been
reported as 27-51% in siblings, 80-100% in monozygotic
twins, and 35-50% in dizygotic twins [32]. In a study, it
was reported that the rate of VUR development in chil-
dren whose parents had VUR was 66% [33]. Therefore,
it could be said that genetic variations also contribute to
scar development significantly. On the other hand, there
may be an association between the increase in the degree
of VUR and the development of scar tissue. It has been
reported that scar tissue develops in 89% of children with
high-grade VUR after an episode of pyelonephritis4. In our
study, there was no relationship between genetic mutation
and the degree of VUR.
There were some limitations in this study. Compound
heterozygous mutation was found to be significantly higher
in patients with scarring, but the study sample size was
small. To confirm these results, the relationship between
genetic and clinical findings can be clearly demonstrated
by studies including a larger number of patients. Another
limitation of the study is the lack of a healthy control group
or a group with UTI but not VUR.
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