The children were grouped according to DTPA, grade and success of treatment. 13 children
with obstructive DTPA were compared to 3 children with a partial obstruction, and
as demonstrated in Fig. 1a we showed that MMP9 was underexpressed and TIMP1 and RECK were overexpressed in children
with obstructive DTPA but the differences were not statistically significant (MMP9,
p?=?0.170; TIMP1, p?=?0.389; RECK, p?=?0.389).

Fig. 1. Expression profile of MMP9, TIMP1 and RECK according to DTPA (a), grade (b) and success of treatment (c) in tissue of UPJ children

Our analysis of MMP9, TIMP1 and RECK expression levels according to grade of obstruction
is shown in Fig. 1b. Overexpression of MMP9 was higher among patients with severe grade of UPJ (?=?12) compared to those with moderate grade (?=?4). However, statistical analysis revealed that these differences were not significant
(p?=?0.694). TIMP1 and RECK did not significantly differ considering grade of UPJ (TIMP-1,
p?=?0.684, RECK, p?=?0.684).

When MMP9, TIMP1 and RECK expression levels were analyzed according to surgical outcome,
surprisingly we found that the median expression levels of MMP-9 was three times higher
in children who were successfully treated by surgery (?=?10) compared to those did not have success (?=?6), with a marginal significance (p?=?0.072), TIMP-1 was underexpressed in 100 % of this cases (p?=?0.00) and RECK was overexpressed in 80 % of this same cases (p?=?0.082). This results is shown in Fig. 1c.

Discussion

UPJ obstruction is mostly considered as a functional obstruction originating from
abnormalities in the smooth muscle of the pelvis and ureter 14]. Although surgery in UPJ obstruction is efficient to protect the patient against
renal function lost, results obtained in both experimental and human-studies suggest
that UPJ obstruction induces permanent modifications of the renal parenchyma.

The nature of the abnormalities at the UPJ in children with congenital intrinsic UPJ
obstruction remains controversial. Many studies revealed that UPJ obstruction is associated
with a significant difference in the collagen and smooth muscle structural components
15]. The finding of the increased tissue matrix ratio was believed to decrease the ureteral
distensibility resulting in damage to muscle cells influencing the contractility 16]. Furthermore, a variety of intrarenal factors lead to progressive interstitial and
renal parenchyma fibrosis in patients with Congenital anomalies of the kidney and
urinary tract, like UPJ, including growth factors, cytokines, chemokines and adhesion
molecules, which are produced by the hydronephrotic kidney. An altered renal expression
of growth factors and cytokines modulates cell death by apoptosis or phenotypic transition
of glomerular, tubular, and vascular cells. Mediators of cellular injury include hypoxia,
ischemia, and reactive oxygen species, while fibroblasts undergo myofibroblast transformation
with increased deposition of extracellular matrix 17].

The present study is the first to investigate the expression of MMP9 and its negative
controllers in obstructed UPJ tissue. The change in expression of ECM components could
be an alternative mechanism leading to UPJ obstruction together with the reduction
of interstitial cells of Cajal. The reduction in peristalsis, result of the reduced
number of Cajal’s cells associated to reduction in distensibility, result of alteration
in ECM components could be the physiopathology of the disease 18]. MMPs have many important functions in wound healing processes and angiogenesis.
In the case of deregulation of their production, matrix degradation and turnover are
the consequences 19] and It has been shown that an increase in ECM turnover influences the neuronal network
within the ureteral wall. Also, some MMPs have been proved to be neurotoxic degrading
ECM proteins like collagen type 1, which are normally able to protect cultured neurons
from cytotoxic cell death 20].

Defective collagen production from smooth muscle cells has been held responsible for
this pathology and decreased neural cells have been thought to play an important role,
especially in intrinsic type obstructions 21]. There are other studies showing that this disintegration in the configuration of
smooth muscle and overdeposition of collagen may be an etiologic factor, and collagen
to smooth muscle ratio may have a prognostic value 15].

There are some limitation that should be pointed out. Our small number of cases would
interfere in our findings and may affect in our subgroups analysis (successful against
failure and intrinsic against crossing vessel group). Since it refers to a low incidence
disease with decreasing surgical indication it may be of difficult to increase sample
size in a small period of time. Also the lack of control group because of the absence
normal tissue also may impact in our findings. At last, there is an intentional bias
in selection, including a higher number of failure cases does not reflects the overall
success in the surgical approach.