Validation of molecular pathways in urgency urinary incontinence

Urinary incontinence (Ul) is a common problem among adult women. Around 25% of
Dutch women under the age of 65 years has Ul-related complaints, which leads to
a decreased quality of life. Two types are distinguished: stress (SUl) and
urgency (UUl) urinary incontinence. SUI is defined as involuntary loss of urine
associated with increased abdominal pressure such as coughing. UUI is defined
as the complaint of involuntary loss of urine accompanied by or immediately
preceded by urgency. Especially UUI has a significant impact on the quality of
life. No effective long-term treatment has been found yet for UUl. lt can be
treated by medications, but they have bothersome side effects. The present
study is part of the DlAgnose en Behandeling van lncontinentie en Prolaps
(DIABlP) project, carried out by three departments of the Radboud university
medical center (Gynaecology, Urology and Genetics), and two small and
medium-sized enterprises: Drug Target lD (DTID) and Nimagen. The DIABIP project
combines clinical and physiological data with lifestyle factors and genetic
information to improve the diagnosis, prognosis and treatment of women with
pelvic floor dysfunctions. The first step is to provide insight into the
biological processes that, when impaired, could be involved in the pathogenesis
of Ul.
Based on GWAS-data and literature research resulted in a concept molecular
landscape for UUI. Based on this landscape several biological processes were
identified:
These processes still need to be validated in vitro.
Proteomics, genomics, and in vitro cell culture tests using the samples derived
from the bladder biopsies are then used to validate the hypotheses and to test
whether 'repurposed' drugs could alter these biological processes in a disease
specific manner. To our knowledge there are no cell cultures available at other
centres to do the planned testing.

1) To isolate and cryopreserve human primary bladder muscle and urothelial
cells from women with isolated UUI so that we can validate the results from the
molecular landscape in vitro.
2) To collect and store human bladder biopsy tissues from women with Ul so that
we can perform Omics (proteomics and/or genomic) analyses to corroborate the
findings from the molecular landscape at tissue level.

Observational study.

During cystoscopy, which is part of the planned procedure of the regular
treatment the patients are undergoing, two additional bladder biopsies will be
taken. The risks of bladder biopsies are minimal, but it can cause: transient
minor bleeding, transient minor paín and discomfort. ln rare case reports, more
severe bleeding or bladder perforation has been described.(1) Cystoscopy
increases the chance of urinary infections, but this is not an added risk for
patients who are already undergoing a cystoscopy procedure. All women receive
antibiotic profylaxis as standard medical treatment.
According to the risk classification of the NFU for patients participating in
this study, the risk has been assessed as "moderate". The method (taking
bladder biopsies) that we will use in this study is identical as in two
previous studies by the department of Urology: 'OAB feasibility; Molecular and
cellular characterization of detrusor smooth muscle cells' (CMO 20041053) and
'The role of GAG's in the pathology of interstitial cystitis (|C/PBS)' (CMO
2009/310). ln the previous studies, bladder biopsies were used for
immunohistology and Western blotting, whereas in the present study in vitro
cell culture tests and omics (proteomics/genomics) will be performed.