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abstract

45 - INVESTIGATING INFLAMMATORY CHANGES IN HUMAN DIABETIC BLADDER DYSFUNCTION

045

INVESTIGATING INFLAMMATORY CHANGESIN HUMAN DIABETIC BLADDER DYSFUNCTION

G. THIAGAMOORTHY1, G.ARAKLITIS 2, J. E. HUNTER 1, S. SRIKRISHNA 1,L. CARDOZO 1, A. GRANT 3, D. ROBINSON 1;
1King's Coll. Hosp., London, United Kingdom, 2KingsColl. Hosp., London, United Kingdom, 3Pharmacology, King'sColl., London, United Kingdom.

Introduction: Up to 80% ofdiabetic patients exhibit some type of diabetic bladder dysfunction(DBD) such as urgency, urinary incontinence (UI) and OAB.[i] Thesesymptoms impair quality of life and although DBD affects more peoplethan diabetic neuropathy, research into the causes of DBD has beenlimited as it does not directly shorten life.
Symptoms of DBD havebeen linked to increased urine production in response to the diureticeffect of urinary glucose. However, changes in bladder function canoccur independently of these changes.[ii] Cystometric studies haveidentified DO in diabetic patients, and this is increasinglyrecognised as a component of DBD. The cellular and molecular changesunderlying DBD are unclear. Although primarily studied for their rolein regulating the immune system, cytokines and chemokines haverecently been implicated in the diverse pathologies of diabetes.[iii]Cytokine expression has been found to be increased in the bladder ina diabetic mouse model but no previous studies of the molecularchanges in human bladder biopsies from patients with OAB/diabeteshave been published. It was therefore postulated whether elevation ofcytokines and chemokines associated with inflammatory processes inthe diabetic human bladder may cause the symptoms of DBD.
Objective:The aim of this study was to investigate the inflammatory molecularchanges in bladder biopsies of diabetic women in order to identifynew targets for treatment.
Methods: This was a prospectivestudy of four groups: Diabetics with DO, non-diabetics with DO,diabetics without DO, and non-diabetic non-DO controls. This was anexploratory study, so was not possible to perform a powercalculation. Expert opinion suggested that 4 biopsies per groupshould be sufficient to provide meaningful pilot data. Ethicsapproval was gained for patients in these groups to undergo bladderbiopsies in a tertiary level urogynaecology department duringcystoscopy to rule out underlying bladder pathologies (DO groups) orfor surgical correction (sling) of stress incontinence (non-DOgroups). The biopsies were taken then “snap-frozen” in liquidnitrogen and stored at -80oC before processing at theresearch facility. The expression of cytokines and chemokines wasquantified at the mRNA level using reverse-transcription PCR.Microfluidic PCR array cards allowed simultaneous measurement of ~100different mRNA transcripts from a single tissue sample. Any genesfound to be abnormally expressed were studied by conventionalquantitative PCR. Quantification was conducted with multiplexedLuminex assays, allowing measurement of 40 separate proteinconcentrations from each biopsy. This technique is a novel way tomeasure changes in many candidate mediators in parallel withoutrequiring large volumes of tissue. It is only available in a fewcentres throughout the world and provided a unique opportunity tolearn more about the molecular changes underlying DBD.
Results:Biopsy specimens from 16 different bladders were collected, four foreach of the pre-determined catgeories. Amongst the array of 40chemokines, it was noted that concentrations of CCL11, CCL13 andCCL21 were consistently greater in the normoglycaemic DO groups thanin any other groups. See Figure. Contrary to our hypothesis there wasno evidence of inflammatory changes in either subset of diabeticbladders. Interestingly, elevated bladder CCL21 has recently beenlinked to the presence of painful bladder syndrome.


Conclusions: DBD is commonlysuffered by people with diabetes. We found indication of inflammatorychanges underlying the diagnosis of DO in non-diabetic women but noevidence of this in diabetics. This highlights an alternate possibletreatment avenue to be explored in patients with DO other than thecurrently recommended pharmaceutical approach and may also indicatean alternate pathophysiology for DBD.
References: [i]Curr Urol Rep 12 419-426(2011) [ii] Neurourol.Urodyn 29354-358(2011) [iii] Clin Sci 122 203-214(2012)