Nikesh Thiruchelvam

Urinary Outflow Obstruction Increases Apoptosis and Deregulates Bcl-2 and Bax Expression in the Fetal Ovine Bladder

During organogenesis, net growth of tissues is determined by a balance between proliferation, hypertrophy, and apoptotic death. Human fetal bladder outflow obstruction is a major cause of end-stage renal failure in children and is associated with complex pathology in the kidney and lower urinary tract. Experimental manipulation of the fetal sheep urinary tract has proved informative in understanding the pathobiology of congenital obstructive uropathy. In this study we used an ovine model of fetal bladder outflow obstruction to examine effects on apoptotic cell death in the developing urinary bladder. While 30 days of obstruction in utero between 75 and 105 days gestation resulted in overall growth of the fetal bladder as assessed by weight, protein, and DNA measurements, we found that apoptosis, as assessed by in situ end-labeling, was up-regulated in fetal bladder detrusor muscle and lamina propria cells and that this was accompanied by a down-regulation of the anti-death protein Bcl-2 and an up-regulation of the pro-death protein Bax. Moreover, activated caspase-3, an effector of apoptotic death, was increased in obstructed bladders. This is the first study to define altered death in an experimental fetal model of bladder dysmorphogenesis. We speculate that enhanced apoptosis in detrusor smooth muscle cells is part of a remodeling response during compensatory hyperplasia and hypertrophy. Conversely, in the lamina propria, an imbalance between death and proliferation leads to a relative depletion of cells.

Effects of In Utero Bladder Outflow Obstruction on Fetal Sheep Detrusor Contractility, Compliance and Innervation

PURPOSEnCongenital bladder outflow obstruction caused by posterior urethral valves is a common cause of end stage renal failure in boys. We hypothesized that fetal bladder outflow obstruction perturbs detrusor contractility and innervation and bladder storage volume-pressure relationships.nnnMATERIALS AND METHODSnSevere bladder outflow obstruction was induced in male fetal sheep by placing a urethral ring and urachal ligation midway through gestation at 75 days. Fetuses were examined 30 days after surgery, when urinary tract dilatation, enlarged bladders and histologically abnormal kidneys were documented. Isolated strips of bladder detrusor from sham operated and obstructed fetuses were subjected to electrical field stimulation, carbachol, KCl and alpha-beta methylene-adenosine triphosphate. Whole bladder storage characteristics were determined by filling cystometry and bladder innervation was investigated by immunohistochemistry and Western blot.nnnRESULTSnTension-frequency contractility studies showed that obstructed fetal bladder strips were significantly hypocontractile versus sham operated controls in response to electrical field stimulation and the specific agonists carbachol, KCl and alpha-beta methylene-adenosine triphosphate. Hypocontractility was greater with nerve mediated stimulation than with carbachol, suggesting relative denervation. Reduced innervation was confirmed by S100 and protein gene product 9.5 immunohistochemistry and by measuring a significant reduction in protein gene product 9.5 protein expression using Western blot. Filling cystometry showed that obstructed fetal bladders appeared more compliant (Delta V/Delta P, where Delta V is the change in volume and Delta P is the change in pressure) with larger capacity, more flaccidity and yet retained stress relaxation.nnnCONCLUSIONSnIn response to severe experimental fetal bladder outflow obstruction the bladder becomes large and hypocontractile, and has aberrant innervation.

A preliminary study of natural‐fill radiotelemetered ovine fetal cystometry

To determine whether fetal cystometric studies by radiotelemetry are feasible in the fetal lamb, and potentially suitable for chronically monitoring fetal bladder pressures in an experimental fetal model of bladder outlet obstruction (BOO), as in utero BOO (e.g. caused by posterior urethral valves) results in significant postnatal bladder dysfunction but the pathophysiological progression of fetal bladder maldevelopment remains poorly understood.

Modeling the urinary tract—computational, physical, and biological methods†‡

Models of the lower urinary tract are used to understand better the physiological and pathological functions of the tract and to gain insight into the relative importance of different components. The key requirement of a model is described, namely: to involve a continuous iteration with experiment; whereby experiments provide parameters and validation for components of the model, which is then used to generate hypotheses, which are tested experimentally. Different types of models are described: computational models that describe mathematically the whole urinary tract or components; physical models useful especially in testing medical devices; and tissue‐engineered models. The purpose of modeling is first described in terms of the ability of models to predict the properties of the system of interest, using components that have a physiological interpretation, and to gain insight into the relative importance of different components. Examples are used to illustrate the use of modeling the urinary tract with reference to the different categories listed above. Neurourol. Urodynam. Neurourol. Urodynam. 30:692–699, 2011.

A 2014 snapshot audit of the role of urodynamics in the UK for Benign Prostatic Enlargement surgery: For and on behalf of the BAUS section of Female, Neurological and Urodynamics.

Dear Editor, In the UK in 2013, 24,000 surgical procedures are performed for benign prostatic enlargement (BPE) each year, with 90% performed by transurethral resection of the prostate (TURP). The Epidemiology ofMale lower urinary tract symptoms (LUTS) survey (EpiLUTS), highlighted how 70% of men aged over 40 reported LUTS, including 50%ofmen during theirworking lives. The Trans-European Research Into the Use of Management Policies for LUTS suggestive of BPH in Primary Healthcare study (TRIUMPH study) showed that in male LUTS, 23% of men are managed conservatively with watchful waiting, 74% of men are treated by medication (primarily with alpha-1 adrenergic antagonists) and only 3% of men undergo surgery for BPE. Although surgical treatment is effective for treatment of voiding LUTS, it is associated with complications and risks and is expensive. Urodynamics (UDS) is advocated as a useful predictor of surgical success and this has been encouraged by international guidance. To understand current UK practice of assessing men with LUTS, the British Association of Urological Surgeons (BAUS) Section of Female, Neurological and Urodynamic Urology undertook a snapshot audit of UK practice for the assessment of men with LUTS. A Survey Monkey snapshot audit was sent out to all registered full members of BAUS via the BAUS office. Questions focused on the type of bladder outlet obstruction (BOO) surgery available, assessment of male LUTS, the role of UDS in example patients and a snapshot audit of the most recent patient who underwent surgery for LUTS in the respondents, unit. There were 207 responses out of a possible 860 (24%). Of the respondents, 80.7% offered monopolar TURP, 58.9% offered bipolar TURP, 19.3% offered green light laser and 15.9% offered holmium laser surgery. 33.8% of respondents still offered open prostatectomywhilst 2.4% (n1⁄4 5) and 4.3% (n1⁄4 9) offered laparoscopic-assisted and robotically-assisted enucleation prostatectomy respectively. Four (1.9%) surgeons also offered Thulium laser surgery for BPE. Testing of patient scenarios showedhigh correlationwith the National Institute forHealth and Clinical Excellence (NICE) and European Association of Urology (EAU) guidelines for the use of UDS. Only 8.8% of respondents used the CT3000 device. Nearly all surgeons use an IPSS symptom score and/or IPSS bother score. With regard to the most recent patient who underwent surgery, nearly half of surgical procedures were undertaken for acute urinary retention (49.7%). Just over a third (37.4%) of patients underwent surgery because they had LUTS thatwas not controlled by medication. 2.1% of patients had LUTS but did not want medication. 15.4% of patients underwent surgery for obstructive uropathy. Low volume indications (<2%) included difficulty in performing clean intermittent self-catheterisation (CISC) and formationofbladder stones.Mostpatientswere66–70 years (24%) or 71–75years (23.5%). Two percent of patients were under 50 years old and 10.5% were older than 80 years of age. Only 16.8% of patients undergoing surgery for BPE underwent prior UDS testing. Table I describes the UDS findings in these patients. Although not stated in the original audit, it is implicit that those patients with definitions of detrusor underactivity (DU) and detrusor overactivity (DO) as a sole diagnosis are not obstructed. BAUS surgeons appear to be in agreementwith regard to UDS testing of scenario patients with LUTS. However, only 17% of patients undergoing BPE surgery actually underwent UDS prior to surgery in this audit. Even if one exludes the 50% who had acute urinary retention, 34% seems remarkably low and reveals a reluctance to use UDS to establish a diagnosis of BOO prior to BPE surgery. One free text comment even stated that ‘‘there is good evidence that urodynamics is not useful in men undergoing HoLEP as most detrusor failure patients can void following HoLEP without the need for CISC.’’ The authors can find no long term evidence to support this statement. UDS has been shown to be a useful predictor of the success of BOO surgery. TURP success rates are 15–29% higher in men with proven BOO as compared to those that have LUTS but are unobstructed. Patients who are over 80 years of age withdetrusorunderactivity (DU)andresidualvolumesofgreater than 1.5 l are at high risk of treatment failure from TURP. Given that there is no evidence to show a greater reduction in BOO from any deobstructing surgical procedure over another, the above TURP evidence likely applies equally to all types of BOO surgery. Hence, the inclusion of UDS in current guidelines. The use of UDS does need to be offset against the associated potential adverse events, which include macroscopic haematuria, urinary tract infection, and urinary sepsis, in addition to the expense associated with UDS. Conversely, avoidable surgery, on men who do not have BOO, and management of

Bladder wall tension during physiological voiding and in patients with an unstable detrusor or bladder outlet obstruction

Sir, Mr Clarke is to be congratulated on his excellent article on the management of hormone-relapsed prostate cancer [1] but we comment specifically on the area of skeletal dysfunction. Mr Clarke has, quite rightly, drawn attention to the importance of medical treatments, chemotherapy and radiotherapy for metastatic bone disease (MBD) from carcinoma of the prostate. He also correctly stated that pathological fractures should be treated with rapid fixation or joint replacement, and gives an example of a patient who has undergone bilateral hip replacement for sclerotic metastases in the pelvis. However, we draw attention to the importance of prophylactic fixation in patients who have MBD, as highlighted in a recent publication [2].