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50 yrs of the pathophysiology of benign UT disorders: advances through fundamental sciences

Saturday 01 Aug 2020 {{NI.ViewCount}} Views {{NI.ViewCount}} Views

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At first glance the urinary tract appears a simple physiological system: to convey urine from the kidneys via the ureters to the bladder; where it is stored, then periodically voided when the urge is sufficiently great and it is socially acceptable. Beneath this exterior lies a panoply of complexity with respect to: development and maintenance of the normal function and integrity of component tissues; co-ordination of activity between different parts of the urinary tract; sensation of urine volume and flow; and even variation of urine composition. Fundamental knowledge of these activities underpins an understanding of urinary tract benign pathologies such as: the overactive/underactive bladder, bladder pain syndromes, or obstruction in different regions of the tract. The last 50 years has seen a significant expansion of basic understanding of these pathologies thanks to the work of many eminent scientists and whilst particular contributors are named here this does not diminish the contributions of others.

The co-ordination and control of urinary tract function by the central nervous system was one of first aspects to be investigated and stood on the shoulders of giants such as John Langley and then Frederick Barrington more than 100 years ago. Subsequently, much has been inspired by the leadership offered by William (Chet) de Groat. It has been established that storage and voiding functions, whereby smooth and skeletal muscle activity of the lower urinary tract are co-ordinated, are hierarchically organised. Involuntary control of spinal cord circuits is achieved through a switch-like process by a brain stem circuit involving a periaqueductal grey – pontine micturition centre (PAG-PMC) interaction, itself controlled by cortical circuits that provide voluntary control. Inevitably much of this evaluation was achieved using animal models, that provided some dissimilarities to humans. However, the work of Clare Fowler and Derek Griffiths, among several others, provided a great leap forward by the application of real-time imaging modalities, such at PET scans and fMRI imaging, that allowed similar circuitry to be shown in humans. Since then such approaches have provided insight into the origin of lower urinary tract disorders associated with, for example, degenerative brain conditions, spinal cord injury and the normal ageing process.

Concerning our knowledge of urinary tract tissues, most emphasis has been on detrusor and urethral smooth muscle. This means there is still much to be done to characterise fully smooth muscles of the ureter, trigone, prostate gland stroma and striated muscle of the rhabdosphincter and maybe the next decade will contribute to this deficiency. Much of what we know about smooth muscle function stems from insights provided by Alison Brading, herself an acolyte of Edith Bülbring who did much to highlight the hitherto overlooked field of smooth muscle physiology after escaping Nazi Germany. Bülbring’s retirement coincided roughly with the beginnings of ICS and also with the development of many methods that took the study of urinary tract tissues to the next step. This methodology included: isolation of single, viable smooth muscle cells, including those from human biopsies; improved methods of electrophysiology and real-time, live-cell intracellular imaging; and latterly molecular and genetic tools. This allowed a proliferation of activity to characterise the cellular physiology underpinning lower urinary tract contractile function. Moreover, a deeper understanding of how exogenous agents/drugs work was gained by pharmacologists, such as Karl-Erik Andersson, through using a combination of these novel techniques with in vivo studies. An example is the relatively rapid time-scale involved in the introduction of 3 agonists to manage overactive bladder – the first new class of therapy for OAB symptoms in more than 30 years.

The bladder wall is increasingly recognised as a more complex tissue than merely detrusor smooth muscle and in recent years the primary focus on muscle physiology has broadened to other cellular layers such as the urothelium and the underlying lamina propria (itself a complex of blood vessels, afferent nerves, interstitial cells and an extracellular matrix). Again, other regions of the urinary tract have been relatively neglected and it remains to be shown if extrapolation of understanding from the bladder is possible. The bladder urothelium was always considered merely as a ‘tight’ epithelium to prevent urine leaking through to bladder wall tissues, but a small degree of solute transport was always recognised. An important step forward was the finding by Douglas Ferguson that bladder wall distension was associated with ATP release, attributed to the urothelium. Thus, the urothelium was also recognised as a sensory transducer monitoring bladder filling. The subsequent 20 years have filled in many of the gaps between bladder wall distension and its translation to frequency-dependent afferent activity. A recent concept, pioneered by Lori Birder, is that the urothelium and lamina propria act as an integrated structure, a sensory web, that regulates the gain of filling sensations and also can impact directly on detrusor function. It recognises the importance of interaction between different bladder wall tissues and provides a substrate to understand the pathophysiology of both filling and voiding dysfunctions. This novel conceptual approach should also shed greater light on the modes of action of current and future drug therapies. For example, antimuscarinic agents and botulinum toxin when introduced were both assumed to reduce overactive bladder activity by suppressing detrusor function, but there is ample evidence they also suppress lower urinary tract sensory transduction. Such a complex interacting system would benefit from development of mathematical simulations that integrate experimental data to model normal and pathological outputs.

The future offers many more opportunities to build on the fundamental knowledge thus far gathered to understand better the pathogenesis of clinical conditions associated with the urinary tract; two neglected examples will suffice. A substantial number of children are born with impaired development of the lower urinary tract. Although surgical correction techniques have improved greatly, poor urinary tract function, of unknown aetiology, persists in a significant proportion. Secondly, urinary tract stones or encrustations of stents continue to manifest with significant morbidity. The introduction of successful management tools, such as lithotripsy to remove existing stones, has removed a focus on research into the physical chemistry of urine that results in stone formation.

It may be anticipated that our understanding of urinary tract dysfunction will continue to progress on the basis of what has been developed over the current lifetime of ICS.

Article by Chris Fry

Picture of Prof Clare Fowler provided with thanks from Prof Fowler

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