1.2.1 Upper Urinary Tracts

The kidneys sit either side of the vertebral column, level with the 12th thoracic to the third lumbar vertebrae, in the retroperitoneal part of the abdomen. The right kidney lies slightly lower than the left, due to the bulk of the liver just above. Sometimes, the kidney fails to lie in the expected anatomical location, and may even be identified in the pelvis (Fig. 1.1). The renal vein, artery and ureter (anterior to posterior) enter or exit the kidney at the hilum, on each kidney’s medial aspect. A kidney weighs approximately 115–175 g and is about 11–14 cm in length, 6 cm wide and 4 cm thick.

The meat of the kidney (its “parenchyma ”) is made up of a rim of cortex and a core of medulla. The cortex houses the glomeruli, which are responsible for filtering the blood, and the tubules, which alter the composition of the urine to meet the body’s homeostatic needs. The medulla holds the loops of Henle, where the concentration of the urine is increased. The basic urine production unit is called a “nephron ”, made up of a glomerulus and its associated tubules and loop. The nephrons drain into a collecting duct, which empties into a series of tubes, the calyces, finally converging to make the renal pelvis, from which the ureter emerges.

On each side, the ureter is a 25-cm-long smooth muscle tube, which transports the urine by pushing it along “peristaltically” in small volumes. The ureter descends in the abdomen along the anterior surface of the psoas major muscle as a retroperitoneal structure. Once in the pelvis (meaning the bony pelvis, as opposed to the renal pelvis from which the ureter begins), the ureters run down the lateral pelvic walls. They turn anteromedially at the level of the ischial spines and enter the bladder low down posteriorly at the ureteric orifice. The entry point, termed the vesico-ureteric junction, is designed to function as a valve allowing flow from ureter into the bladder but not the other way; if that happens, termed “vesico-ureteric reflux ” (Fig. 1.1), it is an anatomical or pathophysiological defect with implications for kidney function and infecti ons.

1.2.2 Lower Urinary Tract

1.2.2.1 The Reservoir

The bladder is a hollow organ in the ant erior part of the pelvic cavity. When empty, it sits behind the pubic bone; it is highly distensible, and when full its dome might be felt through the abdominal wall above the pubic bone (“suprapubically ”). Anatomically it has four main areas: the apex, the body, the trigone and the bladder neck. The apex is a point at the top where the median umbilical ligament attaches. This structure loosely connects the bladder to the umbilicus, and is a remnant of the urachus—an important structure in embryological development, which becomes a connective tissue strand by adulthood. The body is the main part of the bladder, sometimes being described as the “dome”; this makes up the reservoir capacity of the organ. Structurally, the bladder has a considerable amount of muscle, which is termed “the detrusor”. The detrusor muscle is a specialised smooth muscle with fibres orientated in a meshwork, enabling it to constrict on the bladder content and thereby increases pressure in the organ. The lining of the bladder dome is the urothelium, which serves as a barrier against the stored urine, preventing it from getting it into the tissues. The urothelium is associated with a range of physiologically complex cells, which mean the structure is probably very active in sensing the state of the organ and potentially enhancing the ability of the organ to contract effectively.

The bladder is an intra-abdominal organ, and due to its location in the pelvis, it is compressed by the other organs lying higher in the abdomen. When a person stands upright, the bladder is thus squashed by the intestines, liver and spleen. This is very obvious when measuring the pressure in the bladder (“intravesical pressure”) during clinical urodynamics, since the resting pressures when standing can be rather high. Furthermore, contraction of the muscles of the abdomen, and especially the diaphragm, increases the intravesical pressure further.

The trigone is a triangular structure, with the two ureteric orifices and the bladder neck marking the corners (Fig. 1.2). It is the convergence point of the muscles of the ureter, urethra and bladder, and houses a considerable concentration of nerve fibres.

1.2.2.2 The Bladder Outlet

The urethra runs from the internal urethral meatu s (where it joins the bladder) to the external meatus (where urine leaves the body). The urethra differs considerably between men and women. In women (Fig. 1.3), it is comparatively short (roughly 3 cm long) and relatively straight. It traverses the pelvic floor to reach the vestibule of the vagina. In men (Fig. 1.4), it is longer and has several distinct anatomical relationships, which are used to subdivide it. Firstly, it crosses the prostate, which is a sexual gland crossed by the ejaculatory duct (formed by the vas deferens and seminal vesicle); the urethral lumen receives the ejaculatory ducts and ducts from the prostate gland. During ejaculation, the bladder neck remains shut to prevent retrograde ejaculation into the bladder. Because of this, the male bladder outlet is not purely a urinary organ; it is better described as “genito-urinary ”. After the prostate, the urethra crosses the pelvic floor, and this section is termed the membranous urethra. It then enters the section running anteriorly along the underside of the pelvic floor, known as the bulbar urethra . Finally comes the penile or pendulous urethra.

The urethral structure comprises an epithelial lining, a subepithelial vascular bed, longitudinal smooth muscle, an outer layer of circular smooth muscle, and skeletal muscle (the external urethral sphincter). The sphincter complex structurally integrates with the muscles of the pelvic floor. The epithelial lining of the bladder outlet is less complex than in the bladder, and is likely to contribute less physiologically than the urothelium does for bladder function.

Sphincter muscles serve to keep the bladder outlet shut and maintain continence. These have an unusual make-up of smooth muscle and a skeletal muscle component. The smooth and skeletal muscle cells play a role in the contractile function of the bladder outlet. The transition between smooth and skeletal muscle is graded, making it difficult to identify a distinct boundary. In men, the urethral sphincter is covered by the distal part of the prostatic capsule at the prostatic apex, where the skeletal and smooth muscle fibres intertwine. There are differences in the relationship with the external urethral sphincter and other structures in the pelvic floor between men and women. In males, the external urethral sphincter is attached to the levator ani muscle of the pelvic floor by fascia which contains mainly smooth muscle cells. In females, the striated muscles are embedded in a matrix with many elastic fibrils and are continuous with a perineal membrane enabling connection with the pelvic bone (the ischium).

In women, the sphincter muscle is distributed unevenly, with most of the muscle lying dorsally (on top); as a result, sphincter contraction kinks the urethra, which is an efficient way to prevent fluid passing along the tube (much like the bend gardeners make to cut off flow along a hosepipe). In men, the sphincter is circular, so when closed it constricts the urethra, rather than kinking it. Men also have a bladder neck which constricts the outlet shut; this structure only opens when passing urine. In contrast, the sphincter opens when passing urine and also at the time of ejaculation.

The pudendal nerve emerging from the sacral level of the spinal cord (S2-S4) provides motor innervation to the external urethral sphincter. This ensures tonic continuous contraction of smooth muscle in the bladder outlet during storage. The nerve endings in the bladder outlet have been identified as adrenergic, cholinergic and non-adrenergic non-cholinergic endings—which include transmitters like nitric oxide, carbon monoxide, purines and peptides. The tonic contraction is augmented by voluntary skeletal muscle contractions of the sphincter and pelvic floor, to enhance the strength of closure when physically active, or when consciously squeezing the outlet shut. These skeletal muscles are also involuntarily contracted in anticipation or, in response to, exertion—a process known as “gua rding”.

1.3.1 Bladder Filling (Storage)

Urine production is an ongoing process, meaning that urin e passes from the kidneys into the ureters and then into the urinary bladder more or less all the time. As the bladder fills, it acts as a reservoir, since the urethra and urinary sphincters are contracted—meaning that, even though urine is continuously produced by the kidneys, its expulsion is sporadic. The bladder expands as it fills, and this is enabled by the detrusor muscle remaining relaxed (“receptive relaxation”). Consequently, the intravesical pressure changes relatively little, even when the volume held in the bladder changes from empty to its full capacity. This is quantified by the “compliance” value, which is measured through calculating the volume change (the difference between empty and full) divided by the pressure change (the rise in pressure between empty and full). A bladder is described as “compliant” if the intravesical pressure changes by only one or two centimetres of water (cmH₂O) for each additional 100 mls volume in the bladder. In order to be compliant, the smooth muscle detrusor fibres and the connective tissues of the bladder wall need to be able to stretch a considerable amount without increasing their tension (“adaptive relaxation”). Part of the adaptive relaxation is a result of the specific physiological make-up of the muscle, and part is a result of the nervous system releasing transmitters to relax the muscle actively—notably noradrenaline, along with circulating adrenaline, promoting relaxation via β3-adrenergic receptors on the detrusor muscle cells [1].

Beta 3 adrenoceptors are the main β-adrenoceptors expressed in the detrusor smooth muscle cells [2]. Stimulation of these receptors relaxes precontracted bladder strips and decreases spontaneous contractile activity in vitro, and non-voiding contractions in vivo. The main mechanism by which β3-adrenoceptors induce direct detrusor relaxation is through activation of the adenylyl cyclase pathway. However, there is also evidence that these receptors can affect bladder tone by modulating large-conductance Ca2+-activated K+ channels and rho kinase activity. Furthermore, there is now evidence that β3-adrenergic agonists improve OAB symptoms by other mechanisms beyond direct muscle relaxation: mirabegron has been shown to decrease afferent firing during bladder filling in a dose-dependent manner, and to down-modulate nerve-evoked acetylcholine release in the human bladder. This latter effect is mediated by adenosine, released from smooth muscle following β3-adrenoceptor activation, which stimulates prejunctional A1 receptors. Additionally, β3-adrenoceptors can be found in the urothelium, but their role in relaxation during bladder filling is yet to be established. The contributing weight of all these mechanisms on the net clinical effect of mirabegron on OAB symptoms remains to be determined. However, it is clear that the effects of β3-agonists on the human bladder exceed those of direct detrusor relaxation.

1.3.2 Bladder Emptying (Voiding)

Voiding starts with a co nsciou s decision which people take either because they have a desire to void (normal or strong desire to void; NDV or SDV ) or because they feel that voiding foreseeably will be awkward or inconvenient later on. This ability to v oid without a bladder sensation of NDV or SDV is usually decided from social reasons, to minimise interruption of subsequent activity (e.g. a meeting, a journey or a night’s sleep). Voiding is initiated by relaxing the bladder outlet (urethra, sphincter, pelvic floor), with detrusor contraction quickly following. The bladder neck funnels urine out of the bladder into the urethra.

During voiding, parasympathetic nerves distributed throughout the detrusor release acetylcholine (ACh) and ATP [3] from efferent nerve endings, which bind to muscarinic (M₃) and purinergic (P₂x₁) receptors, respectively [4]. The resultant downstream intracellular signalling cascades lead to detrusor contraction, and thus a rise in pressure which delivers the force required to expel urine. The purinergic receptor pathways are rather intriguing since they are clearly described in most animal species, and may contribute in providing a quick detrusor contraction (which could be relevant, for example, in the marking of territory). While they are not normally active in human detrusor contraction, purinergic pathways may contribute in some clinical settings, notably overactive bladder syndrome.

Interstitial cells, present throughout the bladder, and particularly populous in the suburothelium, are structurally similar to myofibroblasts—cells that have a contractile phenotype, but which have a role in moderating the physiological behaviour of the bladder rather than contributing to pressure generation [5]. The networks of interstitial cells are connected by gap junctions and therefore may contribute to the spread of electrical signals, and possibly also chemical mediators throughout the bladder wall. This spread of activity could control spontaneous activity in the bladder, and the wider spread of excitatory signals at the start of voiding. The gap junctions are activated by ATP, suggesting they could mediate the spread of electrical signals initiated by ATP release from the urothe lium.

1.3.3 Sensory Nerves and Sensation

Although the nature of the afferent (sensory) innervation is n ot fu lly understood, it is known that small myelinated (Aδ) fibres emerge from a dense nerve plexus in the detrusor and suburothelium [6]. These respond to changes in passive bladder distension, and possibly the active contractile tone of the bladder as well. Unmyelinated C-fibres are also present, but they have a higher threshold for activation, and they may play more of a role in signalling painful or damaging situations, such as bladder overdistension, chemical irritation, or inflammation. C-fibre activity may also become more apparent during the transition between the filling and voiding phases.

Distension of the bladder wall during filling releases chemical mediators that activate the afferents, and the urothelium is a major source of these compounds [7]. During changes in chemical and physical stresses, urothelial cells respond by releasing ATP, ACh, nitric oxide (NO), prostaglandins and neuropeptides that activate various receptors within the bladder wall (Fig. 1.5). These sensory molecules can therefore exert excitatory and inhibitory actions on the same cell, neighbouring cells, other underlying cells, afferent and efferent nerves, and also blood vessels.

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