Lower Urinary Tract Symptoms in Adults: A Clinical Approach

© Springer Nature Switzerland AG 2020

M. Drake et al. (eds.)Lower Urinary Tract Symptoms in Adultshttps://doi.org/10.1007/978-3-030-27747-5_1

1. The Urinary Tract: Form and Function

B. Chakrabarty¹  , J. Crook¹  , Marcus Drake¹  , Niall Gilliland²  , Dev Gulur³  , D. Kitney¹  , A. Manjunath²  , Pavlo Somov⁴   and B. Vahabi⁵  

(1)

University of Bristol, Bristol, UK

(2)

Bristol Urological Institute, Southmead Hospital, Bristol, UK

(3)

Countess of Chester Hospital, Chester, UK

(4)

National Health Service, Leeds, UK

(5)

University of the West of England, Bristol, UK

B. Chakrabarty

Email: [email protected]

J. Crook

Email: [email protected]

Marcus Drake (Corresponding author)

Email: [email protected]

Niall Gilliland

Email: [email protected]

Dev Gulur

D. Kitney

A. Manjunath

Email: [email protected]

Pavlo Somov

B. Vahabi

Email: [email protected]

1.1 Introduction

1.2 The Structures of the Urinary Tract

1.2.1 Upper Urinary Tracts

1.2.2 Lower Urinary Tract

1.3 How the Lower Urinary Tract Functions: The Micturition Cycle

1.3.1 Bladder Filling (Storage)

1.3.2 Bladder Emptying (Voiding)

1.3.3 Sensory Nerves and Sensation

1.4 How the Nervous System Controls the Lower Urinary Tract

1.4.1 The Spinal Cord

1.4.2 The Brain Roles in Control of the Lower Urinary Tract

1.4.3 Physiological Mechanisms in Bladder Dysfunction

1.5 Implications of Water and Salt Homeostasis

1.5.1 Behaviour and Environment Influences on Fluid Balance

1.5.2 Internal Factors Affecting Fluid Balance

1.5.3 Fluid Sequestration and Loss

References

Keywords

Urinary bladderUrethral sphincterMicturition cycleBladder sensationBladder dysfunction

1.1 Introduction

This chapter introduces the fundamental structures of the lower urinary tract, and how they are regulated from all levels of the nervous system to ensure urine storage and voiding. The key roles of the LUT are in urine storage and voiding. The bladder is the reservoir for the output of urine from the kidneys, which is determined by fluid intake, the need to balance water, salt and toxins, and can be substantially affected by a wide range of diseases. Voiding is decided by the person concerned balancing current social circumstances, sense of bladder fullness and upcoming activity. The scope of influence is very wide for a seemingly minor organ, and this chapter describes the fundamental structures and functions to set the reader up to understand how symptoms come to be a ubiquitous healthcare issue.

1.2 The Structures of the Urinary Tract

The term urinary tract covers the organs responsible for urine production, storage and expulsion. It can be subdivided into two specific regions, according to the relationship to the point where the ureter enters the bladder (the ureteric orifice ):

The upper urinary tracts, consisting of the kidneys and ureters. These serve to create the urine and transport it for storage

The lower urinary tract, consisting of the bladder, sphincter mechanisms and urethra, with the prostate in men. These serve to store the urine, and provide a conduit for expelling urine when appropriate

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.

Fig. 1.1

Cystogram showing the bladder filled with X-ray contrast (black). There is a little bit of air which has risen to the top of the contrast (yellow arrow). There is reflux of the contrast instilled into the bladder, seen entering the right ureter (open red arrow). This has reached the kidney collecting system (solid red arrow), with the kidney evidently lying in the bony pelvis, well out of its expected location which is normally out of sight in the back of the abdomen. There is also contrast in the large intestine (blue arrow); such an appearance can occur if there is a fistula between bladder and bowel, but in this case it was because the patient had a barium enema X-ray done the day before

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.

Fig. 1.2

A surgical view of the trigone . The bladder neck is indicated by the black arrow. There is an erosion of a surgical tape here, which is why the operation was needed. The other corners of the trigone are the ureteric orifices; here they have been catheterised with a fine plastic tube (green arrow) joining them, so they are easy to identify and hence protect during the operatio n.

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.

Fig. 1.3

Urethroscopy in a woman . The urethra is short, and the sphincter muscle is being gently pushed open by the flow of irrigation along the urethroscope. The dark region is the entry to the bladder. The excellent blood supply is characteristic, and one of the mechanisms keeping the female urethra shut for urine storage.

Fig. 1.4

Voiding urethrograms from two men. On the left, viewed obliquely, the urethra of a normal man . The gr een arrow indicates the bladder neck, red arrow is prostatic urethra, purple is bulbar urethra and blue is penile urethra. On the right, viewed in the antero-posterior plan, a man who previously had a radical prostatectomy and subsequently an artificial urinary sphincter (AUS) operation. Green arrow: bladder neck; brown arrow: the location of the normal urethral sphincter is at the level of the base of the pubis; purple arrow: location of the AUS cuff around the bulbar urethra; blue arrow: penile urethra. There is no red arrow as he has no prostatic urethra. The AUS components are the pressure reservoir and manual pump for opening the cuff (filled orange arrows), and the cuff itself (purple)—see Chap. 7

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 How the Lower Urinary Tract Functions: The Micturition Cycle

Micturition or voiding is the process of passing urine in the right place, in which the individual has full conscious control over timing. When not voiding, the lower urinary tract is functioning as the urine storage reservoir, up until the time the person next decides to pass urine. Thus, people switch between storage and voiding modes, leading to a repetitive alternation referred to as the micturition cycle. Much of the process is automatic, subconsciously regulated by natural reflexes, and it is only the decision to go to the toilet and the moment of initiating voiding that are under voluntary control.

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.

Fig. 1.5

Signalling chemicals active in the bladder wall . ATP adenosine triphosphate, ACh acetylcholine, DSM detrusor smooth muscle, MR muscarinic receptor, NGF nerve growth factor, NO nitric oxide, PGs prostaglandins, TRP transient receptor potentials

ATP is a particularly central signalling molecule in the bladder wall. It is possible that the release of ATP during bladder distension may influence nearby afferent nerves, by binding to P2x3 receptors to control afferent firing. It is also possible that ATP may signal to adjacent cells, i.e. detrusor muscle or interstitial cells.

The nerves in the bladder are responsible for constantly signalling to the spinal cord important factors such as pressure and distension so that they are constantly monitored subconsciously, in conjunction with all the other organ systems of the body. Notably, people are not consciously aware of these constant signals; instead, any perception of the bladder arises sporadically, with three particular sensations being reported by most people:

First awareness of filling

Normal desire to void (NDV; when a person would tend to go to the toilet if they weren’t involved in some other activity)

Strong desire to void (SDV; when a person would generally excuse themselves from any other activity in order to go to the toilet).

These conscious sensations represent a selective brain processing of the subconscious spinal data constantly sent by the sensory nerves in the bladder and bladder outlet, matching them so they can be fitted to the complex social and other functions which all individuals encounter.

As urine passes out, it stimulates receptors in the urethra, and this sensory information has two roles:

1.

It helps sustain the detrusor contraction, as a result of a subconscious reflex.

2.

It reaches the brain to make the person consciously aware of the sensation of urine flow.

Voiding concludes when the bladder is fully empty, which means that the urethral receptors no longer report the presence of urine passing out, and the spinal reflex sustaining the detrusor contraction consequently concludes. Transient interruption of flow can be instigated volitionally, signifying voluntary control of the sphincter during voiding. This means the person can deliberately interrupt the urine stream so that the spinal reflex is similarly concluded, but this time by a voluntary action; this is the means by which people can stop voiding should they need to.

1.4 How the Nervous System Controls the Lower Urinary Tract

The central nervous system functions in a hierarchy of levels which each give additional sophistication to overall lower urinary tract function (Fig. 1.6). The most basic function is the motor neurons, which are the nerves located in the spinal cord and directly connected to muscle, responsible for making them contract. In order to make the various functions of the lower urinary tract work, the motor neurons have to be co-ordinated by a conductor, a group of neurons located in the brainstem called the pontine micturition centre (PMC) . The PMC thus ensures the motor neurons work in the right way as a team to deliver the storage and voiding functions of the lower urinary tract, and ejaculation in male genito-urinary function. In order to ensure the reflexes happen in the right context, the brain inputs to the PMC to give it permission to switch between storage and voiding reflexes. The sensory information from the lower urinary tract inputs to the various control centres (spinal motor neurons and PMC), and also is relayed to the brain, where it can become a consciously perceived sensation. These are described in more detail below.

Fig. 1.6

Key parts of th e central nervous system responsible for lower urinary tract function. PMC: pontine micturition centre; PNS: parasympathetic nervous system; SNS: sympathetic nervous system

1.4.1 The Spinal Cord

The motor neurons controlling contractions o f the detrusor muscle of th e bladder are the parasympathetic neurons; the main cell bodies of these are located in the intermediolateral cell grou p in the sacral spinal cord (S2–4), and they send their nerve fibres to the bladder in a network (known as a plexus ).

The bladder outlet receives input from more than one spinal motor centre. The motor neurons controlling contractions of the external urethral sphincter have their cell bodies in the ventral horn of the sacral spinal cord, in a cell group known as the nucleus of Onuf. The fibres from here travel in the pudendal nerve to reach the sphincter. The bladder neck is regulated by the sympathetic neurons located in the intermediolateral cell group in the thoracolumbar spinal cord (T6-L1). The hypogastric nerve carries the sympathetic nerve fibres.

Afferent nerves from the bladder run in the plexus to enter the sacral spinal cord on its dorsal side. Urethral afferents run in the pudendal ner ve, also to the sacral spinal cord.

1.4.2 The Brain Roles in Control of the Lower Urinary Tract

Two centres in the brainstem regulate efficient functioning of th e spinal motor neurons. Most important is the PMC, which regulates which motor neurons are active and when (Table 1.1). This ensures that the reflexes are achieved with synergy; when the PMC cannot communicate with the spinal cord due to a neurological lesion of the spinal cord above the motor centres, they are likely to behave dyssynergically, as in detrusor sphincter dyssynergia.

Table 1.1

Activity of motor neurons in the key (genito)-urinary states

While it is less well established scientifically than the PMC, there is also thought to be a pontine storage centre. This probably ensures that the detrusor is suppressed (inhibited) during urine storage, and may have direct connections to the outlet motor neurones, which are active when voiding is deferred.

The various reflexes are also regulated by other centres. In the brain, areas that are specific to micturition include the following: the neurons of the PMC and the periaqueductal grey matter; cell groups in the caudal and preoptic hypothalamus, and the cerebral cortex in the medial frontal lobe. The PMC is the main coordinator of micturition; it receives messages from the periaqueductal grey matter and hypothalamus, and descending axons are sent from there to the parasympathetic nucleus in the spinal cord. The paraventricular nucleus of the hypothalamus is nonspecific in its projection to all of the preganglionic autonomic motor neurons in the spinal cord, while the neurons of the lateral pons target the sphincter motor nuclei (Onuf’s nucleus). Therefore, the CNS control of micturition relies on multiple neural pathways, working in a hierarchy.

During the storage phase of the micturition cycle, the reflexes are organised within the spinal cord, whereas voiding reflexes are initiated from the brain, working through the PMC . During filling, the parasympathetic nervous system’s control of the bladder is inhibited, detrusor activity is reduced, and tone of the urethral sphincter is increased, thus maintaining continence. The reflexes that are responsible for this are collectively known as the guarding reflex: bladder filling increases afferent signals through the pelvic nerves and inhibits detrusor contraction through interneuronal activity in the spinal cord. Input from the lateral pons or pontine storage centre feeds into the urethral sphincter causing it to maintain constant contraction. Sudden increases in intra-abdominal pressure cause an increase in urethral sphincter tone which enhances resistance, preventing leakage.

The spinobulbospinal reflex works through a pathway consisting of afferent activity from the bladder to the midbrain and pontine centres transmitting efferent signals from the pons to the sacral spinal cord. The spinobulbospinal reflex is either on (voiding) or off (storage). If the only thing that controlled bladder storage or voiding was this reflex, and if it could be only either on or off, then the bladder would void uncontrollably when it reached a certain volume. As this is not the case, other areas of the brain must be involved in maintaining continence, and ensuring micturition occurs at an appropriate time. The decision to void is based on the firing of the micturition reflex and the ability to control this, and one’s emotional state. The area of the brain that controls this aspect of micturition is the periaqueductal grey matter. It coordinates incoming subconscious sensory signals from the bladder and moves them into the consciousness perception (sensations) of the individual, as well as regulating input into the PMC from areas of the brain such as the prefrontal cortex.

The sensation of a full bladder and the desire to void in this situation underpin the emotional and motivational components to bladder storage and voiding. The anterior cingulate cortex, which is part of the limbic system, is hypothesised to receive afferent signals from the periaqueductal grey matter via the thalamus, and it is these signals that may generate a sensation of urgency—a more compelling feeling than the usual strong desire to void. In people with normal bladder function this is less active, while in people with overactive bladder with urgency it is more active. The anterior cingulate cortex is usually activated with the adjacent supplementary motor cortex, and this activation contracts the pelvic floor. This association means that when the urgency to void comes from the anterior cingulate cortex, voiding can sometimes be postponed.

The prefrontal cortex is involved in planning complex tasks and ensuring social appropriateness of behaviour. Since it has a strong association with the periaqueductal grey matter, it is probably responsible for deciding when it is time to pass urine. The prefrontal cortex connects with the hypothalamus, insula and other areas of the autonomic nervous system. The hypothalamus also connects with the PMC. The hypothalamus responds to changes in volume status of the bladder and is an added level of control in the micturition reflex.

Another area that is seen on functional MRI imaging is the insula. Functional MRI reveals that the insula is the area of the brain that receives visceral sensations, and is most active during bladder filling [8]. The insula is involved in homeostasis for the entire body, and insula activation increases as the bladder fills and desire to void emerges. In patients with impaired bladder sensation, the activation of the insula is reduced or absent. The thalamus is involved in connecting the left and right insulas to each other, as well as with other areas of the cortex, and excitation of the thalamus also increases during bladder fil ling.

1.4.3 Physiological Mechanisms in Bladder Dysfunction

The bladder exhibits spontaneous activity, wh ich may normally contribute to maintaining bladder wall tone [9]. Such micromotions are an innate property of the bladder, but they are neither nerve-mediated, nor generally seen in isolated detrusor mus cle. This suggests the need for communications between different layers of the bladder wall to control normal spontaneous activity, perhaps supporting a role for urothelium or interstitial cells underpinning the spontaneous localised contractions. Once this activity becomes excessive, it may contribute to the emergence of abnormal sensations, such as urgency, or abnormal pressure changes (detrusor overactivity). There are four proposed hypotheses for the initiation of spontaneous contractions and its abnormal enhancement in bladder dysfunction:

1.

Myogenic hypothesis. An increase of detrusor electrical excitability and enhanced coupling of detrusor myocytes could lead to increased spontaneous activity [10].

2.

Integrative hypothesis. Similar to the myogenic hypothesis, but a result of influences of all the bladder cell types, not only the muscle [11].

3.

Urotheliogenic hypothesis. As previously mentioned, the mucosa is highly active and releases many chemical agents and transmits electrical activity through the bladder wall. Dysfunction in this structure may lead to the dysfunction [7].

4.

Neurogenic hypothesis. Increased nerve activity may initiate or permit the persistence of spontaneous contractions. Transmitter leakage from nerve terminals may result in activation of receptors on the detrusor mu scle [12].

1.5 Implications of Water and Salt Homeostasis

Regarding the storage and voiding functions of the lower urinary tract in isolation is entirely artificial. Of course, the reservoir and voiding functions of the lower urinary tract largely reflect the demands made of it by the upper urinary tract, in which the rate of urine production is hugely significant. Thus, any proper insight into lower urinary tract symptoms needs to recognise how urine is produced normally, and what causes it to go wrong, with consequent expression in how it influences the lower urinary tract.

Formation of urine is one of the vital processes which maintain homeostasis essential for well-being. Body regulation of fluid and salt is extremely tight, in order to protect cardiovascular and brain function, by ensuring that sodium levels in the serum vary minimally. Due to the rather sporadic nature of fluid and solute intake, tight regulation of urine output is required to sustain constant internal environment. The specific function is to discard any surplus water or surplus salt in the urine, respectively referred to as diuresis or natriuresis, and leading to increased urine volume in either case. As clinicians we are frequently faced with patients whose symptoms are actually secondary to variant urine production, yet which are referred because they may cause the person to pass urine frequently, or when trying to sleep.

1.5.1 Behaviour and Environment Influences on Fluid Balance

Changes in the urine production secondary to external factors are largely physiol ogical. On e of the main factors affecting urine output is fluid intake. Intake varies significantly from person to person and may not be apparent even if it is significantly different from the average. While modern society encourages increased fluid intake on a supposed health basis, the extreme cases may be the result of psychogenic polydipsia which is a potential occurrence in patients with psychiatric disorders. In rare cases, polydipsia may actually be a necessary response to fluid loss (diabetes insipidus) or salt loss (natriuresis), in which situation the person becomes constantly thirsty and has to increase their fluid intake to prevent serious dehydration.

Water loss during heat stress or strenuous exercises may be significant, leading to dehydration and thus reduced urine output. The person may then drink to make up of the loss, and often will overcompensate, leading to a water surplus that then will increase urine volume later. Interestingly, an environment with lowered temperature can significantly increase diuresis and natriuresis secondary to central blood pooling and increase in effective circulatory vol ume.

1.5.2 Internal Factors Affecting Fluid Balance

The blood pressure is a major influence on multipl e body functions, such that maintaining stable blood pressure is vital [13]. Glomerular filtration in the nephron is the first step in making urine, and is tightly related to the blood pressure. Maintaining mean arterial pressure (MAP) at the level of 65–75 mm Hg optimises filtration. At night, systemic blood pressure should drop by 10–20% with sleep, and this may be a contributing factor for lower nocturnal production of urine. This means the bladder is less likely to reach a volume associated with a desire to void and hence is protective against nocturia. In hypertensive patients, non-dipping of the night blood pressure is commonly associated with nocturia.

One of the important regulators of systemic and renal blood pressure is the Renin Angiotensin Aldosterone System (RAAS) . Renin is released in the kidney in response to reduced glomerular perfusion, and this converts Angiotensinogen into Angiotensin I, which in turn is converted to Angiotensin II by Angiotensin Converting Enzyme (ACE) in the lungs. Angiotensin II is a very potent vasoconstricting peptide which affects not only arterioles in the peripheral circulation but also arterioles in the kidneys. Angiotensin II also stimulates release of aldosterone, which leads to retention of water and salt. Aldosterone release may be increased in primary hyperaldosteronism (Conn’s syndrome ) due to an adrenal adenoma or secondary hyperaldosteronism due to over-activation of the RAAS (notably in renal artery stenosis).

Prostaglandins PGE2 and PGI2 production in the kidney is stimulated by Angiotensin II. These can counteract the renal effects of the RAAS. Consequently, inhibition of prostaglandin synthesis with non-steroidal anti-inflammatory drugs (NSAIDs) causes the kidney to reduce urine volume. If a person is already dehydrated, NSAIDs can potentially lead to acute renal failure.