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Ovid: Oxford Handbook of Urology

Authors: Reynard, John; Brewster, Simon; Biers, Suzanne Title: Oxford Handbook of Urology, 1st Edition Copyright ©2006 Oxford University Press > Table of Contents > Chapter 18 – Basic science of relevance to urological practice Chapter 18 Basic science of relevance to urological practice P.648
Physiology of bladder and urethra Bladder The bladder consists of an endothelial lining (urothelium) on a connective tissue base (lamina propria), surrounded by smooth muscle (the ‘detrusor’), with an outer connective tissue ‘adventitia’. The urothelium consists of multi-layered transitional epithelium. It has numerous tight junctions such that render it impermeable to water and solutes. The detrusor muscle is a homogeneous mass of smooth muscle bundles. The bladder base is known as the trigone—a triangular area with the two ureteric orifices and the internal urinary meatus forming the corners. Intravesical pressure during filling is low. The main excitatory input to the bladder is via parasympathetic innervation (S2– 4; cholinergic postganglionic fibres which when activated cause contraction; see p.492). Urethra The bladder neck is normally closed during filling. It is composed of a circular smooth muscle (sympathetic innervation). High pressure is generated at the midpoint of the urethra in women, and at the level of the membranous urethra in men, where the urethral wall is composed of a longitudinal and circular smooth muscle coat, surrounded by striated muscle (external sphincter). The striated part of the sphincter receives motor innervation from the somatic pudendal nerve (S3,4) and has voluntary control (ACh mediates contraction). The smooth muscle component of the sphincter has myogenic tone and receives excitatory and inhibitory innervation from the autonomic nervous system. Contraction is enhanced by sympathetic input (noradrenaline) and ACh. Inhibitory innervation is nitrergic (nitric oxide). Micturition Voiding is mediated by the pontine micturition centre in the brain. During urine storage, bladder neck and sphincter smooth muscle are constricted, and ganglia in the bladder wall are inhibited by sympathetic input, whilst somatic innervation causes contraction of the striated sphincter muscle. As the bladder fills, sensory nerves respond to stretch and send information about bladder filling to the CNS. At a socially acceptable time, the voiding reflex is activated. Stimulation of detrusor smooth muscle by parasympathetic anticholinergic nerves causes the bladder to contract. Simultaneous activation of nitrergic nerves reduces the intraurethral pressure, inhibition of somatic input relaxes the striated sphincter muscle, and sympathetic inhibition causes co-ordinated bladder neck and sphincter smooth muscle relaxation, resulting in bladder emptying. P.649
Renal anatomy: renal blood flow and its regulation The kidneys and ureters lie within the retroperitoneum (literally behind the peritoneal cavity). The hila of the kidneys lie on the transpyloric plane (vertebral level—L1). Each kidney is composed of a cortex, surrounding the medulla which forms projections—papillae—which drain into cup-shaped epithelial-lined pouches called calyces (the calyx draining each papilla is known as a minor calyx, and several minor calyces coalesce to form a major calyx, several of which drain into the central renal pelvis). The renal artery, which arises from the aorta at vertebral level L1/2, branches to form interlobar arteries, which in turn form arcuate arteries, and then cortical radial arteries from which the afferent arterioles are derived. Venous drainage occurs into the renal vein. There are two capillary networks in each kidney—a glomerular capillary network (lying within Bowman’s capsule) which drains into a peritubular capillary network, surrounding the tubules (proximal tubule, loop of Henle, distal tubule, and collecting ducts). The anterior relations of the right kidney are, from top to bottom, the suprarenal gland, the liver, and the hepatic flexure of the colon. Medially, anterior to the right renal pelvis is the second part of the duodenum. The anterior relations of the left kidney are, from top to bottom, the suprarenal gland, the stomach, the spleen, and the splenic flexure of the colon. Medially lies the tail of the pancreas. The posterior relations of both kidneys are, superiorly, the diaphragm and lower ribs and, inferiorly (from lateral to medial), transverus abdominis, quadratus lumborum, and psoas major. Each kidney has 1 million functional units or nephrons (Fig. 18.1), the functional unit of the kidney consisting of a glomerular capillary network, surrounded by podocytes (epithelial cells) of Bowman’s capsule, which drains into a tubular system (proximal convoluted tubule, loop of Henle, distal convoluted tubule, collecting tube, and collecting duct) (see Fig. 18.1). Blood is delivered to the glomerular capillaries by an afferent arteriole and drained by an efferent arteriole. An ultrafiltrate of plasma is formed within the lumen of Bowman’s capsule, driven by Starling forces across the glomerular capillaries. Reabsorption of salt and water occurs in the proximal tubule, loop of Henle, distal tubule, and collecting ducts. Clearance is the volume of plasma that is completely cleared of solute by the kidney per minute. Glomerular filtration rate (GFR) is the clearance for any substance which is freely filtered and is neither reabsorbed, secreted, or metabolized by the kidney. For a substance which is freely filtered at the glomerulus, is neither secreted nor reabsorbed by the renal tubules, and is not metabolized (catabolized), clearance is equivalent to GFR. Where a substance is both filtered at the glomerulus and secreted by the renal tubules, its clearance will be greater than GFR. Where a substance is filtered at the glomerulus, but reabsorbed by the renal tubules, its clearance will be less than GFR. Clinically, GFR is estimated using creatinine, and is ~125ml/min. GFR is directly related to renal blood flow (RBF). Experimentally, GFR can be P.651
accurately measured by measuring the clearance of inulin (a substance which is freely filtered by the glomerulus and is neither secreted nor reabsorbed by the kidneys). Thus, the volume of plasma from which in one minute the kidneys remove all inulin is equivalent to GFR. Normally about one-fifth (120ml/min) of the plasma that flows through the glomerular capillaries (600ml/min) is filtered.

Fig. 18.1 The nephron

Clearance of a substance from the plasma can be expressed mathematically as: Clearance = U × V / P where U is the concentration of a given substance in urine, P is its concentration in plasma, and V is the urine flow. Renal blood flow (RBF) The kidneys represent <0.5% of body weight, but they receive 25% of cardiac output (~1300ml/min through both kidneys; 650ml/min per kidney). Combined blood flow in the two renal veins is about 1299ml/min, and the difference in flow rates represents the urine production rate (i.e. ~1ml/min). Autoregulation of RBF RBF is defined as the pressure difference between the renal artery and renal vein divided by the renal vascular resistance. The glomerular arterioles are the major determinants of vascular resistance. RBF remains essentially constant over a range of perfusion pressures (~80–180mmHg) (i.e. RBF is autoregulated). Autoregulation requires no innervation and probably occurs via:

  • a myogenic mechanism (increased pressure in the afferent arterioles causes them to contract, thereby preventing a change in RBF)
  • tubuloglomerular feedback—the flow rate of tubular fluid is sensed at the macula densa of the juxtaglomerular apparatus (JGA), and in some way this controls flow through the glomerulus to which the JGA is opposed.

Other factors that influence RBF

  • Sympathetic nerves innervate the glomerular arterioles. A reduction in circulating volume (such as blood loss) can stimulate sympathetic nerves, causing the release of NA (which acts on α1-adrenoceptors on the afferent arteriole) to cause vasoconstriction. This results in reduced RBF and GFR.
  • Angiotensin II constricts efferent arterioles and afferent arterioles and reduces RBF.
  • Antidiuretic hormone (ADH), ATP, and endothelin all cause vasoconstriction and reduce RBF and GFR.
  • Nitric oxide causes vasorelaxation and increases RBF.
  • Atrial natriuretic peptide (ANP) causes afferent arteriole dilatation and increases RBF and GFR.

Renal physiology: regulation of water balance Total body water (TBW) is 42L. It is contained in 2 major compartments—the intracellular fluid (ICF or the water inside cells) which accounts for 28L and the extracellular fluid (ECF or water outside cells) representing 14L. ECF is further divided into interstitial fluid (ISF, 11L), transcellular fluid (1L), and plasma (3L). Hydrostatic and osmotic pressures influence movement between the compartments. Water is taken in from fluids, food, and oxidation of food. Water is lost from urine, faeces, and insensible losses. Intake and losses usually balance (~2L/day) and TBW remains relatively constant. Antidiuretic hormone (ADH or vasopressin) ADH is secreted from the posterior pituitary in response to stimulus from changes in plasma osmolarity (detected by osmoreceptors in the hypothalamus) or changes in blood pressure or volume (detected by baroreceptors in the left atrium, aortic arch, and carotid sinus). These changes also stimulate the thirst centre in the brain. The action of ADH on the kidney:

  • Increases collecting duct permeability to water and urea
  • Increases loop of Henle and collecting duct reabsorption of NaCl
  • Vasoconstriction

Conditions of water excess Body fluids become hypotonic, and ADH release and thirst are suppressed. In the absence of ADH, the collecting duct is impermeable to water and a large volume of hypotonic urine is produced, so restoring normal plasma osmolarity. Conditions of water deficit Body fluids are hypertonic, ADH secretion and thirst are stimulated. The collecting duct becomes permeable, water is reabsorbed into the lumen, and a small volume of hypertonic urine is excreted. The ability to concentrate or dilute urine depends on the counter-current multiplication system in the loop of Henle. Essentially, a medullary concentration gradient is generated (partly by the active transport of NaCl) which provides the osmotic driving force for the reabsorption of water from the lumen of the collecting duct when ADH is present. Children have a circadian rhythm in ADH secretion—high at night and low during the day. Adults essentially have a constant ADH secretion over a 24-h period, with slight increases occurring around mealtimes. At these times, increased ADH secretion probably acts to prevent sudden increases in plasma osmolality that would otherwise occur due to ingestion of solutes in a meal. P.655
Renal physiology: regulation of sodium and potassium excretion Sodium regulation NaCl is the main determinant of ECF osmolality1 and volume. Low-pressure receptors in the pulmonary vasculature and cardiac atria, and high-pressure baroreceptors in the aortic arch and carotid sinus, recognize changes in the circulating volume. Decreased blood volume triggers increased sympathetic nerve activity and stimulates ADH secretion, which results in reduced NaCl excretion. Conversely, when blood volumes are increased, sympathetic activity and ADH secretion are suppressed, and NaCl excretion is enhanced (natriuresis). A variety of natriuretic peptides have been isolated which cause a natriuresis. Under physiological conditions, renal natriuretric peptide (urodilatin) is the most important of these. Atrial natriuretic hormone (ANP) may influence sodium output under conditions of heart failure. Renin–Angiotensin–Aldosterone system Renin is an enzyme made and stored in the juxta-glomerular cells found in the walls of the afferent arteriole. Factors increasing renin secretion are:

  • Reduced perfusion of afferent arteriole
  • Sympathetic nerve activity
  • Reduced Na+ delivery to the macula densa

Renin acts on angiotensin to create angiotensin I. This is converted to angiotensin II in the lungs by angiotensin-converting enzyme (ACE). Angiotensin II performs several functions, which result in the retention of salt and water:

  • Stimulates aldosterone secretion (resulting in NaCl reabsorption)
  • Vasoconstriction of arterioles
  • Stimulates ADH secretion and thirst
  • Enhances NaCl reabsorbtion by the proximal tubule

Potassium regulation K+ is critical for many cell functions. A large concentration gradient across cell membranes is maintained by Na+-K+-ATPase pump. Insulin and adrenaline also promotes cellular uptake of K+. The kidney excretes up to 95% of K+ ingested in the diet. The distal tubule and collecting duct are able to both reabsorb and secrete K+. Factors promoting K+ secretion include:

  • Increased dietary K+ (driven by the electrochemical gradient)
  • Aldosterone
  • Increased rate of flow of tubular fluid
  • Metabolic alkalosis (acidosis exerts the opposite effect)

Footnote 1 Osmolality = moles per kg water. Osmolarity = moles per litre of solution. P.656
Renal physiology: acid–base balance The normal pH of extracellular fluid (ECF) is 7.4 ([H+] = 40nmol/L). Several mechanisms are in place to eliminate acid produced by the body and maintain body pH within a narrow range. Buffering systems which limit [H+] fluctuation in the blood Buffer bases which take up H+ ions in the body include:2 Bicarbonate buffer system H+ + HCO3- ↔ H2CO3 ↔ H2O + CO2 Phosphate system H+ + HPO42- ↔ H2PO4- Protein buffers H+ + Protein- ↔ HProtein The Henderson–Hasselbalch equation describes the relationship between pH and the concentration of conjugate acid and base. From this equation, it can be seen that alterations in bicarbonate [HCO3-] or CO2 will effect pH. Metabolic acid-base disturbances relate to a change in bicarbonate, and respiratory acid-base disorders relate to alterations in CO2 Bicarbonate reabsorption along the nephron Bicarbonate is the main buffer of ECF and is regulated by both the kidneys and lungs. 85% is reabsorbed in the proximal convoluted tubule (Fig. 18.2). Carbonic acid is first produced from CO2 and water (accelerated by carbonic anhydrase). The carbonic acid dissociates, and an active ion pump (Na+/H+ antiporter) extrudes intracellular H+ into the tubule lumen in exchange for Na+. Secretion of H+ ions favours a shift of the carbonic acid–bicarbonate equilibrium towards carbonic acid, which is rapidly converted into carbon dioxide and water. CO2 diffuses into the tubular cells down its diffusion gradient and is reformed into carbonic acid by intracellular carbonic anhydrase. The bicarbonate formed by this reaction is exchanged for chloride, and passes into the circulation. Essentially, with each H+ ion that enters the kidney, a bicarbonate ion enters the blood, which bolsters the buffering capacity of the ECF. The remaining bicarbonate is absorbed in the distal convoluted tubule, where cells actively secrete H+ into the lumen via an ATP-dependent pump. The distal tubule is the main site that pumps H+ into the urine to ensure the complete removal of bicarbonate. Once the bicarbonate has gone, phosphate ions and ammonia buffer any remaining H+ions.

Fig. 18.2 Diagram showing bicarbonate reabsorption in the proximal convoluted tubule

Footnote 2 H2O = water; CO2 = carbon dioxide; HCO-3 = bicarbonate; H2CO3 = carbonic acid; H+ = hydrogen ions; HPO2-4 = phosphate ions; H2PO-4 = phosphoric acid.

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