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Ovid: Oxford Handbook of Medical Sciences

Editors: Wilkins, Robert; Cross, Simon; Megson, Ian; Meredith, David Title: Oxford Handbook of Medical Sciences, 1st Edition Copyright ©2006 Oxford University Press, 2006, except ‘Clinical aspects’ section of Chapter 2 (Copyright by Keith Frayn) > Table of Contents > Chapter 7 – Urinary system Chapter 7 Urinary system Urinary Tract Morphology The kidney The kidneys are found bilaterally either side of the vertebral column at T12–L3, outside of the peritoneal cavity. They each measure approximately 11cm long × 6cm wide × 4cm deep. The right kidney sits slightly lower (about 12mm) than the left kidney, since it is displaced by the right lobe of the liver. The kidneys move up and down with respiration but demonstrate little side-to-side movement. Their role is to filter and excrete waste products from blood and urine, as well as to regulate body fluid composition. In addition, the kidneys are important endocrine organs. The renal hilum (the point at which the renal vessels, ureters, and nerves enter and leave the kidney) is an opening on the medial aspect of each kidney. The left renal hilum is at the same level as the transpyloric plane, and the right is usually slightly lower. Moving anteriorly to posteriorly, the hilum usually contains:

  • Renal vein
  • Renal artery
  • Renal pelvis
  • Subsidiary renal artery.

Lymph vessels, nerves, and fat occupy a more variable position within the hilum. The renal pelvis drains urine from the 2 or 3 major calyces of the kidney, with 2 or 3 minor calyces draining into each major calyx. In turn, each minor calyx is fed by renal papillae tissue and this represents the point at which the collecting ducts of the kidney transmit urine into the ureter. The renal pelvis can be intra or extra-renal, depending on whether it is completely enclosed by the kidney. Coverings of the kidney The kidneys are surrounded by four distinct coverings. The fibrous capsule of the kidney almost completely encloses it and is separated from the renal fascia by a layer of perirenal fat. Renal fascia is a fibrous tough tissue around the kidney and adrenal glands which projects bundles of collagen into the surrounding fat, helping to anchor the kidney in position. Together, the perirenal fat and pararenal fat (which lies outside the layer of renal fascia, particularly posteriorly) form a double protective layer of fat around the kidney. Gross structure of the kidneys (Fig. 7.1) The kidney is made up of an outer cortex and an inner medulla. The medulla is lighter brown in colour and comprises up to a dozen renal pyramids which are oriented such that the point feeds into the minor calyces. The cortex comprises all of the outer lateral regions of the kidney, as well as renal columns between the renal pyramids. Medullary rays are striated areas which project from the bases of the renal pyramids, through the renal cortex.

Table 7.1 Anatomical relations
  Right kidney Left kidney
Superiorly Diaphragm separates from pleura and 12th rib Adrenal glands cap superior pole of each kidney
Posteriorly Quadratus lumborum, transversus abdominis, psoas Iliohypogastric nerve, ilio-inguinal nerve, subcostal nerve/vessels
Anteriorly Liver, 2nd part of duodenum, ascending colon Spleen, jejunum, pancreas and blood vessels, stomach, descending colon
Fig. 7.1 (a) Diagram of hemisected kidney to show its component parts. (b) Arrangement of kidney microvasculature.

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Blood supply and lymphatic drainage The renal arteries arise from the aorta at L1–2. The right artery is longer and runs behind the inferior vena cava to cross to the right side. Close to the hilum of each kidney, the artery divides into five segmental end arteries. These segmental arteries supply the segments of the kidney. Each segmental artery gives rise to lobar arteries, which each supply an individual renal pyramid. Two or three interlobar arteries are given off by each lobar artery. These interlobar arteries then enter the renal cortex on either side of the renal pyramid. Arcuate arteries are given off by the interlobar arteries at the intersection of the cortex and medulla over the base of the pyramids. These arteries give off several interlobular arteries which enter the cortex. From these arteries, the afferent glomerular arterioles arise to supply the glomerulus, and ultimately form the vasa recta of the medulla. The venous drainage of the kidney largely parallels the arterial supply, with veins following a similar route to arteries. The renal vein runs anterior to the renal artery as it leaves the hilum. The left vein is longer, having to cross in front of the abdominal aorta. Lymphatic drainage of the kidneys is to the para-aortic and lumbar lymph nodes. Nerve supply of the kidneys Thoracic splanchnic nerves form a renal plexus containing mainly sympathetic and parasympathetic vasomotor nerves. P.469
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The ureters Introduction These are muscular tubes lined with transitional epithelium which, by peristalsis, carry urine produced by the kidneys to the bladder for storage and excretion. They are approximately 25cm long and are commonly considered in four parts, starting with the renal pelvis which narrows to form the abdominal, then pelvic, and, finally, intravesicle (bladder wall) sections of the ureter. Anatomical relations The right ureter is covered by the 2nd part of the duodenum anteriorly at the renal pelvis, and lies behind the posterior peritoneum, lateral to the inferior vena cava. It is crossed by three vessels (Box 7.1):

  • Right colic artery
  • Testicular/ovarian artery
  • Ileocolic artery.

The left ureter passes along the medial border of psoas and behind the sigmoid mesocolon and sigmoid colon. It is crossed by two vessels:

  • Left colic artery
  • Testicular/ovarian artery.

Both ureters cross the pelvic brim level with the division of the right and left common iliac arteries into internal and external segments, and these points mark the beginning of the pelvic sections of the right and left ureters. The final intravesicle part of the ureters runs obliquely through the wall of the bladder. The oblique course allows the opening of the ureters to act like a valve, preventing the back flow of urine from the bladder. There are three narrowings of the ureter where kidney stones are most likely to become lodged:

  • The junction of the renal pelvis with the abdominal part of the ureter
  • The pelvic brim, where the ureter enters the pelvis
  • The pelvisureteric junction, where the ureter enters the bladder wall.

Box 7.1 Blood supply to the ureters

Section of ureter Blood supply
  • Renal pelvis
  • Abdominal
  • Pelvic
  • Intravesicle
  • Aorta and renal arteries
  • Aorta, renal, and testicular/ovarian arteries
  • Testicular/ovarian and internal iliac arteries
  • Internal iliac and inferior vesicle arteries

The ureters are drained by the testicular/ovarian veins. Lymphatic drainage of the ureters is to the lumbar lymph nodes and to the internal, external, and common iliac lymph nodes. P.471
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The bladder The bladder is a balloon-like structure, lined with transitional epithelium. It expands and contracts as it stores and excretes urine, which is produced by the kidneys and drains into it via the ureters. In humans, urine is excreted via the urethra under the voluntary control of the internal meatus. Most adult subjects begin to feel the sensation of a full bladder once it contains approximately 250ml. Relations of the bladder The bladder is a relatively mobile organ within the pelvic cavity surrounded largely by extra-peritoneal fat. It always contains some urine but, after emptying, it is pyramidal in shape, with the apex formed by the bladder wall behind the pubic symphysis. The base is formed by the postero-inferior aspect of the bladder (the fundus). The bladder is anchored at its neck by the pubovesical ligament (in females) or the puboprostatic ligament (in males). In females, the bladder neck sits on the pelvic fascia, which surrounds the short urethra. In males, the bladder neck merges with the prostate and the urethra is much longer, extending along the length of the penile shaft to the external meatus. In adults, the bladder is an extraperitoneal organ but, as it fills, it expands upwards into the abdomen, stripping the peritoneum upwards from the anterior abdominal wall. In children up to 3 years old, the bladder is an intra-abdominal, extraperitoneal organ, due to the relatively small pelvis of a child. The trigone is an area of the bladder wall which is smooth, even when the bladder is empty, because the mucosa in this area of the bladder is adherent to the underlying smooth muscle. This area is bounded by the internal meatus and the two ureteric orifices, forming the triangular area. The internal urethra sphincter (internal meatus) is formed by circular fibres from the smooth muscle of the trigone area. The external sphincter is made of striated (skeletal) muscle as part of the urogential diaphragm muscle. In the rest of the bladder, the mucosa is loosely adherent to the underlying detrusor muscle, causing folding or rugae of the mucosa when the bladder is empty. An interureteric ridge runs between the two ureters, formed by a band of muscle underlying the mucosa. The bladder is bounded, anteriorly, by the pubic symphysis and, laterally, by the obturator internus and levator ani muscles. Posteriorly, in the male, the bladder is surrounded by the rectum, seminal vesicles, and termination of the vas deferens. In the female, it is bounded, posteriorly, by the vagina and superior part of the cervix. Superiorly, the bladder is covered by the peritoneum. Coils of small intestine and sigmoid colon lie above the layer of the peritoneum. The uterus of the female can lie against the posterosuperior aspect of the bladder. P.473
Blood supply of the bladder The internal iliac arteries supply the bladder via the superior and inferior vesicle branches; the superior vesicle artery supplies the anterosuperior part of the bladder. In males, the fundus of the bladder is supplied by the superior vesicle artery. In females, the fundus is supplied by the vaginal arteries. The vesicle venous plexus drains the bladder. In men, this plexus is formed by the vesicle veins and combines with the prostatic venous plexus. The vesicle plexus drains via the internal vesicle veins to the internal iliac veins. In females, the bladder is mainly drained by the vesicle venous plexus which communicates with the vaginal venous plexus and also receives blood from the dorsal vein of the clitoris. As in males, blood is eventually drained to the internal vesicle and the internal iliac veins. Lymphatic drainage of the bladder Lymph is drained from the bladder in parallel to the vesicular blood vessels and mainly to the iliac and para-aortic lymph nodes. Innervation The inferior hypogastric plexuses innervate the bladder and contain sympathetic post-ganglionic fibres (from L1 and L2). Preganglionic parasympathetic fibres form part of the plexus via the splanchnic nerves (S2–4). These preganglionic fibres synapse with the post-ganglionic fibres in the inferior hypogastric plexus. The pelvic splanchnic nerves also carry afferent sensory fibres to the central nervous system. Other afferent sensory fibres are transmitted, via the inferior hypogastric plexus, to the L1 and L2 segments. P.474
Histology of the urinary tract The functional unit of the kidney is the nephron (Fig. 7.2). This can be divided into a number of sections that have distinct structural features related to their function in urine production. The renal corpuscle

  • The endothelial cell wall of the glomerular capillary, the podocytes, and the fused basement membrane of these two cell types makes up the filtration barrier of the kidney (Fig. 7.3)
    • Ions, water, and small solutes (below the size of albumin, ~60kDa) are filtered out of the blood and enter the proximal tubule
  • The macula densa cells, extraglomerular cells, and juxtaglomerular (or granular) cells, with the last part of the Loop of Henle/the initial part of the distal tubule (see below), form the juxtaglomerular apparatus (Fig. 7.4)
    • This is responsible for controlling the Na+ level of the plasma (OHCM6 p.688), which in turn regulates blood pressure (p.480)
    • The granular cells secrete renin in response to low distal tubule Na+.

The proximal tubule

  • Arises directly after the Bowman’s capsule
  • Region of nephron where the majority of filtered solutes are reabsorbed
  • Formed from cuboidal epithelial cells
    • Rich in mitochondria (needed for high levels of active transport)
    • Apical microvilli form brush-border—greatly increases surface area for absorption
    • Basolateral cell membranes have deep infoldings which increase their surface area.
Fig. 7.2 The ultrastructure of the cells that constitute a nephron. (Reproduced with permission from Pocock G and Richards CD (2004), Human Physiology: The Basis of Medicine, 2nd edn, Oxford University Press.)
Fig. 7.3 Electron micrograph of the glomerular filter (×30,000 magnification). E: fenestrated capillary endothelium; P: podocyte foot processes (pedicels) between which are the slit pores; BM: basement membrane (fused BMs of endothelial cells and podocytes). (Reproduced with permission from Young B and Heath JW (ed) (2000), Wheater’s Fuctional Histology, 4th edn, Churchill Livingstone.)
Fig. 7.4 The principal features of a renal glomerulus and the juxtaglomerular apparatus. The wall of the afferent arteriole is thickened close to the point of contact with the distal tubule where the juxtaglomerular cells are located. The cells secrete the enzyme renin in response to low sodium in the distal tubule. (Reproduced with permission from Pocock G and Richards CD (2004), Human Physiology: The Basis of Medicine, 2nd edn, Oxford University Press.).

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Loop of Henle Can be subdivided into three regions based on histology (and indeed function, p.474):

  • Thin descending limb
    • Squamous epithelial cells (thin and flattened cells)
    • Few mitochondria, compatible with their low active transport activity
  • Thin ascending limb
    • Similar to thin descending limb
  • Thick ascending limb
    • Cuboidal epithelial cells, like those of proximal tubule but without a brush-border
    • Rich in mitochondria (high levels of active transport)
  • Not all Loops of Henle are the same length
  • Superficial nephrons have short loops which do not go into the medulla
  • Juxtamedullary nephrons have longest loops which go deep into the medulla.

Distal tubule

  • Cells very similar to those of thick ascending limb
  • The cells from the last part of the thick ascending limb of the Loop of Henle/initial part of the distal tubule contact the afferent glomerular arteriole to form the juxtaglomerular appartatus (see above).

Cortical collecting duct (CCD) CCD epithelium is made up of two cell types:

  • Principal (P) cells
    • Important in regulation of sodium balance (OHCM6 p.688) (p.493)
  • Intercalated (I) cells
    • Important in acid-base regulation (OHCM6 pp.682–3).

Renal blood supply (Fig. 7.5) The renal tubules are encased in a rich network of peritubular capillaries. Afferent arterioles (from the arcuate artery) give rise to the capillary tufts of the glomerulus, and then the outer cortex efferent arterioles give rise to the peritubular capillaries, whereas those close to the medulla give rise to the vasa recta which supplies the inner and outer medulla. The peritubular capillaries and vasa recta drain into the stellate and arcuate veins respectively.

Fig. 7.5 Blood supply of the cortical and juxtamedullary nephrons. (Reproduced with permission from Pocock G and Richards CD (2004), Human Physiology: The Basis of Medicine, 2nd edn, Oxford University Press.)

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Renal Function Glomerular filtration The glomerulus is a capillary knot at which blood is filtered into renal tubules. It provides a high-pressure, large-surface area arrangement to maximize filtration. There are around one million glomeruli. Blood enters glomerular capillaries in afferent arterioles from the renal artery, leaves in efferent ones. Each glomerulus is associated with a single renal tubule. The epithelial cells defining the tubule form the Bowman’s capsule. They envelope the glomerulus, defining Bowman’s space. Together, these structures form the functional unit of the kidney: the nephron (Fig. 7.6). Ultra-filtration occurs within the capsule (Fig. 7.7). Approximately one fifth of cardiac output supplies the kidneys. Renal plasma flow (RPF) is 625ml min-1; glomerular filtration rate (GFR = 125ml min-1; filtration fraction = GFR/RPF = 20%. No volume of blood is entirely swept of a substance: most substances are incompletely filtered from a larger volume. Filtrate lacks cells: composition is essentially plasma minus the proteins. The filter comprises three barriers:

  • Fenestrated endothelial capillary cells
  • Negatively charged basement membrane of capillary endothelium
  • Interdigitating finger-like processes (pedicels) from specialized epithelial cells called podocytes which encircle capillaries. Negatively charged nephrin molecules from the pedicels further interdigitate to define slit pores.

The filter discriminates on the basis of size, charge, and shape. Cell passage is blocked by fenestrations; proteins are excluded by negative charges of basement membrane and slit pores. In nephrotic syndrome (OHCM6 p.270), damage to the basement membrane leads to filtration of proteins and proteinuria. Filtration is driven by Starling forces:

  • Forces driving filtration
    • capillary hydrostatic pressure, (HPcap)
    • osmotic pressure within Bowman’s space, (OPBS)
  • Forces opposing filtration:
    • hydrostatic pressure in Bowman’s space, (HPBS)
    • osmotic pressure in capillary, (OPcap).

Since plasma and filtrate have identical composition (except for proteins), only the osmotic pressure exerted by proteins (π) differs. πBS is essentially zero. Therefore: Net filtration pressure (Puf) = HPcap – (HPBS + πcap) and for any nephron: GFR = Kf × Puf where Kf = surface area × permeability As blood is filtered, HPcap falls only slightly, but πcap rises as [protein] increases. HPBS is low and does not increase—the tubule acts a ‘sink’ for filtrate. As a result, filtration pressure equilibrium (where HPcap = (HPBS + πcap)) is achieved very late along capillary length, if at all.

Fig. 7.6 Diagram of a short looped (cortical) and long-looped (juxtamedullary) nephron to show their basic organization. (Reproduced with permission from Pocock G and Richards CD (2004), Human Physiology: The Basis of Medicine, 2nd edn, Oxford University Press.)
Fig. 7.7 Diagramatic representation of the filtration barrier in the glomeruls and the hydrodynamic forces that determine the rate of ultrafiltration. (Reproduced with permission from Pocock G and Richards CD (2004), Human Physiology: The Basis of Medicine, 2nd, edn Oxford University Press.)

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HPCAP is adjusted to hold GFR steady. Afferent arteriole dilation increases HPCAP; efferent dilation reduces it. Mesangial cells in Bowman’s capsule can contract to alter surface area and hence Kf. There is autoregulation of GFR. If blood pressure rises, GFR is held steady by two mechanisms:

  • Myogenic mechanism: increased stretch of afferent arterioles causes smooth muscle contraction
  • Flow-dependent mechanism (tubuloglomerular feedback): increased GFR increases flow to distal nephron. Macula densa senses distal flow rate; increased flow causes release of chemical which constricts afferent arteriole.

GFR is measured using clearance (OHCM6 pp.684–5). The renal clearance of a substance, ×, is the volume of plasma from which the substance has been completely removed and excreted to the urine. It is an idealized volume—the minimum volume from which the kidneys could have obtained the excreted amount. Clearance can be calculated on the basis that the amount of × removed from the blood = the amount appearing in the urine. Clearance is calculated by measuring [X]plasma, [X]urine, and urine flow rate V. If removal rate = excretion rate, then [X]plasma. volume cleared = [X]urine. V i.e. volume cleared = GFR = ([X]urine/V)/[X]plasma Clearance will equal glomerular filtration rate only if the marker is:

  • Freely filtered
  • Not reabsorbed from the nephron
  • Not secreted into the nephron
  • Not metabolized or synthesized by the kidney.

Inulin clearance obeys these rules: GFR = 125ml min-1. If the marker is reabsorbed, [X]urine will be reduced, so clearance is lowered, and the apparent GFR is lower. Creatinine is commonly used for clinical measurements. Similar methods can be used with substances (e.g. paraaminohippurate) which are totally removed from the blood during passage through the kidney (i.e. secreted into the tubule) to obtain RPF. P.481
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Tubular transport The renal tubule modifies the composition of the primary filtrate to generate urine with appropriate composition for body fluid homeostasis. Most of the filtered load is reabsorbed. Why filter and reabsorb so much?

  • Only transporters for those essential solutes which must be recovered are required
  • Water balance is facilitated by using reabsorptive process for H2O, rather than a secretory one
  • Energetically advantageous—many other solutes can be recovered in association with the reabsorption of Na+.

The tubule follows the Ussing model (p.54) of epithelial transport:

  • Apical membranes with specialized carriers for reabsorption—carrier-mediated processes saturate, so renal tubules exhibit transport maxima for solutes
  • Basolateral membranes with cellular homeostatic functions (especially Na+-K+ ATPase); pathways for solute efflux from the cell (e.g. GLUT)
  • Tight junctions with varying degrees of ‘leakiness’: the tubule becomes increasingly ‘tight’ along its length—the early stages recover filtered essentials (e.g. ions, glucose), the later stages fine-tune urine composition to regulate body fluid composition.

The proximal tubule performs isotonic fluid reabsorption. It is a leaky bulk reabsorptive tissue, with high water permeability. Transport processes are relatively unregulated. Around two-thirds of filtered solutes (Na+, Cl-, HCO-3, glucose, amino acids, Ca2+) and water are reabsorbed here. All absorption is ultimately dependent on transepithelial Na+ absorption. Apical Na+ entry is coupled to movement of other solutes:

  • Na+-glucose co-transport (SGLT)
  • Na+-amino acid co-transporters (systems for cationic, basic, neutral amino acids) (Fig. 7.8)
  • Na+ × H+ exchange (NHE) drives HCO-3 reabsorption and Cl- reabsorption (Fig. 7.9)
  • Na+-Cl- co-transport (NCC)
  • 3Na+-HPO2-4 (or 2Na+-H2PO-4) co-transport (NaPi).

Much Cl- movement happens in later proximal tubule, through paracellular pathways, after electrical and chemical gradients have been established by Na+ movement in preceding processes. Paracellular Mg2+ reabsorption can occur in a similar fashion. Ca2+ enters through apical epithelial Ca2+ channels (ECaC) and is extruded across the basolateral membrane by Ca2+-ATPase, Na+ × Ca2+ exchange (process stimulated by parathyroid hormone). Similar processes for Ca2+ operate in the ascending limb of the loop of Henle and distal tubule. There is also secretion of organic anions such as paraaminohippurate (PAH) using anion exchangers on each membrane. Basolateral accumulation of organic anions is achieved by exchange with a divalent cation (e.g. α-ketoglutarate). PAH then exits to the lumen using another apical anion exchanger.

Fig. 7.8 Process responsible for the reabsorbtion of amino acids in the proximal tubule. (Reproduced with permission from Pocock G and Richards CD (2004), Human Physiology: The Basis of Medicine, 2nd edn, Oxford University Press.)
Fig. 7.9 Schematic representation of bicarbonate reabsorption in the proximal tubule. (Reproduced with permission from, from Pocock G and Richards CD (2004), Human Physiology: The Basis of Medicine, 2nd edn, Oxford University Press.)

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High water permeability due to constitutive aquaporin I water channels means that osmotic gradients established by solute movements are immediately collapsed by osmosis. Tubular fluid remains isotonic. Other parts of the nephron are increasingly specialized:

  • The descending limb of the loop of Henle is permeable only to water, but does not transport solute
  • The ascending limb of the loop of Henle is water impermeable but performs active Na+ absorption in the thick segment using apical Na+-K+-2Cl- co-transport (NKCC)
  • Na+ and Cl- reabsorption continues in the distal tubule on apical Na+-Cl- co-transport (NCC) and in the collecting duct, through apical epithelial Na+ channel (ENaC) in principal cells with Cl- moving paracellularly or through type B intercalated cells. K+ can be secreted here by exit to the lumen through apical K+ channels in principal cells.

Water permeability in the collecting duct is controlled by ADH-regulated insertion of aquaporin II channels. Basolateral membranes possess constitutive aquaporin I and III channels. P.485
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Dilute and concentrated urines The kidney has the capacity to produce dilute or concentrated urines, according to water balance. The default is to produce a dilute urine, but a countercurrent multiplier system can extract large volumes of water to concentrate urine when water intake is inadequate (Fig. 7.10). The loop of Henle is responsible—comparison of the length of loops between different species shows that the longer the loop, the more concentrated the urine. To understand the process, start in the thick ascending limb (TALH): here, active Na+ absorption on NKCC is the key event. This explains the action of loop diuretics such as furosemide, which inhibit NKCC. This transport initiates a cascade of responses:

  • The interstitial fluid surrounding the tubule is made hypertonic
  • Water therefore moves by osmosis from the water-permeable, (but largely Na+-impermeable) descending limb of the loop (DLH). [Na+] rises in the tubule fluid, making the fluid hypertonic. Some influx of Na+ into tALH from interstitium may also occur
  • The ascending limb is permeable to Na+ but not to water. In the thin segment (tALH, which lacks Na+-K+ ATPases), the high [Na+] established in the tubule encourages passive diffusion of Na+ ions across the epithelial cells
  • The absorption of Na+ continues on NKCC, so the tubular fluid is hypotonic when it reaches the distal tubule
  • Na+ absorption also occurs in the distal tubule and collecting duct (CD), further diluting the tubule fluid.

When water intake is sufficient, water is not reabsorbed from the dilute tubular fluid, since the apical membrane in the CD lacks a constitutive permeability to water. Large volumes of a hypotonic urine are produced—diuresis. In hydropenia, circulating ADH raises water permeability of CD. The hypertonic interstitium draws water from CD. Small volumes of hypertonic urine are produced—antidiuresis. ADH actions

  • Increased water permeability in CD: V2 receptor occupation; cAMP generation; PKA activation; insertion of vesicles containing aquaporin II
  • Increased urea permeability in inner medullary CD: PKA phosphorylation of apical urea carrier UT1
  • Increased Na+ reabsorption in TALH: PKA phosphorlyation of NKCC.

Diabetes insipidus (DI) (OHCM6 p.326) results when ADH secretion fails (central DI) or when renal responses are absent (nephrogenic DI). Not all of the interstitial hypertonicity in antidiuresis is due to Na+ reabsorption. Up to 50% can be contributed by urea in inner medulla. Urea, concentrated as tubular fluid is reabsorbed along the nephron, exits on UT1 to the interstitium down a steep concentration gradient. Urea cycles—it diffuses back into tALH, minimizing loss to blood (this trapping establishes high [urea] in interstitial fluid). P.487
The system is a multiplier: from a ‘standing start’, NaCl extraction in tALH promotes water extraction in DLH, raises Na+ in tALH, allows further NaCl reabsorption in ALH. The increase in medullary [NaCl] is hence amplified. Wash-out of interstitial hypertonicity is minimized by low rates of blood flow in medulla and by vasa recta (hairpin capillaries which parallel the loop of Henle). Water leaves and the Na+ enters as blood passes down the descending limb; water moves back in, Na+ leaves as blood flows up the ascending limb. The vasa recta counter-current exchange provide nutrients and O2 to tubules and remove excess solutes and water from the medulla.

Fig. 7.10 Schematic representation of the counter-current multiplier of the renal medulla. (Reproduced with permission from Pocock G and Richards CD (2004), Human Physiology: The Basis of Medicine, 2nd edn, Oxford University Press.)

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Regulation of tubule function The capacity of the collecting duct to separate water and solute movements underlies body fluid homeostasis. Renal regulation of extracellular osmolarity and volume relies on maintaining a constant delivery to the tight, distal epithelium which is regulated by hormones. Glomerular filtration rate (GFR, the volume of plasma filtered by the kidneys) = 180 litre day-1. GFR remains constant in the face of changes to blood pressure (although GFR does change when renal plasma flow changes). This is due to:

  • Myogenic autoregulation of renal arterioles
  • Tubuloglomerular (TG) feedback. Flow sensor (senses Na+ or Cl- absorption) by macula densa in distal tubule detects altered GFR, releases mediator (? adenosine, thromboxane), which adjusts arteriole resistance, resets GFR.

As a result, a constant filtered load is delivered to the renal tubules. The functional activity of each nephron segment depends on events in preceding segments. There is intrinsic and extrinsic regulation. Proximal tubule Proximal tubule reabsorption involves Na+-dependent transepithelial movement of solutes and water, followed by uptake into peritubular capillaries according to Starling forces. Processes can be regulated by:

  • Glomerulotubular balance. Absorption is load dependent: the PT normally reabsorbs a constant fraction (2/3) of filtered load, even when GFR changes. Mechanisms are:
    • Increased solute availability stimulates carrier-mediated transport
    • Starling forces promote enhanced capillary uptake. Increased GFR reduces hydrostatic pressure in the capillary, increases oncotic pressure in the capillary—promotes greater uptake into capillaries
  • Hormone regulation of Na+ × H+ exchange: angiotensin II stimulates, PTH inhibits
  • Renal sympathetic nerves stimulate Na+ absorption.

Loop of Henle Loop of Henle reabsorbs ~20% of the filtered load. Again, reabsorption is proportional to the load delivered. This is the result of dependence on flow rate, which determines contact time and so extent of Na+ transport. If flow rate rises, NaCl stays higher, for longer, in the ascending limb. Increased NKCC activity ‘mops up’ some of the excess Na+, but more NaCl is delivered to the macula densa. TG feedback corrects flow rate by altering GFR. Distal tubule The distal tubule reabsorbs ~7% of the load using NCC; regulatory mechanisms are unknown. The connecting tubule is a major site of Ca2+ P.489
reabsorption, stimulated by PTH. The collecting tubule is a tight epithelium, a heavily regulated site, for ‘fine-tuning’ urine composition:

  • Principal cells reabsorb ~5% Na+ through apical channels, H2O through ADH-regulated aquaporin II channels. K+ is secreted through apical K+ channels. Reabsorption of Na+ is:
    • Proportional to load
    • Increased by aldosterone
    • Inhibited by ANP.

Aldosterone stimulates transcription of ENaC, the Na+-K+ ATPase, metabolic enzymes. Increased exchange of Na+ for K+ on the ATPase means that K+ secretion is proportional to Na+ absorption. Mutations in ENaC lead to constitutive activation of reabsorption—pseudohyperaldosteronism (Liddle’s disease). ANP antagonizes renin—angiotensin—aldosterone cascade, reduces ADH release.

  • Type A intercalated cells perform active H+ secretion; type B cells perform HCO-3 secretion, Cl- reabsorption. Type A predominate, but numbers of type B are upregulated in alkalosis.

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Diuretics Diuretics increase Na+ excretion by inhibiting the reabsorptive process in nephron. Water excretion increases, extracellular fluid volume falls. Used in cases of fluid retention where effective circulating volume compromised by heart, liver, or renal dysfunction and to treat hypertension. Diuretics are classified by their action. They can have disadvantageous effects on electrolyte balance. Common diuretics: Loop diuretics

  • Example: furosemide
  • Uses: acute and chronic oedema (OHCM6 pp.136–8), hypertension (OHCM6 pp.140–3)
  • Action: inhibits NKCC in thick ascending limb of loop of Henle
  • Consequence: compromises generation of medullary interstitial hypertonicity
  • Side-effects: excessive depletion of plasma volume; K+ depletion, alkalosis, uric acid retention.

Thiazaides

  • Example: bendroflumethiazide
  • Uses: hypertension (OHCM6 pp.136–8), oedema in chronic heart failure (OHCM6 pp.140–3)
  • Action: inhibits NCC in distal tubule
  • Consequence: compromises generation of medullary interstitial hypertonicity
  • Side-effects: K+ depletion, alkalosis, Ca2+ retention, uric acid retention.

K+ sparing

  • Example: amiloride, spironolactone
  • Uses: adjunct to K+-wasting diuretic, in mild hypokalaemia
  • Action: amiloride inhibits ENaC in collecting tubule duct; spironolactone antagonizes aldosterone receptor in collecting tubule duct
  • Consequences: reduces regulated Na+ reabsorption through channels in late nephron
  • Side-effects: K+ retention with subsequent acidosis.

Osmotic diuretics

  • Example: mannitol
  • Uses: raised intracranial, intraocular pressure, forced diuresis in overdose
  • Action: trapped in lumen, exerts osmotic potential pull, traps water in tubule
  • Consequence: osmotic pull traps water in lumen
  • Side-effects: Na+ wash-out.

Carbonic anhydrase inhibitors (obsolete)

  • Example: acetazolamide
  • Uses: glaucoma (OHCM6 p.340, 427), mountain sickness
  • Action: inhibits carbonic anhydrase in proximal tubule
  • Consequence: prevents Na+-associated HCO-3 reabsorption
  • Side-effects: acidosis, K+ depletion.

P.491
P.492
Regulation of Body Fluids Regulation of extracellular fluid volume and osmolarity The processes regulating ECF volume and osmolarity are overlapping. Volume must be regulated to maintain appropriate perfusion pressure; osmolarity changes affect cell volume and function (OHCM6 pp.688–9). Volume is regulated by changing NaCl; osmolarity by changing water content. The primary effector for body fluid homeostasis is the kidney. Aldosterone and atrial natriuretic peptide (ANP) (OHCM6 p.689) regulate Na+ excretion, Antidiuretic hormone (ADH or vasopressin) regulates water balance. Changes in one parameter often cause knock-on effects in the other. Volume Na+ is the primary determinant of volume—along with accompanying anions it is the dominant osmolyte. Since osmolarity is held constant at 290mOsm, changes in Na+ change osmolarity, which modifies water excretion. Gain or loss of water to restore osmolarity brings about the volume change. Effective circulating volume (ECV) is detected by:

  • Cardiovascular sensors:
    • Baroreceptors in carotid sinus, aortic arch
    • Stretch receptors in renal afferent arterioles
    • Stretch receptors in atria, pulmonary circulation
  • Renal sensors: the macula densa senses flow of luminal fluid in the distal tubule, which reports GFR and hence ECV.

Afferent neurones from baroreceptors send signals to the medulla in the brainstem. Sympathetic nervous system discharge is altered. Extreme (>15%) falls in ECV also trigger ADH release from the posterior pituitary. Reduced ECV increases sympathetic discharge and enhances:

  • Renin release
  • Afferent arteriole constriction—reduces GFR
  • Proximal tubule Na+ reabsorption.

These processes conserve Na+ and thereby raise ECV by the accompanying H2O conservation. Renin release is also induced by reduced distension of afferent arterioles and by reduced reabsorption across macula densa cells. Renin is an enzyme, and initiates a cascade which occurs in the systemic circulation:

  • Angiotensinogen from liver ⇒ angiotensin I
  • Angiotensin I ⇒ angiotensin II by angiotensin-converting enzyme in lungs, kidneys
  • Angiotensin II ⇒ angiotensin III by aminopeptidases.

Angiotensin II (AII) is a potent vasoconstrictor.

  • Renal effects:
    • Constricts efferent > afferent arterioles. Increased GFR reduces hydrostatic pressure in the capillary and increases osmotic pressure P.493
      of proteins (the oncotic pressure, π): promotes greater uptake into capillaries
    • Reduces flow through vasa recta, conserves medullary hypertonicity
  • Stimulates Na+ × H+ exchange in proximal tubule
  • Stimulates thirst and ADH release
  • Triggers aldosterone release from adrenal cortex.

Drugs can intefere with the cascade: renin inhibited by enalkiren; ACE by captopril; AII receptor antagonized by saralasin. Aldosterone stimulates Na+ reabsorption in collecting duct: steroid actions to increase transcription of ENaC, Na+-K+ ATPase, metabolic enzymes. Spironolactone antagonizes aldosterone receptor. K+ secretion increased by increased Na+ absorption. Raised plasma [K+], ACTH also stimulate aldosterone release. 28 amino acid peptide, ANP, antagonizes rennin—AII—aldosterone axis. Released from atrial myocytes in response to stretch (i.e. raised ECV). Actions diverse; mediated through cGMP. Selected actions include:

  • Inhibition of AII stimulation of proximal tubule transport
  • Inhibition of renin release
  • Inhibition of NCC in distal tubule
  • Inhibition of aldosterone receptor.

Net effect is to raise distal tubule load, inhibit reabsorption, increase excretion. Osmolarity Regulated through water excretion (p.486). Detected by osmoreceptors in hypothalamus. Raised osmolarity (1% change) triggers cell bodies in supraoptic, paraventricular nuclei. Release of 9 amino acid, ADH, from nerve endings in posterior pitutiary. ADH release also induced by larger (15%) fall in volume pressure. ADH actions:

  • V2 receptor-mediated adenylyl cyclase activation, cAMP generation, protein kinase A activation, insertion of vesicles containing aquaporin II
  • Activation of UT1 urea carriers
  • Stimulation of NKCC in thick ascending limb
  • Vasoconstriction.

P.494
Renal regulation of plasma pH The kidneys have two roles in regulation of plasma pH:

  • Reabsorption of filtered HCO-3 ions
  • Excretion of non-volatile acids (NVA).

NVA includes HCl, H2SO4 from amino acid metabolism, H3PO4 from ingested phosphate. Typically, 70mmol of NVA must be excreted. NVA are initially buffered in extracellular fluids by HCO-3. The second function of the kidney is, therefore, in reality, the regeneration of HCO-3 lost in buffering. The renal cellular mechanisms for reabsorption and regeneration of HCO-3 are the same. It is the fate of secreted H+ ions in the tubule lumen which differs. Cellular mechanism—key points:

  • Carbonic anhydrase in tubule cells catalyses hydration of CO2 to yield H+ and HCO-3
  • Apical H+ secretion into lumen on Na+ × H+ exchange (NHE) or H+ ATPase
  • Basolateral HCO3 efflux from cell on Na+-3 HCO-3 co-transporter (NBC) or Cl- × HCO-3 exchanger (AE).

NHE is responsible for greatest portion of acid secretion. It is especially prominent in the proximal tubule, where bulk Na+ reabsorption is occuring. H+-ATPases are most prominent in type A intercalated cells in collecting duct; this primary active transport system can establish high H+ gradients. Basolateral efflux of HCO-3 is largely mediated by NBC in the proximal tubule, where there are large fluxes of Na+. Later nephron segments use AE. Acid is also secreted across apical membranes in medullary collecting duct by an H+-K+ ATPase, although this pump may be more important as a K+ absorber. The operation of this ATPase is one reason why disturbances of K+ or H+ homeostasis are often interlinked. For reabsorption of HCO-3

  • H+ secreted into lumen
  • H+ reacts with HCO-3 in the lumen to form CO2, H2O-catalysed by carbonic anhydrase on apical membrane
  • CO2 formed diffuses along concentration gradient into cell, carbonic anhydrase catalyses reaction with water to reform HCO-3 and H+
  • HCO-3 exits at basolateral membrane, H+ cycles again across apical membrane.

Net result: HCO-3 transfers from lumen to interstitial fluid. For regeneration of HCO-3

  • H+ secreted into lumen
  • H+ titrates HPO2-4, H2PO4-4, or NH3—titrated species are lost in urine
  • HCO-3 generated by hydration of CO2 in cell exits at basoalteral membrane.

P.495
Net result: H+ excreted, HCO-3 returned to interstitial fluid. Balance restored. HCO-3 recovered is equivalent to the one produced by original HCO-3 buffering of NVA. NH3 in lumen is synthesized from glutamine in proximal tubule cells, and diffuses into lumen across the apical membrane. Ionic NH+4 formed by titration is trapped in lumen—increasingly acidic environment means dissociation becomes increasingly unlikely along tubule length. Some NH+4 can be reabsorbed on NKCC into medullary interstitium, but NH3 reforms there and diffuses back into collecting duct where NH+4 is once more generated. Acid secretion across apical membrane can be regulated:

  • NHE—protein kinases can stimulate (PKC-mediated activation by AII) or inhibit (PKA-mediated inihibition by parathyroid hormone)
  • ATPase—acidosis stimulates insertion of vesicles containing the ATPase into apical membrane.

Respiratory and metabolic acidosis (OHCM6 pp.682–3) can upregulate NHE, NBC, and ammoniagenesis. Type B intercalated cells are few in number. Their transporter expression is reversed: ATPase is basolateral, AE is apical. As predicted from the Ussing model of epithelial function, this reverses the function of these cells: they secrete HCO-3, reabsorb H+. In normal circumstances, there is a chronic acidosis, so this function is less important. Numbers of type B cells increase in alkalosis. A reciprocity exists between plasma pH and [K+].

  • Hyperkalaemia (OHCM6 p.692) → acidosis
    • Hyperkalaemia inhibits H+-K+ ATPase, ammoniagenesis, so limiting H+ excretion
  • Acidosis → hyperkalaemia
    • Acidodis reduces K+ secretion in the distal nephron: secretion of H+ and K+ vary reciprocally. Occurs because raised H+ inhibits:
      • Basolateral Na+-K+ ATPase, reducing cell K+ available for secretion
      • Apical membrane permeability to K+.

P.496
Bladder Control and Urinary Continence Micturition Emptying the bladder is referred to as micturition, urination, or voiding. It involves the synchronous contraction of the bladder wall muscle (detrusor) and relaxation of the urethral sphincters. These processes are co-ordinated by a combination of autonomic spinal cord reflexes and voluntary control of the external urethral sphincter which is made of striated muscle (Table 7.2). Consequently, micturition, like breathing, is a mixture of reflex and voluntary actions. The urinary bladder is progressively filled by inflow of urine from the ureters. At low volumes (less than 200–300ml), the bladder is a relatively compliant organ and filling is accompanied by only modest increases in tension in the bladder wall. Above 300ml, tension increases more markedly and this is detected by stretch receptors in the bladder wall smooth muscle. It is at this level of filling that a sensation of fullness is felt in the bladder. Impulses from the stretched detrusor muscle are sent, via sensory nerves (S2–S4), to the pontine micturition centre in the brainstem where the micturition reflex is integrated. In response to these sensory inputs, parasympathetic efferent signals (S2–S4) initiate contraction of detrusor which, since it is a syncitium of smooth muscle cells, contracts. This results in increased pressure and tendency towards expulsion of urine and opening of the bladder neck (internal sphincter). Voluntary control of the bladder arises largely as a result of the external urethral sphincter. This structure is formed where the urethra passes through the urogenital diaphragm (located in the pelvic arch) which comprises skeletal muscles of the pelvic floor under voluntary, cortical control. Contraction of this sphincter prevents the flow of urine and voluntary relaxation has the reverse effect and initiates the flow of urine during micturition. Further, voluntary control of micturition arises from inhibitory inputs from cortical and suprapontine centres to the pontine micturition centre which inhibit the micturition reflex until it is socially acceptable to urinate or the sensation of bladder fullness becomes too intense. Furthermore, sympathetic nerves from the hypogastric plexus inhibit contraction of detrusor and aid the inhibition of micturition by higher cortical centres. During bladder emptying, sensory receptors in the urethra sense the flow of urine and feedback to the micturition centre. This has the effect of enhancing the micturition reflex and increasing the flow of urine. Contraction of abdominal and pelvic muscles can also increase the pressure on the bladder wall, thus aiding micturition. The bladder can be voluntary emptied at any time, even when not full, indicating that higher areas of the brain can initiate the micturition reflex in the absence of afferent input from stretch receptors in the wall of the bladder. Voluntary control of micturition can be lost following damage to inhibitory descending pathways in the spinal cord. Such an insult results in urinary incontinence (OHCM6 pp.500–1). Furthermore, lesion of the para-sympathetic nerve supply to the bladder results in incomplete emptying of the bladder during micturition, which can lead to recurrent urinary tract infections (OHCM6 pp.262–3). Innervation of the micturition reflex

Table 7.2
Type Nerve Spinal segment Function
Parasympathetic (efferent) Preganglionic: pelvic nerves
Postganglionic: in bladder wall
S2–S4
  • Contraction of detrusor
  • Opening of internal sphincter
Sympathetic (efferent) Preganglionic: splanchnic nerve/paravertebral sympathetic chain
Postganglionic: pelvic nerves/hypogastric plexus
T10–L2
  • Inhibit contraction of detrusor
  • Closing of internal sphincter
Somatic (efferent) Pudendal nerve S2–S3 Contraction of external urethral sphincter
Sensory (afferent) Pelvic nerves/pudendal nerve S2–S4 Senses bladder filling, pain, and urinary flow

P.497
P.498
Pathology Renal failure (OHCM6 pp.272–9) Definition Reduction in the function of the kidneys such that there is an accumulation of waste products that the kidneys usually excrete, most easily measured by urea and creatinine in the blood. There are about one million nephrons in each human kidney but these do not divide or regenerate after foetal development, so any reduction in their number will lead to a reduction in renal function. However, the kidneys have a large reserve capacity and actual renal failure only occurs when about 90% of nephrons are non-functional. Thus, chronic renal failure only becomes manifest after the disease process has been present for years and it is often difficult to discover the original precipitating cause. Classification

  • Aetiological—but often unknown, see above
  • Site of problem—but unhelpful because e.g. a pre-renal cause such as low cardiac output acts at a glomerular and tubular level
    • Pre-renal
    • Renal
    • Post-renal
  • Time course—but does not give any indication of cause
    • Acute—occurring suddenly over days or weeks
    • Chronic—insidious development over years.

Causes

  • Glomerulonephritis (OHCM6 pp.268–9)—deposition of material on the glomerular basement membrane and/or inflammation. Mediated by many mechanisms including immune complex deposition, anti-glomerular basement membrane antibodies, sensitized lymphocytes and neutrophils. The classification is complex (and confusing) and is really only useful for postgraduate nephrologists
  • Tubule dysfunction (OHCM6 pp.280–1)
    • Acute ischaemia—low cardiac output, disseminated intravascular coagulation, polyarteritis nodosa, or malignant hypertension in intrarenal vessels
    • Toxins—heavy metals
    • Tubulointerstitial nephritis—hypersensitivity to drugs
  • Outflow obstruction (p.500).

Treatment

  • Treatment of the cause
  • Renal replacement therapy
    • Dialysis
    • Transplantation.

P.499
P.500
Obstructive uropathy (OHCM6 p.266) Definition Obstruction of the urinary tract at some point from the renal pelvis to the end of the urethra (Fig. 7.11). Causes (OHCM6 pp.264–5)

  • Pelvis
    • Staghorn calculus
    • Pelvo-ureteric obstruction—congenital anomaly due to disarray of the smooth muscle in the wall
  • Ureter
    • Calculus
    • Tumour—transitional cell carcinoma (OHCM6 p.498)
  • Bladder
    • Calculus
    • Tumour—transitional cell carcinoma
  • Urethra
    • Prostatic enlargement—benign prostatic hypertrophy (OHCM6 pp.496–7), prostatic carcinoma (OHCM6 p.498) less commonly
    • Urethral valves—congenital anomaly, a neonatal emergency (recognized by no urine in nappy) which must be treated surgically
    • Phymosis—constriction of the end of the urethra by a tight foreskin in males; causes include scarring post-circumcision, balanitis xerotica obliterans (inflammatory condition analogous to lichen planus in general skin)
    • Tumour—transitional cell carcinoma.

Complications

  • Compression atrophy of renal tissue—if there is complete obstruction of a kidney’s outflow, then a large hydronephrosis (OHCM6 p.266) will form as the urine fills up the collecting system to the level of the obstruction. If this is left for any length of time, there will be pressure atrophy of the renal tissue and the kidney will become rapidly nonfunctional. The end stage of hydronephrosis is a distended bag of urine (the dilated collecting system) with a tiny rim of renal tissue around the outside
  • Urinary infection (OHCM6 p.262)—the static urine provides a culture medium for bacterial organisms
  • Hypertrophy of smooth muscle proximal to the obstruction e.g. hypertrophy of the bladder muscle in cases of benign prostatic hypertrophy.
    Fig. 7.11 Diagram showing the different site in the urinary tract where obstruction can occur and the most common pathological causes at those sites.

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