Download Urinary System 1 – The urinary system

Suzie Rayner
Urinary System 1 – The urinary system
Main functional components:
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Kidneys
Clayces, renal pelvis, ureters
Urinary bladder
Urethra and associated sphincters
Neurological control systems for bladder muscle and sphincters
Well-adapted blood vascular supply

Draw a simple diagram of the urinary system indicating the following: kidney,
renal pelvis, ureter, bladder, urethra, sphincter vesicae, sphincter urethrae.
Renal pelvis: funnel-like dilated proximal part
of the ureter in the kidney [acts as funnel for
urine flowing to the ureter
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Kidneys:
Position  Retroperitoneal in upper abdomen
 Surrounded by dense fibrous capsule
 Fascial pouch (renal fascia) is outside fibrous capsule – contains the peri-renal
adipose tissue
 Posteriorly overlapped by ribs 11 and 12, diaphragm and pleural cavity.
Blood Supply  Abundant blood supply from renal arteries
 Short direct branches from abdominal aorta
 Blood pressure drives Ultrafiltration by glomerular capillaries
Structure –
 Cortex - granular looking – due to random organisation
 Cortex consists of glomeruli, where Ultrafiltration occurs, surrounded by
convoluted parts of the tubules
 Medulla – striated – radial arrangement of tubules and micro-vessels
 Medulla contains parallel bundles of straight tubules.
 Both cortex and medulla contain distinct parts of the nephrons (urine
producing units)
 Kidney is multilobar
 Renal columns, consisting of cortex, reach right through the medulla at the
boundaries of the kidney lobes.
 Each lobe drains through its own papilla and calyx
 Minor calyces join to form a few major calyces which all open into renal
pelvis
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
Outline the means of urine transport down the ureters into the bladder and
explain the mechanism preventing reflux of urine from the bladder.
Urine production is 2 staged:
 Ultrafiltration – driven by arterial blood pressure [therefore short, wide renal
arteries]
 Absorption and secretion to modify ultrafiltrate.
Ureters:
 Run vertically down posterior abdominal wall
 Sites of renal colic caused by kidney stones passing down the ureters and
sticking
 Urine transported by peristalsis in their smooth muscle (rhythmic contraction
of muscle)
 Opens obliquely through bladder wall
Reflux of urine prevented by sphincters (?)
Plaques in the ureter prevent osmosis and exchange of ions from the urine back into
the body – would occur without this due to large difference in ion concentrations.
Urethra:
 In females – short and simple, passes through the perineum into the vestibule
(space between labia minora)
 In Males – long, intra-pelvic part within the prostate gland and part within the
penis in addition to the trans-perineal part

Describe the anatomical and histological features allowing expansion of the
bladder as it fills with urine.
Ureters and bladder:
 Lined by urothelium (transitional epithelium)
 3-layered epithelium with slow cell turnover
 Large luminal cells, highly specialized low-permeability luminal membrane Prevents dissipation of urine-plasma gradients
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
Distinguish between the sphincter
urethrae and sphincter vesicae
muscles and their nerve supplies.
Sphincter vesicae:
 At neck of bladder
 Reflex opening
 In response to bladder wall tension
 Controlled by parasympathetic
Sphincter urethrae:
 In perineum
 Tone maintained by somatic nerves in pudendal nerve (S2,3,4)
 Opened by voluntary inhibition of nerves
 Sustained closure keeps sphincter vesicae closed, reduces bladder tone.
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Describe the mechanisms involved in the reflex contraction of the bladder in
response to distension. State the approximate volume of urine in the bladder
that normally initiates a reflex contraction in the adult.
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Urinary System 2 –
Structural basis of kidney function
Kidney function – sensitive to body needs
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Filtration of blood plasma
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Selective reabsorption of contents to be retained
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Tubular secretion of some components
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Concentration of urine as necessary
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Endocrine function – renin, erythropoietin, 1,25-dihydroxycholecalciferol

Describe the structural organisation of the kidney, as seen at a macroscopic
level.
[More detail in previous lecture]
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Draw a diagram showing the main constituent parts of a nephron.
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Mechanism of urine production
in the nephron:
Filtration:
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Blood passing through
glomerulus is filtered
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Filtrate consists of all
components with less
than 50000 molecular
weight
Reabsorption:
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Material to be retained
is reabsorbed in
proximal convoluted
tubule
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Includes ions, glucose,
amino acids, small
proteins and water
Creation of hyper-osmotic
extracellular fluid:
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Main function of the
loop of henle and vasa
recta
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Countercurrent
mechanism
Adjustment of ion content of urine:
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Occurs at distal convoluted tubule and collecting duct
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Controls amounts of Na+, K+, H+, NH4+ excreted
Concentration of urine:
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Occurs at collecting duct
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Movement of water down osmotic gradient into extracellular fluid
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Controlled vasopressin
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Draw a diagram of the structures separating glomerular capillary plasma
from the fluid in Bowman's capsule.
List the features of the cellular structure of the tubules in different parts of
the nephron which make possible the concentration of urine.
Draw a diagram showing the pattern of blood vessels in the kidney, and
state which features contribute to the filtration process, to the reabsorption
process, and to the countercurrent mechanism.
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Renal corpuscle:
Components:
 Bowman’s capsule contains basement membrane, parietal epithelium and
visceral epithelium (surrounds the glomerulus and high pressure of blood
forces ions to filter into glomerulus)
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Glomerulus (capillaries)
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Podocytes (visceral epithelial cells)
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Mesangial cells
Blood supply:
 Enters at vascular pole of corpuscle into afferent arteriole
 Filters through capillary network at high pressure
 Exits at efferent arteriole
Filtration barrier:
 Fenestrae in capillary endothelium
 Specialised basal lamina
 Filtration slits between foot processes ofpodocytes
 Slits allow passage of ions and molecules < 50000 molecular weight
Drainage of filtrate:
 To
proximal
convoluted
tubule, at
urinary
pole
Proximal convoluted tubule:
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Function:
 Reabsorption of 70% of glomerular filtrate
 Na+ movement by Na+ pump
 Na+ movement causes water and anions (-ve) to follow
 Glucose is taken up by Na+/glucose co transporter (movement of Na+ into cell
also moves glucose in)
 Amino acids by Na+/amino acid co-transporter
 Protein uptake by endocytosis
Structure:
 Cuboidal epithelium
 Tight junctions
 Membrane area increased to maximise rate of reabsorption
 Brush border at apical surface
 Interdigitations of basolateral membrane
 Contains aquaporin proteins to mediate water diffusion
 Prominent mitocondria (high energy requirement)
Loop of Henle – the countercurrent mechanism
Descending thin tubule:
 Passive osmotic equilibrium
 Aquaporins present
 Simple squamous epithelium
Ascending thick limb:
 Na+ and Cl- actively pumped out of tubular fluid
 Membranes lack aquaporins
 Therefore, low permeability to water
 Therefore, hypoosmotic tubular fluid, hyperosmotic extracellular fluid
 [Creates a countercurrent mechanism - high extraceullar ion conc. - that
allows water to passively move out of apparatus later on if water needs to be
reabsorbed]
 Cuboidal epithelium, few microvilli
 High energy requirement – prominent mitochondria
Vasa recta:
 Blood vessels also arranged in loop
 Blood in rapid equilibrium with extracellular fluid
 Loop structure stabilises hyper-osmotic
Distal convoluted tubule/cortical collecting duct
 Adjustment of Na+/K+/H+/NH4+
 Controlled by aldosterone
 Cuboidal epithelium, few microvilli
 Complex lateral membrane interdigitations with Na+ pumps
 Numerous large mitochondria
 Specialisation of macula densa, part of juxtaglomerular apparatus
Juxtaglomerular apparatus
 Endocrine specialisation
 Secretes renin to control blood pressure via angiotensin
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Senses stretch in arteriole wall and Cl- in tubule
Cellular components are:
o Macula densa of distal convoluted tubule
o Juxtaglomerular cells of afferent arteriole
Medullary collecting duct
 Completes ion adjustment and controls urine osmolarity
 Passes through medulla – hyperosmotic extracellular fluid
 Water moves down osmotic gradient to concentrate urine
 Rate of water movement is due to aquaporin-2 in apical membrane
o Content varied by exo/endocytosis mechanism
o Under control of vasopressin (neurohypophysis)
 Basolateral membrane has aquaporin-3, not under control
 Duct has simple cuboidal epithelium, single cilium per cell
 Cell boundaries don’t interdigitate
 Smooth muscle wall for peristalsis ( 2 layers)
 Cells contain organelles associated with secretory activity
 Little active pumping (therefore few mitochondria)
 Drains into minor calyx at papilla of medullary pyramid
 Minor and major calyces and pelvis have urinary epithelium
Ureters
 Drain urine from the kidneys
 Peristalsis movement towards the bladder
 Urinary epithelium resists damage by urine
Bladder
 Urine storage organ (capacity of approx. 500ml)
 2 ureters enter posterior wall, urethra leaves inferiorly
 Urinary epithelium resists damage and allows expansion
 Smooth muscle wall (detrussor muscle)
 Autonomic innervation
 Sphincter vesicae at urethral exit
Urinary epithelium – a.k.a. urothelium, transitional epithelium
 Specialised form of epithelium – only found in urinary tract
 Found in part of kidney, ureters, bladder, part of urethra
 All cells contact basal lamina (but looks stratified)
 Epithelium is resistant to urine and able to stretch
 Cells appear squamous or cuboidal according to degree of stretch
 Luminal cells are specialised for
extremely low permeability
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Urinary System 3 –
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Renal blood flow and glomerular filtration
Main functions of kidney:
 Excretion of metabolic products (e.g. urea, uric acid, creatinine)
 Excretion of foreign substances (drugs)
 Homeostasis of body fluid, electrolytes, acid-base balance
 Regulates blood pressure
 Secretes hormones (renin, erythropoietin)
Filtration occurs where fluid is ‘forced’
through the semi-permeable walls of
glomerular capillaries into Bowman’s capsule.
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Indicate what proportion of the cardiac output normally perfuses the kidney.
Renal blood flow:
 Delivers oxygen, nutrients and substances for excretion
Kidneys normally receive 20% of cardiac output (approximately 1litre/min)
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Define the term “freely filtered”.
Filtration: formation of an ultrafiltrate of plasma in the glomerulus.
An abrupt fall in glomerular filtration is renal failure.
Abnormalities in renal circulation and urine production lead to reduced glomerular filtration
(and therefore to renal failure)
Passive process of filtration (same as ‘freely filtered’?):
 Fluid is ‘driven’ through semipermeable walls (fenestrated) of the glomerular
capillaries
 Fluid is driven into Bowmans capsule space
 Driving force is the hydrostatic pressure of the heart
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State that the permeability barrier in the glomerulus discriminates mainly on the
basis of size (although electrical charge also influences the filtration of charged
proteins).
Fenestrated capillaries are highly permeable to:
 Fluid
 Small solutes
Impermeable to:
 Cells
 Proteins
 Drugs
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Compare the composition of the glomerular filtrate and the plasma.
Primary urine: a clear fluid completely free from blood and protein, produced containing
electrolytes and small solutes.
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Define glomerular filtration rate (GFR) and filtration fraction and give typical values
for each in a normal healthy young adult.
Glomeruli of each nephron filter only plasma, not blood cells. Plasma makes up 55% of
blood, thus renal plasma flow = 0.55l/min
Glomerular filtration rate: the amount of plasma filtered from the glomeruli into the
Bowmans capsule per minute.
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The sum of filtration rate of all functioning nephrons, therefore loss of
nephrons will reduce surface area, therefore GFR will reduce.
Each nephron unit can filter 20% (therefore filtration factor = 0.2) of blood
plasma in each cycle
In typical adult GFR = 20% of 550ml/min = 110ml/min
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GFR is the primary indicator of renal disease → filtration fails, build up of substances
in blood therefore reduction in GFR.
If increased plasma conc. of urea and creatinine, markers of renal disease.
 Write an equation for the net filtration pressure across the glomerular membrane in
terms of the hydrostatic and osmotic pressures involved.
GFR = Kf x (Pgc – Pt – πgc)
Puf = Pgc – Pt – πgc
Puf = net ultrafiltration pressure
Pgc = pressure in glomerular capillaries
Pt = hydrostatic pressure in tubules
Πgc = oncotic pressure generated by plasma proteins
Kf = ultrafiltration coefficient (membrane permeability and surface area)
Ultimately there is net Ultrafiltration pressure of 10-20mmHg.
GFR is not a fixed value, it is subject to physiological regulation. This is achieved by neural
or hormonal input to the afferent/efferent arteriole, resulting in changes in GFR.
Kidney diseases may reduce number of functioning glomeruli = reduced surface area =
reduced Kf.
Drugs/hormones can cause dilation of glomerular arterioles, increasing Kf
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Explain how net filtration pressure will be affected by (a) a large fall in arterial
blood pressure (b) a fall in plasma protein concentration and (c) ureteral obstruction
Autoregulation of GFR
Myogenic mechanism:
 Vascular smooth muscle constricts when
stretched
 This keeps the GFR constant when blood
pressure rises
Autoregulation ensures fluid and solute excretion remain
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constant (otherwise varying pressure will vary urine production and cause loss of important
ions)
Tubularglomerular feedback:
 NaCl concentration in fluid is sensed by macula densa in juxtaglomerular apparatus
 Macula densa signals afferent arteriole and changes its resistance and so GFR
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Describe and explain the effect of changes in renal blood flow on GFR.
Renal plasma flow:
 Measured by PAH (para aminohippurate) clearance = 625ml/min
 PAH is filtered and actively secreted in one pass of the kidney, therefore amount
PAH excreted = amount filtered and secreted.
Clearance of PAH = renal plasma flow (filtered and secreted)
Amount excreted = amount filtered – amount reabsorbed + amount secreted
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Define renal clearance and explain its use in assessing renal function.
Renal clearance:
 As substances in blood pass through the glomeruli they are filtered to different
degrees
 The extent to which the substances are removed from the blood is called clearance
 Clearance is the number of litres of plasma that are completely cleared of the
substance per unit of time.
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Using clearance we can estimate the GFR:
 If molecule is freely filtered and neither reabsorbed or secreted in the nephrons, then
amount filtered = amount excreted.
 Therefore the GFR can be measured by measuring the clearance.
However, hard to find such a molecule:
INULIN:
 Plant polysaccharide
 Freely filtered, not reabsorbed or secreted
 Not toxic
 Measurable in urine and plasma
Has to be transfused as not found in mammals → therefore use an endogenous molecule with
similar clearance.
Practical measurement of GFR is done using creatinine clearance:
 Waste product from creatine in muscle metabolism
 Amount of creatinine released is fairly constant
 If renal function is stable, creatinine in urine is stable
Therefore low GFR value may indicate renal failure.
Summary of clearance, reabsorption and secretion:
If substance is reabsorbed, the clearance will be less than 120ml/min
If substance is not reabsorbed or secreted, clearance will be 12oml/min = glomerular filtration
rate.
If substance is secreted, clearance will be >120ml/min (e.g. PAH = renal blood flow)
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Urinary System 4 – Tubular function
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In the context of renal function, define the terms reabsorption and secretion.
Explain the meaning of transcellular and paracellular transport.
Draw a diagram of the wall of the early proximal tubule showing the
following: tubular fluid, luminal membrane, basolateral membrane,
peritubular capillary, tight junction, Na+/K+ “pump” and one example of each
of the following: an ion-selective channel, co-transport of two solutes,
counter-transport of two solutes.
Explain how active sodium transport acts as a driving force for the
reabsorption of water and many other ions and molecules.
Describe the main routes for Na+ entry into tubular cells in the thick
ascending limb of the loop of Henle, in the distal convoluted tubule and in the
principal cells in the cortical collecting tubule.
Contrast the osmolarity of the tubular fluid (a) in Bowman’s space (b) at the
end of the proximal tubule and (c) emerging from the loop of Henle.
Average day consume 20-25% more salt and water than lost
Therefore, this needs to be lost, as well as other waste products – in order t maintain
homeostasis.
In ideal situation, all excess ions, water and waste would be pumped into bladder. However
there are no pumps for water or waste products, therefore it doesn’t work.
Urine is produced by passive filtration through molecular sieve
BUT
Cannot afford to lose all the water and small molecules that pass through filter
So REABSORB.
Controlled re-absorption and secretion:
Controlled by having regional specialisation of the tubule system and transport
mechanisms
 Allows 99% of ultra filtrate reabsorbed
 How solute is balanced and plasma conc. and pH maintained.
Osmolarity – ‘a measure of the osmotic pressure exerted by a solution across a semipermeable membrane’
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It is dependent on the number of particles crossing, not the nature
All concentrations of the different solutes added together – each ion counts
separately.
Plasma osmolarity has a small range.
Urine osmolarity has a large range.
[Any solute present at equal amounts on either side of semi-permeable membrane has
no net movement, therefore no effect on water movement]
Reabsorption and secretion can occur paracellular (through tight junctions) or
transcellular (through cell).
Reabsorption: movement from lumen → capillary
Secretion: movement from capillary → lumen
Most important secretion is H+ and K+ (drugs can also be secreted e.g. choline,
creatinine, penicillin)
Types of transport in the tubules [SUMMARY OF PREVIOUS LECTURE]
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Osmosis
Active transport
Co-transport
Counter transport
Passive transport
Movement down electrical gradient
Relationship between solute and rate:
 Passive - Protein independent transport (lipophilic molecules)
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Passive - Protein dependent transport (hydrophilic molecules)
Active – Direct ATP dependent
Active – Indirect ATP dependent
Water transport – osmosis:
 Paracellular – down tight junctions
 Transcellular - Dependent on aquaporins
Aquaporins regulate passive uptake system of water.
Different types of transporters in different parts of the nephrons give the
different roles.
There is a limited amount of material that can be reabsorbed.
HOWEVER, if limit is exceeded, excess is excreted in urine
 e.g. glucose in T1DM
 Vitamin B
 Vitamin C
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Na+/K+ pump is most important in the kidney:
 Moves H+ out of cell
 Moves glucose, amino acids, bicarbonate into cell
Basolateral membrane
 Na/K pump keeps intracellular Na low an K high.
 Large concentration and electrical gradients favour Na movement into cell
Early proximal tubule
 Na+ entry down a large electrochemical gradient
 Can bring ‘uphill’ entry (co-transporter) of glucose and amino acids, and exit
of H+
 Carbonic anhydrase activity leads to Na+ reabsorption and increased urinary
acidity
Proximal convoluted tubules are affected by metabolic poisons:
Passive reabsorption
Active reabsorption
Urea
Glucose
Water
Amino-acids
Sodium
Potassium
Calcium
Vitamin C
Uric acid
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Renal proximal tubular wall:
Net secretion of some substances plasma → proximal tubular fluid
 Important as drugs and other substances excreted in this way
 Some drugs enter tubular fluid and act further down the nephrons
Ascending loop of Henle:
 Na/K/Cl co-transporter is blocked by diuretics
Distal convoluted tubule:
 Ca2+ from lumen → blood
 Na+/Cl- co-transporter linked to Ca2+ reabsorption
 Sodium reabsorbed depending on aldosterone (greater dependence as more
distal)
 Na+/K+/H+/NH4+
 Water reabsorbed under ADH(vasopressin) control
Collecting duct and distal part of distal tubule:
Involves:
 Apical Na+ channel sensitive to aldosterone
 Linked K+ channel
 pH control
Principle cell:
 Important in Na+, K+ and H2O balance – mediated by Na/K ATP pump
 Apical Na channel is aldosterone sensitive, blocked by amilioride
Intercalated cell:
 Important in acid-base balance
 Mediated via H-ATP pump
Cortical collecting duct principle cell has very tight epithelium, therefore little
paracellular transport. Relies on vasopressin.
Proximal tubule:
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 Reabsorbs 60% of all solute
 100% glucose and amino acids
 90% of bicarbonate and water
 65% filtered Na
Loop of Henle:
 Allows urine concentration
 Reabsorbs 25% of filtered Na
Distal tubule:
 Reabsorbs 8% of filtered Na
Collecting duct:
 Reabsorbs 2% Na, only if aldosterone is present
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Urinary system 5 –
Mechanism of acid-base balance
Definitions:
Acid – substance that can release H+ in solution
Base – substance that can accept H+ in solution
Buffer – addition or removal of H+ will result in minimal change of pH
pH – measure of hydrogen ion concentration, indicates acidity, pH=-log[H+]

Give the normal arterial plasma pH and the limits compatible with life.
H+ is maintained in very narrow limits at a low conc.
pH = 7.40 [Range = 7.35 – 7.45]
If pH is outside range 7.2-7.6, serious pathological condition
Range compatible with life = 6.80-7.80
Urine pH range = 4-8.5

Explain in terms of physiological buffering the importance of the
bicarbonate buffer system.
Control of pH is particularly important because:

Metabolic reactions are highly sensitive to pH

H+ ions change shapes of proteins – including enzymes

H+ are created and destroyed all the time

Sources of H+ ions:
o Protein breakdown
o CO2
o Exercise (lactic acid production)
Acid-Base balance regulation:

Extra and intracellular buffers

Control of partial pressure of CO2 in blood by altering rate of alveolar
ventilation

Control of plasma bicarbonate concentration by changes in renal H+
excretion
[Note: Think compensatory mechanisms in acid-base]
Principle buffers:
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Buffering process:

In metabolic acidosis, only 15-20% of the acid load is buffered by
CO2/bicarbonate system in the extracellular fluid, most of remainder is
buffered in the cells

In metabolic alkalosis, 30-35% of OH- load is buffered by cells

In respiratory acidosis/alkalosis, almost all buffering is intracellular
Extracellular buffer:

CO2/HCO3- system is most important extracellular buffer

HCO3- and PCO2 are regulated independently
o HCO3- regulated by changes in renal H+
o PCO2 by changes in rate of alveolar respiration
Buffering at local level:

H2SO4 and HCl produced during metabolism are not circulated as free
acids but are immediately buffered

These reactions minimise increase in extracellular H+

BUT excess H+ must still be excreted by kidney to prevent progressive
depletion of HCO3Sources of body H+ ions:
Physiologically
Produced
Pathologically
Carbohydrates and fats H2O and CO2 Hypoxia,
carbohydrates and fat
Sulphur-containing
Sulphuric
Diabetes,
amino acids e.g.
acid
carbohydrates
Cysteine
Arginine, Histidine,
HCl
Lysine
Further sources:
Volatile acids
Produced from
metabolism of
carbohydrates and fats
Result in CO2
production
Produced
Lactic acid
Ketoacids (βhydroxybutyric
acid)
Non-volatile acids
Derived from
metabolism of proteins
Only 50-100meq/day
of acid produced this
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15,000mmol CO2
produced per day
CO2 lost through
respiration

way
H+ ions excreted by
kidneys
Give the Henderson-Hasselbach equation when applied to the bicarbonate
buffer system. Cite a normal value for plasma HCO3- concentration.
Overview of control of pH:
Lungs: release CO2
Kidney: release H+
GI tract: release bicarbonate
CO2 + H2O → H2CO3 → H+ + HCO3Regulated by carbonic anhydrase?
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
State that the kidneys help to control plasma HCO3- concentration by (a)
variable reabsorption of filtered HCO3-, and (b) variable addition of new
HCO3- to the blood perfusing the kidneys.
Explain the mechanism and indicate the sites of HCO3- reabsorption.
Bicarbonate reabsorption:

Approximately 80% of bicarbonate is reabsorbed in proximal tubule –
mostly in first 1-2mm

Remaining 20% reabsorbed in thick ascending limb of loop of Henle and
outer medullary collecting tubule
H+ ion excretion is regulated by:

Extracellular pH is primary physiologic regulator
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In pathological states these can affect acid excretion independent of systemic pH:
o Blood volume
o Aldosterone
o Plasma potassium
Effective circulating volume:

Has important effects on bicarbonate reabsorption

Most important effect is increased bicarbonate reabsorption associated
with volume depletion
4 influencing factors:

Reduction in glomerular filtration rate (GFR, normally 120ml/min)

Activation of renin-angiotensin-aldosterone system

Low plasma Cl
Low plasma K+ due to urinary losses (diuretics) or GI losses (vomiting,
diarrhoea)
Examples of increased bicarbonate reabsorption with volume depletion:

Hypovolaemia associated with diuretics causes increased HCO3reabsorption with high levels of plasma HCO3
Eating low salt diet causes small rises in plasma HCO3
Clinically important in patients with metabolic alkalosis – patient volume
depleted, not possible to excrete excess HCO3- to correct acid-base balance.
[NOTE: Secretion: Blood → urine, Excretion: urine → out of body]
Increased H+ secretion:
Primary (directed at balancing acid-base)

Decreased plasma HCO3- conc. (reabsorbed into

Increased paCO2 (arterial partial pressure)
Secondary (not directed at balancing acid-base)

Increase in filtered load of bicarbonate

Decrease in ECF volume

Increase in angiotensin II

Increase in aldosterone

Hypokalaemia
Decreased H+ secretion:
Primary

Increased plasma HCO3- conc.

Decreased paCO2
Secondary

Decrease in filtered load of bicarbonate

Increase in ECF

Decrease in aldosterone

Hyperkalaema

State the limits of urine acidity and alkalinity. Thus explain why it is
impossible for the kidneys to add significant amounts of new bicarbonate to
the blood simply by excreting free H+ ions.
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Renal H+ excretion:

Must excrete 50-100mmol of noncarbonic acid generated each day
Mechanisms involved:
o Proximal tubule
o Thick ascending limb of loop of Henle
o Collecting ducts

Mechanisms reabsorb bicarbonate filtered into urine

Secreted H+ ions are excreted with filtered buffers (phosphates, creatinine)

Secreted H+ ions are excreted with manufactured buffer (ammonia –
manufactured from glutamine in proximal tubule)
Problems in excreting daily acid load:

Cannot be excreted as free H+

All filtered bicarbonate needs to be reabsorbed, as losing bicarbonate is
effectively = adding H+ ions
Renal H+ pump action:
In proximal tube:

H+ secreted into lumen by Na+/H+ exchanger

HCO3- ions are returned to systemic circulation by Na+- HCO3- cotransporter
In collecting tube:

Luminal pump mediated by active H+ - ATPase pump

And Cl- HCO3- exchanger in basolateral membrane
Excretion of H+ with filtered
buffer:

Lowest urine pH that can
be achieved is 4

Still represents very low
free H+

Combined H+ with filtered
urinary buffer such as
phosphate or ammonia

Describe in outline the mechanisms involved in the excretion of acid
phosphate and of ammonium salts. Indicate how these events contribute
new bicarbonate to the blood.
New bicarbonate formation:

Bicarbonate reabsorption < bicarbonate lost (during the titration of the nonvolatile acids produced by metabolism)
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
To maintain acid-base balance, the kidneys must replace this loss
Ammonium excretion:

Ability to excrete H+ ions as ammonium adds important degree of
flexibility to renal acid-base regulation

NH3 produced in tubular cells predominantly from glutamine

Some of excess NH3 diffuses into tubular lumen

Excreted H+ combines with NH3 to form ammonia
Summary of ammonia and bicarbonate production, excretion and transport:


Explain in general terms what is meant by respiratory compensation and
renal compensation for acid-base disturbances.
Explain the terms: respiratory acidosis, respiratory alkalosis, metabolic
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acidosis, metabolic alkalosis.
Acid-base
disturbance
Respiratory
acidosis
Plasma pH Plasma
CO2
Low
High
Plasma
Caused by
bicarbonate

Reduced
alveolar
ventilation
Compensation
Renal compensation –
increased bicarbonate
and ammonia secretion
(several days)
Cellular buffering
minimises change in
intervening acute phase
Respiratory
alkalosis
Metabolic
acidosis
High
Low
Low
-

-
Low



Metabolic
alkalosis
High
-
High
Increased
alveolar
ventilation
Addition of nonvolatile acids
Loss of non-volatile
alkalis
Failure to reabsorb
sufficient
bicarbonate
 Loss of non-volatile
acid (vomiting)
 Raised aldosterone
pH rises back towards,
but not above, normal.
Renal compensation –
decreasing bicarbonate
reabsorption and
ammonia secretion
pH falls back towards
normal
Respiratory
compensation by raised
ventilation due to
peripheral chemoreceptor
stimulation
Renal excretion of net
acid increases if possible
Reduced ventilation
Renal excretion of excess
bicarbonate, can be
limited if low blood
volume with Na and Cl
depletion
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Analysis of acid-base disorders

Directed at identifying the underlying cause

Treatment can be initiated

Medical history and associated physical findings often provide valuable
clues about nature and origin

Require arterial blood analysis
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Urinary system 6 –
Sodium and potassium balance

Explain why extracellular fluid volume is determined primarily by the body's
sodium content. Thus explain the importance of the renal control of sodium
excretion in the control of extracellular fluid volume.
The main determinant of extracellular fluid volume is the number of osmoles
present. Sodium is the most abundant of these, therefore the largest determinant.
Therefore to control the ECF, sodium must be regulated.
Effect of high sodium diet on body weight:
Increased sodium causes an
increase in body weight due the
increased water volume that is
retained.
(1g Na+, 100g H2O)
Effects of changing sodium levels:
The opposite of this occurs with decreased dietary
sodium.


Compare the daily amounts of sodium filtered
with the amounts normally appearing in urine.
State the approximate proportions of filtered
sodium normally reabsorbed in (a) the proximal
tubule and (b) the loop of Henle.
65% proximal tubules
25% thin ascending limb of loop of
Henle
8% distal convoluted tubule
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2% collecting ducts (when in presence of aldosterone)

State that the bulk of the glomerular filtrate is reabsorbed in the proximal
tubule and loop of Henle and that the fraction of the filtered load reabsorbed
in these segments is not very responsive to changes in sodium, potassium or
water balance. Contrast this with the function of the distal nephron.

Name the site of secretion of aldosterone and list three factors that influence
the rate of production of this hormone.
Aldosterone:
 Steroid hormone
 Synthesised and released from adrenal cortex
 Released in response to angiotensin II
[3 factors that influence rate of synthesis: angiotensin II, atrial natriuretic peptide
(ANP), Brain natriuretic peptide (BNP)]
As steroid hormone, hormone passes through cell membrane, binds with protein and
receptor, causing protein to be released. Hormone-receptor complex enter nucleus and
act as a transcription factor [affecting production of other transcription factors,
regulatory proteins, transport molecules]

Describe the effect of aldosterone on sodium reabsorption, indicating its
principal site of action.



Acts on collecting ducts
Induces formation of Na-K-ATPase pumps
Induces expression of apical Na channel of the collecting duct (and probably
also promotes activity)
Aldosterone stimulates:
 Na reabsorption
 Potassium secretion
 Hydrogen ion secretion
Aldosterone excess leads to hypokalaemic alkalosis (too little potassium retained)
Diseases associated with aldosterone:
Hypoaldosteronism
Decreased Na reabsorption from distal
nephrons
Increased urinary loss of sodium
ECF volume falls
Hyperaldosteronism
Increased Na reabsorption from distal
nephrons
Decreased urinary loss of sodium
ECF volume rises
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Increased Renin, angiotensin II, ADH
Decreased renin, angiotensin II, ADH
Increased ANP(atrial natriuretic peptide),
BNP(brain natriuretic peptide)
Liddle’s syndrome:
 Inherited disease of high BP
 Due to a mutation in the aldosterone activated Na channel in the collecting
duct
 Defective channel is always on, therefore too much Na is reabsorbed
 Results in sodium retention → hypertension
How is change in BP measured?
Baroreceptors:
 Heart → atria
 Vascular system → carotid sinus, aortic arch, pulmonary vasculature,
juxtaglomerular apparatus
Atrial natriuretic peptide (ANP) [also BNP from brain]:
 Produced and secreted by atria of heart
 Released in response to atrial stretch (high BP)
Actions of ANP:
 Vasodilatation of renal (and other systemic) blood vessels
 Inhibition of sodium reabsorption
 Inhibits renin and aldosterone release
 Reduces BP
Reduced blood pressure mechanism on whole nephron:
Increased blood
pressure
(volume
expansion) has
opposite effect.

Explain
three
ways in
which an
increase
d concentration of Angiotensin II can influence renal function.
How to measure change in Na in distal nephrons:
 Macula densa monitor the Na in tubular fluid
 Juxtaglomerulur cells stimulated to secrete rennin
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Effects of angiotensin II:


Give three stimuli that lead to an increase in renin release
Describe the effect of renal sympathetic nervous activity on the renal
vasculature and on renin release.
Renin release is stimulated by:
 Decreased renal perfusion pressure
 Decreased Na in distal tubule
 Decreased angiotensin II
 Increased sympathetic activity (β adrenoceptors)

Name one other hormone that can directly influence renal sodium
reabsorption
ADH

State that small variations in Na+ intake can be counterbalanced by changes
in Na+ reabsorption in the collecting ducts (under the influence of
aldosterone) but that more substantial variations resulting in extracellular
fluid volume contraction or expansion lead to widespread co-ordinated
changes in renal function
Maintenance of sodium balance:
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

Small variations in sodum intake can be countered by changes in sodium
reabsorption in the collecting ducts (largely regulated by aldosterone)
More substantial variations (and other changes in fluid balance, e.g.
haemorrhage) lead to a complex set of inter-related changes in renal function
ACE inhibitors lower BP as they inhibit production of angiotensin II, effecting both
vascular and kidney.

Explain that the prime function of diuretics is to increase renal Na+ excretion
(usually by reducing Na+ intake into the tubular cells). Give one example of a
class of diuretic drug acting in each of the following sites: the proximal
tubule, the loop of Henle, the early distal tubule and the cortical collecting
ducts.
Diuretic drugs:
Region acted on
Proximal convoluted
tubule and descending
loop of Henle
Proximal convoluted
tubule
Drug (and example)
Osmotic diuretics –
glucose (as in diabetes
mellitus)
Carbonic anhydrase
inhibitors
Thick ascending limb of
loop of Henle
Distal convoluted tubule
Distal convoluted tubule
Loop diuretics –
furosemide
Thiamides
K+ sparing diuretics
Action
(carbonic anhydrase leads
to Na+ reabsorption
through H+ secretion)
Therefore:
Inhibits H+ secretion,
promoting Na+ and K+
excretion
Blocks triple transporter
(Na, 2CL, K pump)
Block Na/Cl co-transporter
Amiloride – block Na
channels
Spironolactone –
aldosterone antagonist

Compare the daily amount of potassium filtered with the amount normally
appearing in the urine.
Kidneys excrete 90-95% of K+ ingested from diet



K+ is main intracellular ion
Extracellular K+ has effects on excitable membranes:
o High K+ depolarises membranes
o Low K+ causes heart arrhythmias
Hypokalemia ECF, one of the most common electrolyte imbalances.
Causes of hypokalaemia:
 Diuretics
 Surreptitious vomiting
 Diarrhoea
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Suzie Rayner

Genetics

State that under normal conditions potassium ions are reabsorbed in the
proximal tubule and loop of Henle but secreted into the lumen of the late distal
tubule and cortical collecting duct. State that potassium excretion depends
largely on the extent of this secretion.


K+ is freely filtered in glomerulus, most reabsorbed in proximal convoluted
tubule and loop of Henle
Distal convoluted tubule and collecting ducts can secrete K+ when necessary
(main control of excretion)
Aldosterone stimulates Na+ reabsorption and K+ excretion

Describe the cellular mechanism of potassium secretion

In distal convoluted tubule and collecting duct, aldosterone stimulates:
 Na+/K+ pump, moving K+ from blood → principle cell
 Na+ channel, moving Na+ into principle cell
 Inhibits K+ channel, blocking K+ from moving into lumen
 K+ moved back out into blood via K+ channel in basal cell wall

Explain how potassium secretion (and therefore excretion) is influenced by:
plasma potassium concentration, aldosterone, tubular fluid flow rate, acidbase balance
Potassium secretion:
Amount of filtered load reaching each point of
nephron.

K+ excretion rate is largely determined
by the amount of K+ secreted in
collecting ducts
The secretion from the collecting ducts
increases as:
 Increase in K+
 Increase in aldosterone
 Increase in tubular flow rate
 Increase in plasma pH
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Suzie Rayner
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Suzie Rayner
Urinary system 7 – Control of water excretion

State the minimum and maximum osmolarity of the urine in humans and
indicate the nephron sites responsible for the production of (a) dilute urine
and (b) concentrated urine.
[Mentioned in previous lecture]
Osmolarity – ‘a measure of the osmotic pressure exerted by a solution across a semipermeable membrane’
 It is dependent on the number of particles crossing, not the nature
 All concentrations of the different solutes added together – each ion counts
separately.
Plasma osmolarity has a small range.
Urine osmolarity has a large range.
Affects of excess salt, water or volume:

Excess volume – oedema and BP increase

Excess water – dilute salt, cells will swell (hypotonic)

Excess salt – cells will shrink (hypertonic)
Osmolarity varies:
Osmolarity
Water
Increased
Decreased
Decreased
Increased
Constant
Decreased
Constant
Increased
Regulation of water and salt balance are inter-related.
Salt
Increased
Decreased
Decreased
Increased
Water balance is used to regulate plasma osmolarity.
The level of salt determines the extracellular fluid volume.
[Revision of tissues – MCD]
Extracellular fluid (lymph, plasma, interstitial, transcellular – CSF, synovial) =
15L
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Intracellular fluid = 25L
Excretion of water:
Mechanism
Skin and sweat
Controllable?
Variable but
uncontrollable
Volume
Normally
450ml/day
Faeces
Uncontrollable
Normally
100ml/day
Respiration
Uncontrollable
Urine output
Variable and
Controllable
Normally
350ml/day
Normally
1500ml/day

(a)
(b)
Varies with…
Fever
Climate
Activity
Diarrhoea up to
20L/day with
cholera
Activity
Explain why the final concentration of the urine depends on:
the osmolarity of the medullary and papillary interstitium;
the permeability of the collecting ducts to water.
Kidney makes different
concentrations of urine by:
Fraction of filtered load reaching
different points in the nephron



The fraction of the filtered load reabsorbed in the proximal tubule and
loop of Henle is little changed by small variations in fluid balance
Fraction of filtered load reabsorbed in collecting ducts is very variable
This is also true for renal handling of Na+, K+, H+
Crucial factor for water is osmolarity of the plasma and the concentration of
vasopressin.
Interstitial osmolarity varies.
But water cannot be pumped,
therefore relies on gradient.
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Gradient is established by counter current exchange mechanism:
Cortico-medullary gradient results because of:

The shape of the loop of Henle

The fact that the descending limb is water permeable, Na+ and Climpermeable and the ascending limb is water impermeable, Na+ and Clpermeable

Active transport of Na, Cl into the interstitial fluid from the ascending limb

Urea absorbed from inner medullary collecting duct into interstitial tissue

As a result solute accumulates in the medullary interstitial fluid forming
a gradient.
Why don’t medullary blood flow eliminate countercurrent gradient?
Vasa Recta is blood supply

Permeable to water and solutes

Water diffuses out of descending limb
and solutes diffuse into descending
limb

Opposite occurs in the ascending limb

Thus oxygen and nutrients are
delivered without loss of Gradient.
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Suzie Rayner

State that the medullary and papillary interstitium is hypertonic as a result
of the accumulation of NaCl and urea.

Describe how changes in plasma osmolarity influence the release of
vasopressin (antidiuretic hormone) from the posterior pituitary, using the
term 'hypothalamic osmoreceptors'.
Describe the action of vasopressin on the collecting ducts, and hence
explain how urine volume is regulated in accordance with the state of
hydration of the body.

Vasopressin:

Peptide hormone (Nonapeptide)

Synthesised in hypothalamus

Secreted from posterior pituitary (neurohypophysis)

Binds to specific receptors on basolateral membrane of principle cells in
the collecting ducts

Leads to insertion of aquaporin 2 on luminal membrane (aquaporin 3 and 4
on capillary side), hence increasing water permeability

Also stimulates urea transport from inner medullary collecting ducts into
thin ascending limb of loop of Henle and interstitial tissue.
Vasopressin release is triggered by:

Osmoreceptors in the hypothalamus regulate ADH (vasopressin) release if
osmolarity is > 300mOs

Also stimulated by marked fall in blood pressure or volume (via
baroreceptors or stretch receptors

Ethanol inhibits ADH release, leading to dehydration as urine volume
increases

Describe how changes in plasma osmolarity and volume influence thirst.
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Suzie Rayner
Water diuresis (low ADH) – solute reabsorbed, water not, lowers urine osmolarity to
around 50mOsmol/l – large volume of dilute urine
Maximal antidiuresis (high ADH) – osmotic equilibration in cortex and medulla leads
to high urine osmolarity – small volume of concentrated urine
Dehydration mechanism is
opposite of water load EXCEPT
that dehydration causes thirst.
[Water load causes drop in salt
conc. in blood – decreased plasma
osmolarity]
Feedback control by ADH ensures that
plasma osmolarity is kept in the normal
range – and determines urine output and
water balance
Diabetes Insipidus
Characterised by:

Excretion of large amounts of watery urine ( up to 30L/day)

Unremitting thirst
Caused by:

Insufficient secretion of ADH

Inheritance of 2 mutant genes for ADH receptor

Inheritance of 2 mutant genes for aquaporin
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Why do we have concentrated urine in the morning?

Asleep therefore not drinking

Decreased water in blood, increasing osmolarity of blood and extracellular
fluid

Increased osmolarity is sensed by hypothalamus (due to Na+ present), Na+
excretion into filtrate increases

ADH released

Collecting reabsorb more water from the filtrate – conc. urine, and
maintained blood osmolarity levels.
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