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YEAR 1 - Physiology and Pharmacology (Anton) > 11. Uro-Genital System (TT) > Flashcards

11. Uro-Genital System (TT) Flashcards

1
Q

What are some of the functions of epithelia?

A
  • Separate internal environment from external environment
  • Regulate the movement of solutes and water to and from the body (i.e. absorption and secretion)
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2
Q

What are the two categories of epithelia based on their function?

A
  • Absorptive -> Active Na+ transport drives solute and water reabsorption
  • Secretory -> Active Cl- transport drives fluid secretion
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3
Q

What are some of the features of epithelia that are common to all epithelia?

A
  • Sheets of cells (may be multiple layers)
  • Separated from neighbouring cells by lateral intercellular spaces
  • Held together by tight junctions close to their luminal edge
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4
Q

What are the two cardinal properties of epithelia?

A

1) Unidirectional transport -> The ability to translocate ions from one

This is enabled by the second cardinal property…

2) Asymmetry -> Note the particular asymmetry of the sodium-potassium ATPase that is responsible for this

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5
Q

Give another name for the unidrectional transport across epithelial cells.

A

Vectorial transport

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6
Q

What are the names of the two sides of an epithelial cell?

A
  • Apical
    • External-facing membrane
    • A.k.a. Luminal or mucosal
  • Basolateral
    • Internal-facing membrane
    • A.k.a. Contraluminal or serosal
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7
Q

What are some of the differences between the apical and basolateral membranes of epithelia?

A
  • Morphology (villi)
  • Biochemistry (protein distribution)
  • Function (ion selectivity)
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8
Q

What are the apical and basolateral membranes of epithelial cells separated by?

A

Tight junctions

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9
Q

On which membrane of epithelial cells is the Na+/K+-ATPase found? Which way does it pump each ion?

A
  • Basolateral
  • Pumps sodium out of the cell and potassium into the cell
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10
Q

Describe the sodium gradient across each membrane side of an epithelial cell and how this arises.

A

There is an inwards sodium gradient on each side of the membrane, which is created by the Na+/K+-ATPase on the basolateral membrane.

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11
Q

What are the functions of tight junctions between epithelial cells?

A
  • Hold cells together
  • Separate apical and basolateral membranes
  • ‘Reflect’ solutes and water
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12
Q

What is the difference between tight and leaky epithelia?

A

It relates to how well the tight junctions prevent the movement of solutes and water:

  • Tight -> Prevent any significant movement of molecules between cells.
  • Leaky -> The tight junctions aren’t tight. They form imperfect seals and are a low-resistance, leak pathway (‘shunt’) for ions and water.
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13
Q

Compare what tight and leaky epithelia are specialised for and where each is found.

A

Leaky:

  • Specialised for the bulk handling of isosmotic solutions (either for absorption or secretion)
  • Found proximally: Proximal tubule, Small intestine

Tight:

  • Can withstand large osmotic gradients
  • More selective in the way they handle the load with which they are presented.
  • They are more highly regulated
  • Found distally: Collecting duct, Colon
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14
Q

Why are tight epithelia more selective?

A

The only pathway for transport of solutes and fluid across the epithelia is across the cell membrane, which is highly dependent on the proteins there.

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15
Q

How are tight and leaky epithelia typically combined?

A
  • Leaky epithelia are more proximal, tight epithelia are more distal
  • Combining the two allows bulk absorption and then fine control
  • For example, the bulk absorption of water and solutes (that have been filtered in the glomerulus) in the renal tubule and then fine tuning of the urine composition in the collecting duct
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16
Q

Explain the concept of transcellular and paracellular transport, and compare the process by which each occurs.

A
  • Transcellular
    • Through the cells
    • Depends on active transport processes
  • Paracellular
    • Between the cells
    • Occurs passively via diffusion and convection
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17
Q

What does the direction of paracellular transport in epithelia depend on?

A
  • Electrical, chemical gradients for ions
  • Osmotic, hydrostatic pressure gradients for water
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18
Q

What is the effect of moving ions across an epithelium?

A

It creates a potential difference across the cell.

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19
Q

Ion movement across an epithelium creates a potential difference across the epithelium. What determines the size and orientation of this potential difference?

A
  • Orientation -> Depends on which ions move, and in which direction
  • Magnitude -> Depends on whether the epithelium is leaky (so that charge ‘shunts’)
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20
Q

How is size of the potential difference across an epithelium affected by whether it is leaky or tight?

A

In leaky epithelia, the potential difference is typically reduced because of shunts. This is where the charge can move between cells (paracellular pathway), collapsing the potential difference.

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21
Q

How can the permeability of tight membranes to water be increased?

A

Insertion of water channels, which is induced by ADH.

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22
Q

Compare how sodium is absorbed on the apical side of tight and leaky membranes.

A
  • Tight -> Channels
  • Leaky -> Carriers
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23
Q

Compare the properties of tight and leaky epithelia.

A
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24
Q

Compare the potential difference that can be established across tight and leaky epithelia.

A
  • Tight -> In the order of 30mV
  • Leaky -> In the order of 5mV
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25
Q

Describe the basic underlying process by which absorption across epithelia occurs.

A

Ussing model:

  • The model relies of the asymmetrical expression of membrane transport proteins:
    • Basolateral membrane -> High permeability to potassium ions + Presence of Na+/K+-ATPase
    • Apical membrane -> High permeability to sodium
  • The driving force is the active movement of sodium out across the basolateral membrane by the Na+/K+-ATPase
  • This causes sodium to diffuse into the cell across the apical membrane
  • Potassium moved in by the Na+/K+-ATPase can easily diffuse out across the basolateral membrane
  • The unilateral movement of sodium is used to drive the movement of other solutes:
    • This depends on the selection of transport proteins (e.g. co-transporters) on the membranes
    • The composition of these proteins depends on the cell type
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26
Q

In epithelial cells, which membrane has the properties of a ‘regular’ cell (e.g. muscle or nerve cell) and what are these properties? Compare this to the properties of the other membrane.

A

Basolateral membrane has the properties of a regular cell:

  • Na+/K+-ATPase
  • K+ leak channels (high permeability to potassium, PK)
  • Low permeability to sodium (PNa)
  • Ca2+-ATPase
  • Cl- x OH- exchanger
  • Hormone receptors

Apical membrane on the other hand:

  • High PNa
  • May also contain specialised transport systems adapted to the functions of specific tissues
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27
Q

Compare the permeabilities of the apical and basolateral membranes in an epithelial cell.

A
  • Apical -> High PNa
  • Basolateral -> Low PK
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28
Q

Name the different types of proteins on the apical membrane of tight and leaky epithelia (that rae not necessarily found on normal cells).

A

Tight:

  • Na+ channels

Leaky:

  • Na+-glucose symport
  • Na+-amino acids symport
  • Na+/K+/2Cl- symport (kidney)
  • Na+ x H+ antiport (kidney)
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29
Q

How can the sodium channels on the apical membrane of epithelial cells be inhibited and regulated?

A
  • Inhibited -> By amiloride (a diuretic)
  • Regulated -> By aldosterone
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30
Q

Describe how an epithelium can be used to absorb glucose using sodium gradients.

A
  • Na+/K+-ATPase sets up sodium gradient across basolateral membrane and also across the apical membrane
  • Sodium can diffuse across the apical membrane into the cell
  • This is used by a sodium-linked glucose transporter (SLGT) to transport glucose into the cell by secondary active transport
  • The glucose can then diffuse across the basolateral membrane through GLUT transporters
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31
Q

Explain the water permeability of tight epithelia and how this can be regulated.

A
  • Tight epithelia have a very low water permeability becasue there is very little paracellular transport, so all transport must go through cells
  • In the collecting duct, there is the possibility of switching on water permeability by ADH, which causes insertion of aquaporins into the apical membrane
  • (Note: The basolateral membrane always contains aquaporins, so all control is at the apical membrane)
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32
Q

Explain the water permeability of leaky epithelia and how this can be regulated.

A
  • Leaky epithelia have a very high water permeability:
    • Mainly due to lots of transcellular transport through aquaporin I and III channels, which there are lots of
    • There is also a lot of paracellular transport due to less complex tight junctions between cells
  • Permeability cannot be regulated
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33
Q

How is the membrane potential of the apical membrane of epithelial cells calculated?

A
  • In tight epithelia, the only channels are sodium channels, so the membrane potential is close to the Nernst potential for sodium ions
    • ENa = nRT/F (log [Na]mucosa/[Na]cell)
  • In leaky epithelia, the situation is complicated by the presence of other transport proteins (such as co-transporters) and the shunt
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34
Q

How is the membrane potential of the basolateral membrane of epithelial cells calculated?

A
  • There are two electrogenic forces:
    • Na+/K+-ATPase
    • Leak of potassium out of the cell through channels
  • EBLM = EK + Epump
    • Where EK = nRT/F (log [K]serosa/[K]cell)

Note: The electrogenic effect of the ATPase is relatively small, so the membrane potential is approximated to the Nernst potential for potassium.

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35
Q

How is the potential across an entire epithelial cell calculated?

A

It is the sum of the apical and basolateral membrane potentials:

ET-E = EAM + EBLM

This approximates to the Nernst equilibrium potential for sodium plus the Nernst equilibirium potential for potassium.

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36
Q

Describe the basic process by which secretory epithelia work.

A
  • Na+/K+-ATPase pumps sodium out of the cell at the basolateral membrane as per usual
  • The Na+/K+/2Cl- symport utilises this gradient to move chloride ions into the cell at the basolateral membrane
  • Cl- ions exit passively into the lumen down the chemical gradient via Cl- channels
  • This sets up a negative p.d. in the lumen
  • K+ recycles across the basolateral membrane
  • Na+ ions move passively across the epithelium via the paracellular pathway, driven by the transepithelial p.d.
  • Together, the sodium and chloride draw water into the lumen down an osmotic gradient.
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37
Q

What is a nephron?

A
  • The nephron is the microscopic structural and functional unit of the kidney.
  • It is composed of a renal corpuscle and a renal tubule.
  • The renal corpuscle consists of a tuft of capillaries called a glomerulus and an encompassing Bowman’s capsule.
  • The renal tubule extends from the capsule.
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38
Q

Draw the structure of a nephron and associated blood vessels.

A
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39
Q

What is the glomerulus? What is it connected to?

A
  • It is a capillary knot
  • It is supplied by an afferent capillary and drained by an efferent capillary
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40
Q

What is the Bowman’s capsule? What is it connected to?

A
  • The part of the nephron that wraps around the glomerulus and carries out filtration
  • It is connected to the PCT of the renal tubule

Note: It is also known as the glomerular capsule.

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41
Q

Describe the path of blood through the kidney (at a nephron).

A
  • Blood flows through an afferent capillary into the glomerulus
  • Blood exits the glomerulus via an efferent capillary
  • Blood then returns to the renal vein via paratubular capillaries (that run alongside the renal tubule) and vasa recta (that wrap around it)
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42
Q

What is a renal corpuscle?

A
  • It is a glomerulus along with the Bowman’s capsule that surrounds it
  • It is the blood-filtering component of the kidney
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43
Q

What is the Bowman’s space?

A

The space within the Bowman’s capsule, connected to the renal tubule.

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44
Q

Draw a diagram and explain the basic principle of how a nephron works to produce urine.

A

There are 3 main processes:

  • First, the Bowman’s capsule filters blood from the glomerulus -> Blood cells and proteins remain in the blood
  • Next, there is reabsorption of solutes and water from the renal tubules into the blood
  • There is also secretion of solutes from the blood into the tubular fluid
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45
Q

Draw the structure and processes occurring in the nephron.

A
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46
Q

What is glomerular filtration?

A

The filtration of a clear fluid (free from blood cells and proteins) is filtered from the glomerulus into the Bowman’s capsule.

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47
Q

Describe the early studies into glomerular filtration.

A
  • Bowman first described the microscopic structure of the glomerulus in 1842
  • Ludwig proposed the theory of capillary ultrafiltration in 1844
  • Wearn and Richards obtained the first samples from Bowman’s space by micropuncture in 1921-> Showed that the filtrate in the Bowman’s space is identicle to plasma but lacks proteins
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48
Q

Draw a diagram of the structure of the Bowman’s capsule.

A

Note: In the diagram on the left you can see a part of the ascending limb of the loop of Henle, which passes close to the afferent arteriole.

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49
Q

Aside from capillary endothelial cells, name some other cells that are found within the glomerulus.

A
  • Podocytes -> Modified epithelial cells that wrap around capillaries of the glomerulus.
  • Mesangial cels -> Modified smooth muscle cells that are interwoven with the glomerulus

Together they support the structure and function of the glomerulus (i.e. in filtration).

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50
Q

What part of the renal tubule passes by close to the afferent arteriole of the glomerulus?

A

Ascending loop of Henle

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51
Q

What is the name for the layer of cells where the ascending loop of Henle comes in contact with the glomerulus?

A

Macula densa

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52
Q

Describe the permeability and pressure of the capillaries in the glomerulus.

A
  • High permeability to water
  • Low permeability to proteins
  • Pressure is very high (45mmHg) and regulated by constriction of afferent and efferent arterioles
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53
Q

On this diagram of a glomerulus, what is the name for the whole structure surrounding the glomerular capillaries and what do these letters stand for:

  • AA
  • EA
  • M
  • P
  • FP
  • PE
  • BS
  • PT
  • MD
A

It is the juxtaglomerular apparatus:

  • AA - Afferent arteriole
  • EA - Efferent arteriole
  • M - Mesangial cells
  • P - Podocytes
  • FP - Foot processes (of podocytes)
  • PE - Epithelial cells of Bowman’s capsule
  • BS - Bowman’s space
  • PT - Proximal tubule
  • MD - Macula densa
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54
Q

For a solute undergoing filtration into the Bowman’s capsule, what are the three layers it must pass through?

A
  • Capillary endothelial cells
  • Endothelial basement membrane
  • Foot processes of podocytes (epithelial cells)
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55
Q

What type of capillaries are the ones in the glomerulus?

A

Fenestrated (60nm holes)

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56
Q

Describe the properties of the basement membrane of the endothelial cells in the glomerulus (the second layer that solutes must pass through in glomerular filtration).

A

It is rich in negatively-charged glycosaminoglycans.

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57
Q

Describe the structure and location of podocytes in the kidney.

A
  • They are found wrapped around the capillaries in the glomerulus
  • They have foot processes that wrap around the capillary and end in pedicels that interdigitate, forming slit pores
  • They form the 3rd layer of filtration that solutes must get through in glomerular filtration
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58
Q

Where are mesangial cells found in the kidney and what is their function?

A
  • They are smooth muscle cells are interwoven with the capillaries in the glomerulus
  • They can contract to modify the surface area of the capillaries, controlling the rate of glomerular filtration
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59
Q

Label this diagram.

A
  • CL is the capillary lumen
  • The layer above it with gaps is the fenestrated capillary lumen
  • The dense band above that is the basement membrane
  • The triangular structures above that are the foot processes and pedicels -> Arrows indicate pores
  • CB is the Bowman’s capsule
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60
Q

Describe what is found between interdigitating pedicels in the glomerulus and what this forms.

A
  • A negatively charged mesh of proteins called nephrins
  • The gaps between the nephrins create slit pores, which are the final filtration unit
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61
Q

Describe and explain the different factors affecting the permeability of a molecule in glomerular filtration.

A
  • Size
  • Shape -> Need to fit through slit pores (although of similar size, haemoglobin is better filtered than albumin)
  • Charge -> Negative charge reduces filterability
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62
Q

What is the mass and size limit for passing through the filter in glomerular filteration?

A
  • Molecular weight: ~68kDa
  • Molecular radius: ~4nm
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63
Q

Which charge on molecules makes them less permeable to passing through the filter in glomerular filtration and why?

A
  • Negative charge reduces permeability
  • This is due to the:
    • Negative basement membrane (GAGs)
    • Negative nephrins between podocytes
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64
Q

What is the function of each layer in the filter in glomerular filteration?

A
  • Endothelial layer -> Only a barrier for cells
  • Basement membrane -> Negative charges repel negatively-charged macromolecules such as albumin
  • Epithelial podocyte layer with filtration -> Also negatively charged and contributes to the barrier
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65
Q

What is nephrotic syndrome and what does it illustrate the importance of?

A
  • Where damage to basement membrane occurs, and proteinuria results
  • This illustrates the importance of the basement membrane in filtering out proteins
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66
Q

What is the name of the type of forces that drives glomerular filtration?

A

Starling forces

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67
Q

Draw all of the Starling forces involved in glomerular filtration.

A

Note: It is oncotic pressure, not osmotic. This is because it is dependent on the proteins, since all of the other solutes should be the same on each side of the filter.

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68
Q

Which of the Starling forces at the glomerulus act towards the Bowman’s space and which act towards the glomerulus?

A

Towards Bowman’s space:

  • PGC = hydrostatic pressure in capillary
  • ΠBS = oncotic pressure of filtrate in Bowman’s space

Towards glomerulus:

  • PBS = hydrostatic pressure in Bowman’s space
  • ΠGC = oncotic pressure of glomerular capillary plasma
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69
Q

Which of the Starling forces at the glomerulus should approximate to 0 and why?

A
  • ΠBS (oncotic pressure of filtrate in Bowman’s space)
  • It approximates to 0 because there should be almost no proteins that filter through to the glomerular space
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70
Q

Write an equation for the net filtration pressure in glomerular filtration.

A

Net filtration pressure (PUF) = (PGC + ΠBS) -(PBS + ΠGC)

Where:

  • PGC = hydrostatic pressure in capillary
  • ΠBS = oncotic pressure of filtrate in Bowman’s space
  • PBS = hydrostatic pressure in Bowman’s space
  • ΠGC = oncotic pressure of glomerular capillary plasma
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71
Q

What does GFR stand for and what is it?

A
  • Glomerular filtration rate
  • It is the rate at which the glomerular filtrate is produced
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72
Q

Write an equation for GFR in glomerular filtration.

A

Rate of formation of filtrate (GFR) = Kf x PUF

Where:

  • Kf = Filtration coefficient = Permeability x Surface area
  • PUF = Net filtration pressure = (PGC + ΠBS) - (PBS + ΠGC)
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73
Q

What keeps glomerular filtration going?

A
  • High hydrostatic pressure in capillary
  • Drainage of the filtrate into the renal tubule

This helps maintain a pressure gradient across the filter.

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74
Q

What maintains a high hydrostatic pressure in the capillaries in the glomerulus?

A

The efferent arteriole is more constricted than the afferent.

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75
Q

What is the name of the the process by which glomerular filtration happens?

A

Ultrafiltration -> This is where hydrostatic pressure forces a liquid against a semi-permeable membrane..

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76
Q

Draw a graph and explain how the Starling forces and net filtration pressure change along the length of the glomerular capillaries.

A
  • The PBS (hydrostatic pressure of the Bowman’s space) is low and constant along the whole length of the capillary
  • The PGC (hydrostatic pressure of glomerular capillary) is high and constant along the whole length of the capillary
  • The ΠBS (oncotic pressure of fluid in Bowman’s space) approximates to 0 since very few proteins are in the glomerular filtrate
  • The ΠGC (oncotic pressure of plasma in glomerular capillaries) increases along the length because as fluid is filtered the remaining proteins become more concentrated
  • The PUF (net filteration pressure) decreases along the length of the capillary because ΠGC increases along the length
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77
Q

What is the name for the point when the PUF (net filtration pressure) in glomerular filtration is equal to 0?

A

Point of filtration pressure equilibrium

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78
Q

What does the GFR (glomerular filtration rate) depend on? Which variables are the most important for regulation and pathology?

A

GFR = Kf x ((PGC + ΠBS) - (PBS + ΠGC))

  • PGC is most important variable -> Varies with blood pressure and resistance of afferent and efferent arterioles
  • PBS may vary if the ureter is blocked (e.g. kidney stones)
  • Kf (filtration coefficient) -> Mesangial cells can contract and vary the surface area, which is one of the two variables that Kf depends on
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79
Q

PGC (hydrostatic pressure in glomerular capillary) is the main regulator of GFR (glomerular filtration rate), controlled by the afferent and efferent arterioles. How are these arteries controlled? What are the different effects of increasing/decreasing the resistance of each one?

A

Resistance of afferent and efferent arterioles is regulated by sympathetic nervous system, angiotensin II and by tubuloglomerular feeback.

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80
Q

Describe the idea of auto-regulation of GFR and the main ways that this happens.

A
  • Auto-regulation is the way in which renal blood flow and consequently GFR (glomerular filtration rate) remain constant over a relatively wide range of arterial blood pressures
  • This happens by two main mechanisms:
    • Myogenic regulation (Bayliss effect)
    • Tubulo-glomerular feedback
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81
Q

Describe how the myogenic mechanism allows for auto-regulation of blood flow and GFR in the glomerulus.

A

Thi happens by the Bayliss effect:

  • Increase in pressure stretch arteriole smooth muscle
  • This causes opening of stretch-mediated channels in the cell membranes -> This leads to influx of cations and therefore depolarisation
  • This causes opening of VGCC and entry of calcium -> This causes contraction of the smooth muscle
  • Therefore, the resistance increases and so blood flow decreases -> This maintains the blood flow relatively constant over a range of arterial blood pressures
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82
Q

Describe how the tubulo-glomerular feedback allows for auto-regulation of blood flow and GFR in the glomerulus.

A

This is a flow-dependent mechanism:

  • Macula densa (part of the juxtaglomerular apparatus) in the ascending limb of the loop of Henle detect the flow rate in the loop of Henle (distal flow rate)
  • If distal flow rate increases (because GFR has increased), the macula densa cell release a signal (adenosine) onto the adjacent afferent arteriole
  • This causes constriction of the arteriole, which increases the resistance and decreases glomerular pressure, so GFR is reduced
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83
Q

What is a typical value for the GFR (glomerular filtration rate)?

A

125ml/min

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84
Q

What other variable is measured in order to calculate the GFR in the kidneys?

A

Clearance

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85
Q

Define renal clearance.

A
  • Clearance is the volume of plasma from which substance X is completely removed.
  • This is an idealised variable since plasma is not completely clearance of solutes -> So you have to think about the minimum volume of plasma that would be contain the amount of the solute that was cleared
  • For example, 50% of glucose removed from 200ml in a minute of blood is a clearance of 100ml/min
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86
Q

What assumption is used when using clearance to approximate GFR (glomerular filtration rate)? What does this assumption rely on?

A

The amount of X removed from the blood = The amount appearing in the urine. It is dependent on:

  • Freely filtered
  • Not reabsorbed from the nephron
  • Not secreted into the nephron
  • Not metabolised or synthesised by the kidney
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87
Q

What are the units for clearance?

A

ml/min (the same as GFR)

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88
Q

Write an equation for renal clearance in terms of variables that can be measured.

A

C = (U x V) / P

Where:

  • C = Clearance (ml/min)
  • U = Concentration of solute in urine (mmol/ml)
  • V = Volume of urine produced per unit time (ml/min)
  • P = Concentration of X in the plasma (mmol/ml)
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89
Q

Derive the equation for renal clearance (used to estimate GFR) in terms of variables that can be measured.

A
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90
Q

What markers may be used to calculate renal clearance as an estimation of GFR? Why? [IMPORTANT]

A
  • Inulin and creatine
  • This is because they obey all of the rules underlying the assumption that the excretion rate of the marker is equal to the removal rate of the marker at the kidneys (e.g. they are not secreted into the nephron)
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91
Q

If a marker used to measure renal clearance (to estimate GFR) is reabsorbed from the nephron back into the blood, how will this alter the estimate for GFR?

A

The concentration of it in the blood will be reduced (U), so the value for GFR will be too low.

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92
Q

What is the filtration fraction in the kidneys and what is a typical value for it? [IMPORTANT]

A
  • It is the fraction of the fluid reaching the kidneys that gets taken up into the Bowman’s capsules
  • It is equal to the the ratio of the glomerular filtration rate (GFR) to the renal plasma flow (RPF).
  • It is normally about 20%.
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93
Q

What is the order of the nephron segments?

A
  • Bowman’s capsule
  • Proximal tubule
  • Descending limb of loop of Henle
  • Ascending limb of loop of Henle
  • Distal tubule
  • Collecting duct
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94
Q

Describe how the epithelia in the renal tubule change along its length.

A

The proximal tubule is a leaky epithelium and then the epithelia become progressively tighter until at the collecting duct it is very tight. This means that further down the tubule is more subject to hormones like aldosterone and ADH.

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95
Q

Describe the general function of the 3 main parts of the nephron.

A
  • Bowman’s capsule -> Ultrafiltration of water and solutes from the plasma, leaving proteins and blood cells in the blood
  • Proximal tubule -> Reabsorption of everything that is needed back into the interstital fluid (so it can go into the blood)
  • Rest of nephron further further down stream -> Fine tuning of urine composition to maintain body homeostasis
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96
Q

Does the renal tubule reabsorb things directly into the blood?

A

No, it reabsorbs them into the interstital fluid, from which they can diffuse into the blood (CHECK THIS!)

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97
Q

Why do the kidneys use a “filter and then reabsorb” approach, instead of just filtering anything that is unwanted straight out from the blood?

A
  • The second approach would require transporters for any solute that would need to be filtered out at any point -> By using the “filter and reabsorb” method, everything can be filtered out and then only transporters for specific essential nutrients are required for reabsorption
  • Also, water cannot be moved out using a transporter, so the “filter and reabsorb” method uses that fact that water follows solutes that are filtered, and then only reabsorbes the water
  • Also, it is energetically advantageous, since many other solutes can be recovered in association with the reabsorption of Na+
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98
Q

Which processes in the nephron does the Ussing model cover?

A

Reabsorption into the blood via the interstitial fluid (where the basolateral side is on the side of the blood).

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99
Q

What is the function of the proximal tubule? What things are reabsorbed into the interstitial fluid and secreted into the nephron and how? [IMPORTANT]

A
  • It is a bulk reabsorber of solutes into the interstital fluid (since it is a leaky epithelium
  • It uses carrier proteins in conjunction with an Na+ gradient to allow for this reabsorption

Reabsorbed from filtrate into the interstitial fluid:

  • Using carriers -> Na+, Cl-, HCO3-, Ca2+, Glucose, Amino acids (+ maybe PO3- - Check this)
  • By osmosis (via paracellular pathway and aquaporins) -> Water
  • By solvent drag (i.e. carried by the osmotic water) -> K+, Ca2+, Mg2+

Secreted into the filtrate:

  • Organic anions and cations (endogenous and exogenous) -> e.g. uric acid + penicillin (mentioned in spec)
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100
Q

What is the function of the descending and ascending limbs of the loop of Henle? What things are reabsorbed into the interstitial fluid and secreted into the nephron and how? [IMPORTANT]

A
  • It is involved in the reabsorption of water and ion from the filtrate, as well as establishing an osmotic gradient in the interstitial fluid that is used to extract water from the collecting duct later along the nephron

DESCENDING LIMB

Reabsorbed from filtrate into interstitial fluid:

  • Through channels -> Water

ASCENDING LIMB:

Reabsorbed from filtrate into interstitial fluid:

  • By carriers -> Na+, Cl-, HCO3-
  • Via paracellular route -> Na+, K+, Ca2+, Mg2+
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101
Q

What is the function of the early distal tubule, late distal tubule and collecting duct? What things are reabsorbed into the interstitial fluid and secreted into the nephron and how? [IMPORTANT]

A
  • The end of the nephron is involved in fine tuning the urine composition to maintain body homeostasis, including diluting the urine appropriately

EARLY DISTAL TUBULE

Reabsorbed from filtrate into the interstitial fluid:

  • Using carriers -> Na+, Cl-

LATE DISTAL TUBULE AND COLLECTING DUCT

Reabsorbed from filtrate into the interstitial fluid:

  • Through channels -> Na+, Water
  • Using carriers -> Urea

Secreted into filtrate:

  • Using carriers -> H+
  • Through channels -> K+
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102
Q

Compare the water permeability of the descending and ascending limbs of the loop of Henle.

A

Descending has a higher water permeability.

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103
Q

Compare how the transport proteins and transport routes change along the length of a nephron.

A
  • At first, they are mostly carriers, then they are mostly channels further along the nephron.
  • The paracellular route becomes less significant further down the nephron.
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104
Q

Describe the cells in the proximal tubule.

A
  • All one cell type
  • Have brush-border microvilli
  • Form a leaky epithelium
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105
Q

What are the segments of the proximal tubule?

A
  • S1 + S2 -> Convoluted tubule
  • S3 -> Straight tubule
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106
Q

Describe the permeability of the proximal tubule to ions and water, and the potential difference across it.

A
  • High permeability to ions -> Shunt leads to low potential difference
  • High permeability to water
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107
Q

The proximal tubule reabsorbs organic solutes, salt and water into the interstitial fluid. How much of each does it reabsorb? What is notable about this process?

A
  • Reabsorbs all organic solutes (e.g. glucose)
  • Reabsorbs 2/3 of salt and water
  • It does this isotonically, meaning that at any point in the tubule you cannot detect an osmotic gradient
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108
Q

Describe the general principle of how reabsorption occurs in the proximal tubule.

A

It works by the Ussing model:

  • Active Na+ transport out of the cell by Na+/K+-ATPase on basolateral membrane underlies transport
  • It creates a sodium gradient across the apical membrane
  • Na+ absorption is coupled to absorption of most organic solutes and anions, and to H2O
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109
Q

Describe the two phases of reabsorption in the proximal tubule.

A

First half of proximal tubule:

  • Na+ uptake coupled with:
    • Organic solutes (glucose, amino acids)
    • Phosphate
    • Bicarbonate

Second half of proximal tubule:

  • Na+ uptake coupled with Cl-
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110
Q

Describe how glucose absorption occurs in the proximal tubule.

A
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111
Q

What is the name for the symporter of glucose and sodium in the proximal tubule apical membrane? What are the different isoforms?

A
  • SGLT (sodium-glucose linked transporter) with 2 isoforms:
    • SGLT2 -> In S1 and S2 -> 1 Na+ per 1 glucose
    • SGLT1 -> In S3 -> 2 Na+ per 1 glucose (greater power to go against concentration gradient

Note: These are specific to D-glucose.

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112
Q

What is the name for the glucose channel in the basolateral membrane of proximal tubule cells?

A

GLUT

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113
Q

Describe the concept of Tm and glucose overspill in the proximal tubule. [IMPORTANT]

A
  • Tm = Transport maximum -> This is because glucose reabsorption is mediated by carrier proteins, so there is a maximum rate at which the glucose can be reabsorbed from the filtrate
  • If the plasma glucose is above the threshold, all of it will be filtered into the filtrate, but not all of it will be reabsorbed back into the blood, so some is excreted -> This is the glucose overspill
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114
Q

Give an approximate value for the point at which glucose overspill occurs.

A

200mg of glucose per 100ml of plasma

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115
Q

Describe how amino acid reabsorption occurs in the proximal tubule.

A
  • It is the same process as with glucose (Ussing model), except for the use of different transporters on the apical membrane.
  • There are at least 4 distinct symporter types for:
    • Cationic (basic) amino acids (lys, arg, his, sys)
    • Anionic (acidic) amino acids (asp, glu)
    • Neutral amino acids (ala, val, leu, ser, thr)
    • Glycine and imino acids (gly, pro, hydroxypro
  • These are stereospecific for L-amino acids
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116
Q

What part of proximal tubule transport can be an underlying cause of cystinuria and what can this lead to?

A
  • A defect in the cationic amino acid symporters on the apical membrane of the proximal tubule
  • Cystinuria predisposes to formation of kidney stones
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117
Q

Describe how reabsorption of bicarbonate in the proximal tubule occurs.

A

It uses a slightly different mechanism to the typical Ussing model:

  • Hydrogen ions in the cell are transported into the tubule lumen by a sodium-hydrogen antiporter or H+-ATPase
  • Bicarbonate (HCO3-) in the tubule lumen reacts with the H+ ions to form carbonic acid (H2CO3)
  • Carbonic anhydrase on the apical membrane of the cells catalyses the breakdown of carbonic acid into CO2 and H2O, which can diffuse into the cell
  • Carbonic anhydrase now recombines CO2 and H2O into carbonic acid, which dissociates into bicarbonate and H+
  • Carbonic acid now moves across the basolateral membrane by one of two ways:
    • Na+/3HCO3- symporter -> This is unusual because it goes against the sodium gradient set up by the Na+/K+-ATPase, but it is down the gradient of the bicarbonate, so the 3:1 ratio allows this to happen
    • Cl-/HCO3- antiporter
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118
Q

Describe how reabsorption of chloride in the proximal tubule occurs. (Note: This only happens in the later part of the proximal tubule, S3)

A

There are 2 pathways:

  • Paracellular
    • Via tight junctions and lateral intercellular space
    • Passive movement down electrochemical gradient, since the interstitial fluid is now positive from prior reabsorption of cations (electrical gradient) and there is also a chemical gradient due to prior osmotic movement of water concentrating the chloride
  • Transcellular
    • Hydrogen ions are moved out of cell across apical membrane by Na+/H+ antiport
    • The hydrogen ions are used to move bicarbonate across (see other flashcard), but once they are all used up, the H+ can react with anions (formate, HCOO-) to form an uncharged complex
    • The uncharged complex can diffuse across the apical membrane into the cell, before splitting back into the H+ and anion
      • H+ ion recycles back into Na+/H+ antiport
      • Anion goes into anion/Cl- antiport, moving the Cl- into the cell
    • Note that the coupling of these two antiports means that essentially the sodium diffusion gradient is used to pump the chloride across the membrane, just like in the other transport processes, but indirectly.
    • Chloride moves across basolateral membrane through the K+/Cl- symport
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119
Q

Describe how reabsorption of calcium in the proximal tubule occurs.

A

It is unusual because it does not rely on the sodium gradient established. It can move in one of two ways:

  • Paracellularly by solvent drag
  • Transcellularly
    • Diffuse across the apical membrane into the cell down its concentration gradient via channels (ECaC - Epithelial calcium channels)
    • Ca2+ moves across the cytosol bound to calcium-binding proteins
    • It moves across the basolateral membrane by two transporters:
      • Calcium ATPase
      • Ca2+/3Na+ antiporter
        *
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120
Q

Where in the nephron does calcium reabsorption into the interstitial fluid happen and what can it be regulated by?

A
  • Proximal tubule, Ascending loop of Henle, Distal tubule
  • Stimulated by: Parathyroid hormone (PTH), Vitamin D
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121
Q

Describe how secretion of cations into the filtrate occurs at the proximal tubule. Give an example of this sort of cation.

A

For example, PAH (para-amino hippurate):

  • Sodium gradient across the basolateral membrane (established by Na+/K+-ATPase) is used by a sodium/anion symport to accumulate the anion in the cell
  • This creates an outwards anion gradient across the basolateral membrane
  • The gradient is utilised by a PAH-/anion antiport to move PAH- into the cell
  • PAH- is moved across the apical membrane into the renal tubule lumen by another PAH-/anion antiport
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122
Q

Describe how the concept of Tm applies to PAH secretion and how this can be used clinically.

A
  • PAH secretion is a transporter-mediated process, so it can be saturated.
  • The maximum rate of secretion is the Tm.

Clinically, clearance of PAH can be used to estimate RBF (renal blood flow):

  • Below the point when the secretion mechanism becomes saturated, all of the PAH that enters the kidneys ends up in the urine (1/5th by filtration and 4/5th by secretion)
  • Therefore, by calculating the clearance gives an estimate for the blood flowing through the kidneys (RBF)
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123
Q

What is the difference between GFR and RBF?

A
  • GFR (glomerular filtration rate) -> The rate at which the glomerular filtrate is produced
  • RBF (renal blood flow) -> The blood flow through the kidneys
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124
Q

Below the plasma concentration of PAH at which the secretion mechanism gets saturated, what fraction of the PAH ends up in the filtrate by filtration and what fraction ends up there by secretion?

A
  • Filtration = 1/5th
  • Secretion = 4/5th
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125
Q

Draw a graph to show how the composition of the tubular fluid changes along the length of the nephron. [EXTRA]

A

The y-axis is the ratio of the concentration of the solute in the TF to its concentration in the plasma.

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126
Q

Describe how the tranepithelial potential difference changes along the length of the proximal tubule.

A
  • The transepithelial p.d. changes sign along the length of the proximal tubule, as a result of reabsorptive processes:
    • In S1, the lumen is negative (-2mV) -> Due to Na+ reabsorption
    • In S2 and S3, the lumen is positive (+2mV) -> Due to Cl- reabsorption
  • In S2, the lumen positivity drives passive Na+ reabsorption via paracellular route (accounts for up to 30% of Na+ reabsorption)
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127
Q

In the proximal tubule, is the transcellular route the only way for sodium reabsorption?

A
  • No, there is also a large amount (about 30%) of absorption by the paracellular route.
  • This is driven by the positivity of the lumen
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128
Q

Describe how water is reabsorbed in the proximal tubule.

A
  • Water moves passively down its concentration gradient, which is set up by the prior movement of ions and other solutes into the transcellular space
  • This occurs via:
    • Paracellular route -> Through the leaky tight junctions
    • Transcellular route -> Cells express lots of aquaporins
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129
Q

Explain why the reabsorption of solutes and water in the proximal tubule is considered to be an isotonic process.

A
  • There is no discernible osmotic difference between the lumen and interstitial fluid, so absorption appears ‘isotonic’
  • This is because the leaky epithelium is highly permeable to water (since it is leaky and has lots of aquaporins), so only a small osmotic gradient is required to drive water movement and any gradients are quickly minimised
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130
Q

Name two ‘hidden’ osmotic gradients that could drive water reabsorption in the proximal tubule. [EXTRA, I think]

A
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131
Q

What type of aquaporins are expressed in the membrane of proximal tubule cells and what proportion of water reabsorption goes through these?

A
  • Aquaporin I
  • About 90% of water reabsorption in the proximal tubule occurs through these (other 10% is through paracellular route)
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132
Q

Describe how phosphate reabsorption in the proximal tubule occurs. (This is not included in lectures, but it occurs, apparently)

A
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133
Q

Compare the protein distrubution on the membranes of the early and late proximal tubules.

A
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134
Q

Haven’t made flashcards on the final page of the tubular transport lectures. Check whether the diagrams on there have been covered in later lectures.

A

OK.

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135
Q

Describe briefly the role of the loop of Henle, distal tubule and collecting duct in the process of dilute or concentrated urine formation.

A
  • Loop of Henles -> Involved in concentrating the interstitial fluid near the distal tubule and collecting duct, so that there is an osmotic gradient for water reabsorption there if necessary.
  • Distal tubule + Collecting duct -> Involved in concentrating the urine and control of ion content of the urine.
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136
Q

Draw a graph to show how the osmolarity of the glmoerular filtrate changes along the length of the nephron. Explain why this occurs.

A
  • The proximal tubule involves isoosmotic processes, so the osmolarity remains at 300mOsm/L, but there is removal of solutes and water, so the flow rate falls from 125ml/min to 45ml/min.
  • The descending limb of the loop of Henle removes water, causing the flow rate to decrease, and concentrates the filtrate to about 1200mOsm/L.
  • The ascending limb removes solutes, causing a reduction in the osmotic potential to around 100mOsm/L. The flow rate out of the LOH (due to removal of water in the descending limb) is around 25ml/min.
  • If ADH is present, water removal occurs in the distal tubule and collecting duct, so that the filtrate is more concentrated and the flow rate is lower.
  • If ADH in not present, the filtrate remains relatively unchanged.
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5
Perfectly
137
Q

What is another name for the acending limb of the loop of Henle?

A

Diluting segment

138
Q

Compare the value for daily water intake and loss in non-urine ways (sweat, faeces and airways).

A
  • Daily water intake = 2500ml
  • Loss in sweat, faeces and airways = 1000ml

Therefore, around 1500ml per day are lost in the urine, although this value depends on changes to the intake and loss pathways.

139
Q

What is the range of urine osmolarity? [IMPORTANT]

A

30 - 1200mOsM

140
Q

If the default of the kidneys to produce dilute or concentrated urine?

A

Dilute, because the daily intake typically greatly exceeds the daily loss.

141
Q

The body must be able to regulate solute concentration in the urine independently of water concentration in the urine, since the two of these factors are not related. How does the body achieve this?

A
  • A countercurrent system in the loop of Henle concentrates the interstital fluid and creates an osmotic gradient for water movement out of the distal tubule and collecting duct
  • Regulation of the distal tubule and collecting duct then determines whether this gradient is used to reabsorb water from the filtrate
142
Q

What part of the nephron is important in determining how concentrated the urine produced by the kidneys can be?

A
  • The loop of Henle
  • Comparison of the length of loops between different species shows that the longer the loop, the more concentrated the urine
143
Q

Which parts of the nephron are in the cortex and which are in the medulla?

A
144
Q

What is a countercurrent system?

A

Where there is a hairpin, so that the flow in one limb is in the opposite direction to the other limb.

145
Q

What are the two important countercurrent systems in the kidney nephron and how are these different?

A
  • Loop of Henle
    • This is a countercurrent MULTIPLIER
    • Which is a mechanism that expends energy to CREATE a concentration gradient.
  • Vasa recta
    • This is a countercurrent EXCHANGER
    • Which is a mechanism in which opposing flow MAINTAINS a concentration at all points along the exchanger.
146
Q

Describe the two extreme scenarios of diuresis and antidiuresis.

A
  • Diuresis = water loss
    • Large volume of dilute (hypotonic) urine
    • 20l/day, 50mOsm/l
  • Antidiuresis = water conservation
    • Small volume of concentrated (hypertonic) urine
    • 0.5l/day, 1200mosm/l
147
Q

What is the hormone can controls the concentration of urine? What are its alternative names?

A
  • Antidiuretic hormone (ADH)

Also known as:

  • AVP
  • Vasopressin
148
Q

What is hydropenia?

A

A condition where your body is deficient in water.

149
Q

Where is the effect of ADH on the collecting duct and what is the mechanism of action?

A
  • Principle cells of the collecting duct and distal tubule
  • It increases the permeability to water, so water moves from the filtrate back to the interstitial fluid (and then the blood)
  • This is done by the insertion of aquaporin II into the cell membranes of collecting duct cells
150
Q

What is the structure of ADH?

A

It is a 9 amino acid peptide.

151
Q

Describe the site of synthesis and release of ADH>

A
  • Synthesised in neuroendocrine cells in the (supraoptic and paraventricular nuclei of the) hypothalamus
  • Transported along the axons
  • Stored in the nerve terminals in the neurohypophysis (posterior pituitary)

Hypothalamus neuroendocrine cells -> Transported along axons -> Stored in posterior pituitary

152
Q

What are the differenr types of aquaporin and where are they found?

A
  • AQP1 -> Proximal tubule and descending limb cells.
  • AQP2 -> Apical membrane of collecting duct principal cells subjected to ADH
  • AQP3 and AQP4 -> Basolateral membranes of collecting duct principal cells
153
Q

Draw a chart to compare the water permeability of different parts of the nephron.

A
154
Q

Describe the mechanism of action of ADH on the collecting duct.

A
  • Binding to a V2 receptor on the basolateral membrane of principle collecting duct cells
  • This causes activation of adenylate cycle, which increases cAMP in the cell
  • This leads to activation of PKA, which phosphorylates several targets
  • One of the targets are parts of the cytoskeleton associated with the vesicles that contain aquaporins II -> This phosphorylation causes fusion of the vesicles with the apical membrane, inserting the aquaporins into the membrane
  • This allows water molecules to enter the cell, after which they can exit via aquaporins III and IV in the basolateral membrane
155
Q

What is diabetes insipidus? What are the different types?

A
  • A condition characterised by the production of large volumes of dilute urine
  • Neurogenic diabetes insipidus -> Failure of ADH release
  • Nephrogenic diabetes insipidus -> Aquaporin insertion into the membrane, or a mutation in the aquaporin gene
156
Q

In order to have the option of extracting water from the collecting duct, there must be an osmotic gradient created between the filtrate and the interstitial fluid. How is this created?

A

A

157
Q

What are the two parts of the ascending limb of the loop of Henle?

A
  • Thin ascending limb -> The lower part of the ascending limb, with thin cells that lack mitochondria
  • Thick ascending limb -> The upper part of the ascending limb, with thick cells that have mitochondria
158
Q

Compare the water, sodium and urea permeability of the descending loop of Henle, the thin ascending loop of Henle and thick ascending loop of Henle.

A
  • Descending loop of Henle
    • High permeability to water
    • Impermeable to Na+
    • Low urea permeability
  • Thin ascending loop of Henle
    • Impermeable to water
    • High Na+ permeability
    • Low urea permeability
  • Thick ascending loop of Henle
    • Impermeable to water
    • Some Na+ permeability -> Due to active transport of Na+
    • Low urea permeability
159
Q

What are the two divisions of the distal tubule and the collecting duct?

A
  • Distal tubule / Outer medullary collecting duct
  • Inner medullary collecting duct
160
Q

Compare the water, sodium and urea permeability of the distal tubule/outer medullary collecting duct and the inner medullary collecting duct.

A

Distal tubule/outer medullary collecting duct:

  • Water permeability increased by ADH
  • Low Na+ permeability -> Due to active transport of Na+
  • Impermeable to urea

Inner medullary collecting duct:

  • Water permeability increased by ADH
  • Low Na+ permeability -> Due to active transport of Na+
  • Urea permeability increased
161
Q

Draw a table to compare the permeability of the various segments of the nephron to water, sodium and urea.

A
162
Q

Can all of the ascending limb of the loop of Henle acrtively tarnsport sodium ions?

A

No, only the thick ascending limb of the loop of Henle (the upper part). This is because there is insufficient ATP production deep in the medulla.

163
Q

Only the thick ascending limb of the loop of Henle can actively transport sodium from the filtrate. Why then can sodium also be reabsorbed in the thin ascending limb of the loop of Henle?

A

Reabsorption of water in the descending limb of the loop of Henle concentrates the salt in the filtrate and provides a gradient for the passive reabsorption in the thin ascending limb.

164
Q

According to the spec, what is the purpose of the counter-current multiplication in the loops of Henle?

A
  • To establish a cortico-papillary interstitial osmotic gradient.
  • This gradient ensures that there is a concentration gradient between the collecting duct lumen and the interstitial fluid at all points along the collecting duct (for water reabsorption, if required)
165
Q

What is the cortico-papillary interstitial osmotic gradient?

A
  • It is the osmotic gradient between the cortex and papilla (in the medulla) of the kidney
  • It is essentially a gradient from low to high osmolarity as you go from the outside to the inside of the kidney
  • It is set up by the counter-current multiplication in the loop of Henle
166
Q

What are the two mechanisms involved in the counter-current multiplication in the loop of Henle?

A
  • NKCC co-transport
  • Urea concentration in the interstitial space
167
Q

What is the ‘single effect’?

A
  • The active absorption of sodium ions by the thick ascending loop of Henle.
  • It initiates a series of events that lead to counter-current multiplication
168
Q

Describe the reabsorption of sodium ions in the thick ascending loop of Henle (i.e. the ‘single effect’).

A
  • Na+/K+-ATPase on the basolateral membrane creates a sodium gradient inwards across the apical membrane
  • This is used by an NKCC (a carrier that moves 1 sodium, 1 potassium and 2 chlorines) on the apical membrane
  • The potassium diffuses back out across the apical membrane trhough channels
  • The sodium is pumped out via the ATPase and chloride also exits on the basolateral side by diffusion through channels
  • The net result is the absorption of sodium and chloride into the interstitial fluid, so that there is hypertonicity that can be used to extract water from the descending limb
169
Q

What is NKCC and how can it be regulated?

A
  • A carrier that uses a sodium gradient to transport 1 Na+, 1 K+ and 2 Cl- into cells of the thick ascending loop of Henle across the apical membrane
  • It can be stimulated by ADH (via V1 receptors on the basolateral membrane that are coupled to PLC -> So that the IP3 cascade leads to phosphorylation of NKCC)
  • It can be inhibited by loop diuretics, such as furosemide
170
Q

Describe how counter-current multiplication in the loop of Henle works.

A

1) Thick ascending loop of Henle

  • Active transport of sodium (and diffusion of chloride that follows it) out of thick ascending loop of Henle
  • Water does not follow because the thick ascending loop is impermeable to water (thus the name ‘diluting segment’ of the loop of Henle)

2) Descending loop of Henle

  • Water moves out of the descending loop of Henle due to the hypertonicity of the interstitial fluid created by the thick ascending loop
  • The filtrate becomes gradually more concentrated

3) Thin ascending loop of Henle
* Sodium is able to passively diffuse into the interstitial space

There is a snowball effect where this cycle self-reinforces. The resulting axial hypertonicity gradient in the medulla can be used to extract water from the collecting duct.

171
Q

Is the concentration of the interstitial fluid greater next to the bottom or top of the loop of Henle?

A

At the bottom -> This is the cortico-papillary interstitial gradient.

172
Q

Draw the process of counter-current multiplication in the loop of Henle (showing how the cortico-papillary interstitial gradient is produced).

A
173
Q

How is urea involved in the formation of dilute and concentrated urine?

A
  • ADH increases the permeability of the collecting duct to both urea and water
  • Urea is responsible for up to 50% of the osmolarity of the inner medullary interstitial fluid
  • Movement of urea into the interstitial space of the inner medulla near the collecting duct draws water out of the collecting duct, helping concentrate the urine
174
Q

What is the evidence for the importance of urea in creating concentrated urine?

A

Animals on low protein diets tend to produce more dilute urine.

175
Q

How is urea reabsorbed into the interstitial fluid in the inner medullary collecting duct and how is this mediated?

A
  • It occurs via facilitated diffusion proteins called UT
  • This is upregulated by ADH
176
Q

What happens to urea after it is reabsorbed into the interstitial fludi from the collecting duct?

A
  • The loop of Henle has a low permeability to urea, so the urea can be passively reabsorbed into the renal tubule
  • This ensures that the urea doesn’t pass back into the blood
177
Q

Describe briefly the role of NKCC and urea in creating the cortico-papillary interstitial osmotic gradient.

A
  • NKCC -> Involved in beginning the snowball effect that concentrates the interstitial fluid with salt
  • Urea -> Further concentrates the interstitial space depending on release from the collecting duct (upregulated by ADH)
178
Q

Compare the permeability of the two limbs of the vasa recta in the kidneys.

A

Both limbs have the same permeability, which is why they are a counter-current exchanger, not a counter-current multiplier.

179
Q

What do the vasa recta deliver and absorb?

A
  • Deliver nutrients to the medulla
  • Remove reabsorbed water
180
Q

What is the purpose of the counter-current exchange system in the vasa recta?

A

It helps minimise the washing away of solutes in the interstitial fluid by the blood. This helps maintain the gradient for the reabsorption of water from the collecting duct if necessary.

181
Q

Describe the principle of how the counter-current exchanger of the vasa recta work and how it can be regulated.

A
  • In the descending limb, the water moves out of the vessel due to the surrounding hypertonic interstitial fluid
  • Solutes also diffuse into the vessel down their concentration gradient
  • The gradually makes the blood more concentrated, so after it turns the hairpin loop, solutes diffuse out of the blood into the interstitial fluid and water diffuses back in
  • This keeps the solutes trapped in the interstitial fluid (which is important), while water is reabsorbed
  • ADH can slow blood flow, so there is more time for these equilibritive processes to occur
182
Q

What are the 4 actions of ADH in concentrating urine?

A
  1. Insertion of aquaporins II in collecting duct principle cells
  2. Activation of NKCC in thick ascending loop of Henle
  3. Activation of urea transporters in the inner medullary collecting duct principle cells
  4. Slowing of the blood flow through the vasa recta
183
Q

What is the defining property of the collecting duct that allows it to regulate extracellular volume and osmolarity?

A
  • The capacity to separate water absorption from solute absorption
  • This goes against the natural tendency of water to follow solutes
184
Q

Describe the hormones that regulate water retention and sodium retention in the collecting duct.

A

Water:

  • ADH -> Increases water retention

Salt:

  • Angiotensin/Aldosterone -> Increase sodium retention
  • ANP (Atrial natriuretic peptide) -> Decrease sodium retention
185
Q

Draw and explain a diagram to show how water retention and sodium retention are linked.

A
  • When there is increased intake of sodium, there is increased concentration and osmolarity of body fluid
  • ADH increases water retention, so concentration falls but volume increases
  • ANP increases salt excretion (while angiotensin-aldosterone system increases sodium retention, so it is downregulated)
  • Increased salt excretion leads to lower osmolarity, so ADH is down-regulated and water is not retained
  • This means that the volume also falls back to normal

In this way, the two mechanisms allow maintenance of osmolarity and volume.

186
Q

Is GFR changeable?

A
  • Generally, it remains constant in response to blood pressure, at around 125ml/min, due to the Bayliss effect and tubuloglomerular feedback
  • However, it CAN change independently of blood pressure -> For example, if renal plasma flow is reduced
187
Q

Are the processes in different segments of the renal tubule interlinked?

A
  • Yes, the functional activity of each nephron segment depends on what happened in previous segments
  • There is intrinsic and extrinsic regulation
188
Q

What are the two stages in the reabsorptive process in the proximal tubule?

A
  • Across epithelium into interstitial fluid -> Active Na+ transport provides primary driving force for isotonic fluid movement of solutes and water across epithelium
  • From interstitial fluid into blood -> Fluid and solute uptake into peritubular capillaries is driven by Starling forces
189
Q

What are the different ways that the reabsorptive process in the proximal tubule can be regulated?

A
  • Glomerulotubular balance (DO NOT confuse with tubuloglomerular feedback)
  • Hormones
    • Angiotensin II (+ Acidosis)
    • Parathyroid hormone
  • Sympathetic nervous system
190
Q

What is glomerulotubular balance?

A
  • The phenomenon whereby a constant fraction of the filtered load of the nephron is resorbed across a range of Glomerular Filtration Rates (GFR)
  • In other words, if the GFR spontaneously increases, the rate of water and solute resorption in the tubule proportionally increases, thus maintaining the same fraction the filtered load being resorbed.
191
Q

Demonstrate glomerulotubular balance on a graph.

A
  • The graph shows how delivery to the distal tubule changes as GFR changes
  • Line 1 is if no reabsorption occured
  • Line 2 is if reabsorption was always constant
  • Line 3 is with glomerulotubular balance (reabsorption proportional to GFR)
192
Q

By what mechanism does glomerulotubular balance occur?

A

There are two main mechanisms:

  • Increased GFR causes greater rate of transport by symports (e.g. Na+-glucose)
  • Starling forces determine balance of uptake into capillaries vs paracellular backflux into tubule lumen
193
Q

Is all of the water and solutes that are reabsorbed into the interstitial fluid at the proximal tubule reabsorbed into the blood? Draw a diagram to show this.

A

No, some backflux occurs into the lumen of the tubule (shown by arrow 3). This is typically much less than the reabsorption into the blood (arrow 2).

194
Q

Describe how Starling forces maintain glomerulotubular balance when GFR is reduced due to efferent arteriole dilation.

A
  • Efferent arteriole dilation reduces GFR, but increases hydrostatic pressure in the efferent arteriole
  • This means that the Starling forces are altered and there is less reuptake into the blood and more backflux into the lumen of the proximal tubule
  • As a result, the drop in GFR does not cause such a large drop in the flow of filtrate into the distal tubule (i.e. a roughly constant delivery of filtrate to the distal tubule occurs at all GFR values)
195
Q

What fraction of the load (water and solutes) are reabsorbed at the proximal tubule?

A

About 2/3rds

196
Q

Describe the hormonal control of the proximal tubule.

A

Na+/H+ exchanger on the basolateral membrane:

  • Stimulated by angiotensin II, acidosis and sympathetic nerves (by activation of adenylate cyclase)
  • Inhibited by parathyroid hormone (by inhibition of adenylate cyclase)

The exchanger is involved in the reuptake of bicarbonate and then chloride ions from the tubule lumen. The parathyroid hormone is involved in increasing calcium reuptake in times of hypocalcaemia. Sympathetic stimulation is important in raising blood pressure (e.g. in response to haemorrhage).

197
Q

Describe the nervous control of the proximal tubule.

A
  • Na+/H+ exchanger on the basolateral membrane is stimulated by sympathetic activity, increasing sodium reuptake.
  • This is important to raise blood pressure (since water follows the

Stimulated by angiotensin II and acidosis (by activation of adenylate cyclase)

Inhibited by parathyroid hormone (by inhibition of adenylate cyclase)

The exchanger is involved in the reuptake of bicarbonate and then chloride ions from the tubule lumen.

198
Q

What are the different ways that the reabsorptive process in the loop of Henle can be regulated?

A
  • Load-dependent absorption
  • Hormones
    • ADH
    • Aldosterone
    • Glucocorticoids
199
Q

Describe the hormonal control of the reabsorptive processes in the loop of Henle.

A

NKCC transport protein is stimulated by:

  • ADH
  • Aldosterone
  • Glucocorticoids

These therefore increase sodium reabsorption.

200
Q

The reabsorption of sodium in the loop of Henle is load-dependent. What fraction of the filtered load is reabsorbed in the loop of Henle?

A

20%

201
Q

Describe how the reabsorption of sodium in the loop of Henle is load dependent.

A

The reabsorption is essentially dependent on the flow rate:

  • If the flow rate is increased, there is less time for passive sodium reabsorption in the thin ascending loop of Henle
  • So more sodium reaches the thick ascending loop of Henle
  • However, this extra sodium load is dealt with by increased activity of the NKCC (‘mopping up’)
  • Increased salt delivery to the macula densa also triggers tubuloglomerular feedback

These processes help to ensure that a constant sodium load is delivered to the distal tubule.

202
Q

Aside from decreasing the GFR, how does increased flow past the macula densa trigger feedback?

A

It decreases renin release from granular cells in the afferent arteriole wall.

203
Q

What are the different segments of the distal nephron? What is the function of each?

A
  • Distal convoluted tubule -> Sodium-chloride co-transport reabsorption
  • Short connecting tubule -> Calcium reabsorption
  • Connecting tubule -> Tight epithelium for Na+, Cl-, K+ and H+ fine tuning
  • Collecting duct -> Tight epithelium for Na+, Cl-, K+ and H+ fine tuning

The epithelia along the distal nephron become gradually tighter, so that the transport processes become simpler.

204
Q

What transport processes occur in the distal tubule? How is this regulated?

A
  • It continues the reabsorption of the NaCl from the filtrate
  • It does this using a Na+-Cl- co-transporter on the apical membrane (working in conjunction with the Na+/K+-ATPase on the basolateral membrane)
  • It is stimulated by angiotensin II and aldosterone
  • It is inhibited by thiazides

Since the process is carrier mediated, reuptake is proportional to the load.

205
Q

What fraction of the filtered load is reabsorbed in the distal tubule?

A

7%

206
Q

What transport processes occur in the short connecting tubule? How is this regulated?

A
  • Reabsorption of calcium by a similar process to the one in the proximal tubule
  • It can be upregulated by parathyroid hormone
207
Q

What transport processes occur in the collecting tubule and collecting duct? How is this regulated?

A
  • Fine tune the composition of the urine by:
    • Reabsorption of Na+ and Cl- (and sometimes water)
    • Secretion of K+ and H+
208
Q

What are the two types of cell in the collecting tubule and collecting duct? What does each do?

A

Principal cells:

  • Reabsorb about 5% Na+ through amiloride-sensitive channels
  • Reabsorb H2O (through regulated aquaporin channels)
  • Secrete K+ through channels

Intercalated cells:

  • Passive Cl- absorption
  • Active H+ secretion
209
Q

Give a summary of the transport processes in the distal nephron.

A
210
Q

How does reabsorption of sodium from the collecting tubule and collecting duct occur?

A

Through amiloride-sensitive sodium channels.

211
Q

What is the function of principal cells in the collecting tubule and collecting duct?

A
  • Reabsorb of Na+ through amiloride-sensitive channels
  • Reabsorb H2O through regulated aquaporin channels
  • Secrete K+ through channels
212
Q

What is the function of intercalated cells in the collecting tubule and collecting duct?

A

Intercalated cells:

  • Passive Cl- reabsorption
  • Active H+ secretion (H+ absorption in alkalosis)
213
Q

What is the function of aldosterone in the body?

A
  • It acts to conserve sodium.
  • It has the opposite function of ANP.
214
Q

What is the function of ANP in the body?

A
  • Causing a reduction in expanded extracellular fluid volume by increasing renal sodium excretion.
  • It has the opposite role to aldosterone.
215
Q

What does ANP stand for?

A

Atrial natriuretic peptide

216
Q

What is the purpose of hydrogen ion secretion into the tubular fluid at the collecting tubule and collecting duct?

A

The hydrogen ions serve to regenerate bicarbonate ions that have been consumed by buffering non-volatile acid.

217
Q

Draw a diagram to show the processes by which sodium ions are reabsorbed from the tubular fluid, and potassium ions and hydrogen ions are secreted into the fluid.

A
218
Q

How does aldosterone affect sodium reabsorption, and potassium and hydrogen secretion in the collecting duct? [IMPORTANT]

A

Effects on the principle cells:

  • Aldosterone stimulates sodium reabsorption from the tubular fluid
  • It also stimulates potassium secretion into the tubular fluid, since potassium secretion is proportional to sodium reabsorption (due to the Na+/K+-ATPase)

Effects on the intercalated cells:

  • Aldosterone stimulates hydrogen secretion from the tubular fluid
219
Q

Which channel is responsible for sodium reabsorption in the collecting duct? What can a mutation in it result in?

A
  • ENaC -> Epithelial sodium channel
  • A mutation in ENaC leads to constitutive activation
  • The pseudohyperaldosteronism which results is called Liddle’s disease
220
Q

Draw the renin-angiotensin-aldosterone system. [IMPORTANT]

A
221
Q

What triggers the renin-angiotensin-aldosterone cascade?

A

A drop blood pressure and fluid volume causes granular cells in the afferent arteriole walls in the kidney to release renin.

222
Q

What does renin do?

A

Converts angiotensinogen to angiotensin I.

223
Q

Where is angiotensinogen produced?

A

In the liver.

224
Q

What converts angiotensin I into angiotensin II?

A

ACE (angiotensin converting enzyme).

225
Q

Where is ACE produced?

A

In the lungs.

226
Q

What are the actions of angiotensin II?

A
  • Causes vasoconstriction
  • Causes release of aldosterone

Other actions:

  • Stimulates sodium reabsorption at several renal tubular sites
  • Stimulates ADH release from the posterior pituitary
  • Stimulates thirst centers within the brain
  • Enhaces sympathetic activity
  • Stimulates cardiac hypertrophy and vascular hypertrophy
227
Q

How does angiotensin increase sodium reabsorption at the renal tubule?

A
  • Stimulates Na+/H+ exchangers located on the apical membranes of cells in the proximal tubule and thick ascending limb of the loop of Henle
  • Stimulates apical Na+ channels in the collecting duct
228
Q

What is aldosterone and where is it released from?

A
  • It is a steroid hormone
  • Released from the adrenal cortex
229
Q

How does angiotensin II cause release of aldosterone?

A

It binds to AT1 (angiotensin receptors) on the adrenal cortex.

230
Q

What cells does aldosterone act on? [IMPORTANT]

A

Principle cells of the collecting duct.

231
Q

By what mechanism does aldosterone have an effect on principle cells of the collecting duct?

A
  • It binds to a receptor in the cytoplasm
  • This causes translocation of the receptor to the nucleus
  • This induces the transcription of proteins that are involved in the reabsorption of sodium from the lumen of the collecting duct:
    • Epithelial sodium channel (ENaC)
    • Basolateral Na+/K+-ATPase
    • Proteins involved in ATP production
  • Aldosterone also have must faster effects by increasing the activity of the channels by protein kinases that phosphorylate the transport proteins
232
Q

What are some inhibitors for the different stages of the renin-angiotensin-aldosterone system?

A
  • Renin -> Inhibited by enalkiren
  • ACE -> Inhibited by captopril
  • AT1 receptor -> Inhibited by saralasin
233
Q

What is an antagonist for aldosterone receptors?

A

Spirolactone

234
Q

Draw some graphs to show the effect of aldosterone on sodium, potassium and chloride excretion in the urine.

A
235
Q

What is natriuresis and what hormone can stimulate it?

A
  • Loss of sodium in the urine
  • It is stimulated by ANP (atrial natriuretic peptide)
236
Q

What is ANP released from and when?

A

Atria of the heart, when they are stretched.

237
Q

What is the general action of ANP and by what mechanism is this achieved?

A
  • It antagonises the renin-angiotensin-aldosterone system, so that blood pressure falls and salt retention is decreased
  • It does this by raising intracellular cGMP levels
238
Q

Describe all of the effects of ANP.

A
  • Afferent arteriole dilation and efferent arteriole constriction -> Increased GFR
  • Reduces renin release
  • Reduces aldosterone release
  • Inhibits angiotensin II actions in PT and systemic circulation
  • Reduces ADH release and inhibits ADH actions
  • Inhibits aldosterone action

Overall this results in increased filtration but reduced sodium reabsorption, so salt is lost in the urine.

239
Q

What is the main stimulus for the release of ADH?

A
  • Increased osmolarity of the blood.
  • It can also be affected by changes in blood volume, but much greater changes are required for this to happen.
240
Q

What are the different types of diuretics you need to know about?

A
  • Loop diuretics
  • Thiazide diuretics
  • Osmotic diuretics
  • Potassium-sparing diuretics
  • Carbonic ahydrase inhibitors
241
Q

What are loop diuretics used for? Why?

A
  • Treatment of heart failure and hypertension (i.e. when a rapid diuresis is needed in emergencies)
  • Can also be used in the longer term when weaker diuretics (thiazides) are found to be insufficient.
  • They are also used occasionally to correct some electrolyte disturbances, particularly hypercalcaemia.

This is because of a short half-life in the plasma since they are actively excreted in the proximal tubule as well as being filtered at the glomerulus. For chronic conditions, they can be given orally.

242
Q

What is the most common loop diuretic?

A

Furosemide

243
Q

How do loop diuretics work?

A
  • Inhibit the NKCC (Na/K/2Cl transporter) in the thick ascending limb of the loop of Henle -> This is a site of significant sodium absorption, so sodium reabsorption into the interstitial fluid is reduced
  • So more sodium remains in the tubule and less is the interstitial fluid, so there is less of an osmotic gradient for water reabsorption in the collecting duct
244
Q

Aside from inhibition of the NKCC in the ascending loop of Henle, what is the additional effect of loop diuretics? [EXTRA]

A

They are vasodilators of:

  • Systemic resistance arterioles -> Useful in lowering arterial pressure in hypertension and in reducing peripheral resistance in cardiac failure
  • Renal resistance arterioles -> Useful in increasing GFR and so potentially increasing diuresis
  • Vasa recta of the renal medulla -> Resulting in a “washout” of the accumulated osmotically active substances of the medullary interstitium, and so further reducing the osmotic potential there and increasing the potency of the diuresis
245
Q

What are some of the side-effects of loop diuretics?

A
  • Hypokalaemia
  • Hypovolemia

Both of these are classic diuretic side effects that are discussed on later flashcards. Loop diuretics also result in calcium and magnesium loss, which relates to the loss of the charge gradient normally generated by the NKCC2 pump, as shown in the diagram.

246
Q

For loop diuretics, give a summary of:

  • Uses
  • Common example
  • Mechanism of action
  • Side-effects
A
  • Uses -> Heart failure and hypertension (acutely and chronically if needed), Correcting electrolyte balances
  • Common example -> Furosemide
  • Mechanism of action -> Inhibition of NKCC in thick ascending loop of Henle
  • Side-effects -> Hypokalaemia, Hypovolemia, Calcium and magnesium loss
247
Q

What are thiazide diuretics used for?

A
  • Treatment of heart failure and hypertension, just like loop diuretics.
  • Thiazides are less potent than loop diuretics, and are usually used as a first attempt at diuretic therapy, with a switch to loop diuretics if the thiazide’s effect is not strong enough.
248
Q

What is the most common thiazide diuretic?

A

Bendroflumethiazide

249
Q

How do thiazide diuretics work?

A
  • Inhibit the sodium-chloride symporter (NCC) on the luminal (apical) surface of the distal convoluted tubule.
  • More sodium therefore remains in the lumen, which causes more water to remain in the lumen, increasing the volume of urine produced.
250
Q

Compare the effects of loop diuretics and thiazide diuretics on calcium excretion.

A
  • Loop diuretics increase calcium excretion
  • Thiazide diuretics reduce calcium excretion -> This can be used in treatment of conditions such as stone formation in the urinary tract
251
Q

What are some of the side-effects of thiazide diuretics?

A
  • Hypokalaemia
  • Hypovolemia

These are the classic side-effects of diuretics, including loop diuretics.

252
Q

Compare the action of loop and thiazide diuretics.

A
  • Both act by reducing the reabsorption of salt from the renal tubule
  • However, loop diuretics act on the thick ascending loop of Henle NKCC, while thiazide diuretics act on the distal tubule NaCl transporter
  • Loop diuretics are more potent and involve a greater loss of potassium
253
Q

For thiazide diuretics, give a summary of:

  • Uses
  • Common example
  • Mechanism of action
  • Side-effects
A
  • Uses -> Heart failure and hypertension, Occasionally in treatment of stone formation in the urinary tract
  • Common example -> Bendroflumethiazide
  • Mechanism of action -> Inhibition of NaCl transporter in the distal tubule
  • Side-effects -> Hypokalaemia, Hypovolemia
254
Q

With which types of diuretics is potassium loss a problem?

A

Loop diuretics and thiazide diuretics

255
Q

Describe how diuretic drugs can cause excess potassium loss and thus hypokalaemia.

A

Directly:

  • Diuretics cause an increased amount of sodium to remain in the renal tubule (e.g. by inhibition of the NKCC or NaCl transporter)
  • This means that there is greater reuptake of sodium in the distal convoluted tubule and collecting duct, which requires the Na+/K+-ATPase that pumps potassium into the urine

Secondary effect:

  • The effects of the diuretic drug activate the juxtaglomerular apparatus, which responds by releasing renin
  • This leads to the eventual release of aldosterone, which:
    • Increases activity of the Na+/K+-ATPase in the distal nephron (a rapid response)
    • Causes the transcription of more ion channels and transporters (for the luminal surface) and of more Na+/K+-ATPases (for the basolateral surface)

Overall, the increased reuptake of sodium in the distal tubule and collecting duct means that there is a stronger electrochemical gradient for potassium and hydrogen secretion into the urine.

256
Q

Why does aldosterone affect the hydrogen secretion into the urine of the distal tubule and collecting ducts?

A
  • It increases reuptake of sodium in the distal tubule and collecting duct by various methods (see flashcard)
  • This means that there is a stronger electrochemical gradient for potassium and hydrogen secretion into the urine.
257
Q

What condition relating to hormones can diuretics cause?

A

Secondary hyperaldosteronism

258
Q

What is hyperaldosteronism?

A
  • A disease in which the adrenal glands make too much aldosterone
  • This leads to hypertension (high blood pressure) and low blood potassium levels.
259
Q

Which diuretics carry a higher risk of hypokalaemia: loop or thiazide?

A

Loop, because they stimulate greater sodium uptake from the tubular fluid.

260
Q

What is typically prescribed along with loop diuretics?

A

A potassium supplement

261
Q

Do loop diuretics and thiazide diuretics cause acidaemia or alkalaemia?

A

Alkalaemia (due to increase H+ secretion into the urine).

262
Q

What are potassium-sparing diuretics used for?

A

They are used when:

  • Aldosterone levels are too high in disease, such as:
    • Cardiac failure
    • Hypertension
  • Aldosterone levels are too high as a natural response to diuretic therapy (sinc aldosterone conserves water indirectly by conserving salt)
263
Q

How do potassium-sparing diuretics work?

A

They block the actions of aldosterone (a sodium-conserving hormone) by:

  • Antagonising aldosterone receptors
  • Inhibit the epithelial Na+ channel in the collecting duct (so that less sodium is reabsorbed from the urine in the collecting duct)
264
Q

What are the two main types of potassium-sparing diuretics?

A
  • Aldosterone antagonists
  • Inhibitors of the epithelial Na+ channel in the collecting duct
265
Q

What are the most common potassium-sparing diuretics?

A
  • Aldosterone antagonists -> Spironolactone
  • Inhibitors of the epithelial Na+ channel in the collecting duct -> Amiloride
266
Q

Why might different diseases cause high levels of aldosterone that may be treated using potassium-sparing diuretics?

A
  • In cardiac failure -> Aldosterone levels are elevated because of:
    • Reduced renal perfusion
    • Increased sympathetic drive to the kidney (due to the baroreceptor reflex, responding to a fall in arterial blood pressure)
  • In hypertension -> Some patients have elevated plasma renin and aldosterone levels, possibly reflecting a primary disease process in the kidney
267
Q

Why may aldosterone levels be raised in fiuretic therapy?

A
  • Diuresis activates the juxtaglomerular apparatus, which releases renin and causes the production of aldosterone.
  • Potassium-sparing diuretics may be used in these cases.
268
Q

What is usually secondary to loop and thiazide diuretic use? Why is this a nuisance?

A
  • Hyperaldosteronism
  • This is a nuisance because it increases sodium reabsorption in the distal tubule (so reducing the effects of the primary diuretic drug) and in increasing sodium reabsorption it causes the loss of potassium ions and protons at the same site.
269
Q

How are potassium-sparing diuretics used in conjunction with other drugs?

A

Potassium-sparing diuretics are sometimes added to loop diuretics or (less commonly) thiazides to reduce the risk of hypokalaemia.

270
Q

What are the side-effects of potassium-sparing diuretics?

A

They do not typically have many side-effects unless too much is given, in which case they can result in hyperkalaemia.

271
Q

For potassium-sparing diuretics, give a summary of:

  • Uses
  • Common examples
  • Mechanism of action
  • Side-effects
A
  • Uses -> Treating hyperaldosteronism in heart failure and hypertension, Used alongside other diuretics
  • Common examples -> Spironolactone, Amiloride
  • Mechanism of action -> Antagonist of aldosterone receptors (spironolactone), Blocker of sodium channels in collecting duct (amiloride)
  • Side-effects -> Potential hyperkalaemia
272
Q

What are osmotic diuretics used for?

A
  • Osmotic diuretics are used rarely, because they are difficult to control without causing side-effects
  • But they are useful when retained fluid must be removed quickly -> e.g. Cerebral oedema.
273
Q

What is the most common osmotic diuretic?

A

Mannitol

274
Q

How do osmotic diuretics work?

A

In treating oedema:

  • Osmotic diuretic is infused into the blood (through a venous cannula);
  • Osmotic diuretic increases the osmotic pressure of the plasma, causing water to move out of the inflamed area and into the blood

In the nephron:

  • Osmotic diuretic is easily filtered at the glomerulus and so it moves from the blood into the urine readily
  • This increases the osmotic potential of the fluid in the tubule, so that there is less fluid reabsorption into the interstitial fluid
275
Q

What are the side-effects of osmotic diuretics?

A
  • If the osmotic diuretic is given too quickly, water will be drawn out of the inflamed area more quickly than it can be filtered: in this case, the effective circulating volume increases and there is a risk of overloading the heart, causing heart failure.
  • Dehydration can also occur if the osmotic diuretic is given for too long
276
Q

What are two examples of endogenous osmotic diuretics? What is the result of this?

A
  • Diabetes mellitus -> Glucose acts as the diuretic
  • Glomerulonephritis -> Protein acts as the diuretic

Both of these situations can lead to quite rapid dehydration of the patient, indicating the potency of the osmotic diuretic mechanism.

277
Q

What are the uses of carbonic acnhydrase inhibitor diuretics?

A

They are very rarely used clinically as a diuretic, but the diuretic effect is a notable side-effect when they are used to treat other conditions.

278
Q

What is the most common carbonic anhydrase inhibitor diuretic?

A

Acetazolamide

279
Q

How do carbonic anhydrase inhibitor diuretics work?

A
  • Carbonic anhydrase important in the metabolism of bicarbonate in the kidney.
  • Inhibition of this enzyme results in a weak diuresis driven partly by excretion of sodium bicarbonate.
  • The loss of bicarbonate leaves the patient with an acidaemia, and so the diuresis is self-limiting (because the amount of bicarbonate being filtered falls as the patient becomes more acidaemic).
  • In the proximal tubule, carbonic anhydrase also indirectly influences chloride absorption (through its effects on bicarbonate), and so diuresis induced by acetazolamide is a mixture of sodium bicarbonate and sodium chloride.
280
Q

Aside from the core diuretics in the spec, what are some other types of diuretic? [EXTRA]

A
  • ADH antagonists
  • ANP agonists
  • Angiotensin antagonists
281
Q

Name the most common drug for each of these diuretic types:

  • Loop diuretics
  • Thiazide diuretics
  • Osmotic diuretics
  • Potassium-sparing diuretics
  • Carbonic anhydrase inhibitors
A
  • Loop diuretics -> Furosemide
  • Thiazide diuretics -> Bendroflumethiazide
  • Osmotic diuretics -> Mannitol
  • Potassium-sparing diuretics -> Sprinolactone + Amiloride
  • Carbonic anhydrase inhibitors -> Acetazolamide
282
Q

Give a summary of the mechanism of action of these diuretics:

  • Loop diuretics
  • Thiazide diuretics
  • Osmotic diuretics
  • Potassium-sparing diuretics
  • Carbonic anhydrase inhibitors
A
  • Loop diuretics -> Inhibit NKCC in thick ascending loop of Henle
  • Thiazide diuretics -> Inhbit NaCl transporter in distal tubule
  • Osmotic diuretics -> Increase osmotic potential of the tubular fluid
  • Potassium-sparing diuretics -> Antagonists of aldosterone or Inhibit sodium channels in the collecting duct
  • Carbonic anhydrase inhibitors -> Inhibit bicarbonate reabsorption in the proximal tubule
283
Q

Compare the half-life of loop diuretics and thiazide diuretics.

A

Loop diuretics are actively secreted into the proximal convoluted tubule as well as being filtered at the glomerulus, and so their plasma half-life is less than that of the thiazides (which are filtered but not secreted).

284
Q

Which diuretics also have a mild vasodilator effect?

A

Loop diuretics and thiazides

285
Q

Draw a diagram to summarise the integration of salt and water balance in the kidneys.

A
286
Q

Compare and explain the effects of drinking 1L of water and 1L of isotonic saline on urine flow.

A
  • Drinking water changes the osmolarity of the body fluids, so less ADH is released and so aquaporins are removed from the collecting duct membrane, which causes rapid water excretion
  • Drinking isotonic saline does not change the osmolarity of the body fluids, so there is no immediate change in ADH. However, naturiesis is preferred over sodium conservation, so salt is lost, diluting the urine and gradually increasing water loss due to this

In other words, with the saline you have to wait for the sodium excretion to drive water excretion, so it takes longer to return to the lower blood volume.

287
Q

Does it take longer to offload 1L of saline or 1L of water?

A

1L of saline, since the there is no reduction in ADH immediately.

288
Q

Which receptors detect changes that trigger ADH release? What other changes does this detection cause?

A
  • Osmoreceptors (of hypothalamus) -> Increase in osmolarity triggers ADH release
  • Baroreceptors -> Decrease in blood volume triggers ADH release

Detection by these receptors can also stimulate thirst.

289
Q

Aside from increasing water retention in the kidneys, what does ADH also do?

A

Stimulate vasoconstriction, increasing blood pressure.

290
Q

Draw a diagram to summarise control of blood osmolarity.

A
291
Q

What physiological changes trigger ADH release? What is the sensitivity to each?

A
  • Increased blood osmolarity (osmoreceptors)
    • Only a 2% change in osmolarity required to trigger significant ADH release
  • Decreased blood volume (baroreceptors)
    • Over 15% change in BP required to trigger significant ADH release

The sensitivity of osmoreceptors to blood osmolarity is increased when blood volume drops.

292
Q

What are the different sensors of the effective circulating volume of blood? How do they trigger a response in the kidneys?

A

Cardiovascular (result in changes to sympathetic nervous discharge):

  • Baroreceptors -> Carotid sinus + aortic arch
  • Stretch receptors -> Atria + pulmonary circulation
  • Pressure receptors -> Renal afferent arterioles

Renal (result in renin release from afferent arteriole):

  • Macula densa -> Senses Na+, Cl- reabsorption, which depends on GFR, which depends on ECV

Overall, increased sympathetic nervous system discharge and decreased distal flow (of NaCl) to the macula densa cause increased renin release.

293
Q

Where is renin released from?

A

Granular cells of the afferent arteriole

294
Q

What ultimate effects does renin lead to?

A
  • Sodium retention
  • Volume expansion
  • Vasoconstriction
295
Q

Describe the response of the macula densa to changes in the flow rate and NaCl reaborption in the distal tubule.

A
  • When the flow rate and NaCl reabsorption is increased, it is a marker of increased GFR and therefore high blood pressure and blood salts
  • Therefore, the macula densa releases ATP, which acts on the afferent arteriole and has 2 effects
  • ATP causes constriction of the afferent arteriole, decreasing GFR
  • Adenosine (a metabolite of ATP) also inhibits the release of renin, so salt retention is reduced and systemic vasodilation occurs
296
Q

What are some factors that stimulate and inhibit renin release?

A

Stimulated by:

  • Sympathetic nerve activity and circulating catecholamines
  • Prostagladins

Inhibited by:

  • Increased NaCl reabsorption across the macula densa
  • Angiotensin II
  • ADH
  • Increased stretch of juxtaglomerular cells
297
Q

What ion can affect the rate of release of aldosterone?

A
  • Increased plasma K+, since sodium reabsorption involves the sodium-potassium pump that causes the opposite flux of potassium.
  • This means that hyperkalaemia can be resolved by aldosterone.
298
Q

Does angiotensin cause greater constriction of the afferent or efferent renal arterioles?

A
  • Efferent
  • This is because this maintains higher peritubular pressure, so GFR remains high

Check this - Do the Starling forces balance this change?

299
Q

How does angiotensin II cause increased sodium reabsorption in the proximal tubule?

A
300
Q

Compare the sites of action of angiotensin II and aldosterone in terms of increasing sodium reabsorption.

A
  • Angiotensin II -> Proximal tubule
  • Aldosterone -> Collecting duct
301
Q

How does angiotensin II affect tubuloglomerular feedback?

A
  • It increases the sensitivity of TG feedback in response to changes in distal flow rate
  • This is due to a change in the affinity of the carriers that are transporting chloride across the macula densa cells
302
Q

How many sphincters does the bladder have? What is the type of muscle in each?

A
  • Internal -> Smooth muscle
  • External -> Striated muscle
303
Q

In males, where is the prostate positioned relative to the sphincters of the bladder?

A

It is between the internal and external sphincter

304
Q

Draw a schematic diagram for the male and female urinary tracts, starting with the bladder.

A
305
Q

What smooth muscle is found in the bladder?

A

Detrusor muscle

306
Q

The detrusor muscle acts as a…

A

Syncitium

307
Q

What is the function of the urothelium of the bladder?

A

Prevents penetration of urine into the detrusor muscle (due to its many tight junctions).

308
Q

What is the function of the suburothelium of the bladder?

A

Has a role in sensing the filling of the bladder.

309
Q

Describe which sympathetic, parasympathetic and somatic nerves (including nerve roots) innervate the bladder and its sphincters.

A
  • Parasympathetic
    • Pelvic nerve (S2-S3) -> Acts on bladder
  • Sympathetic
    • Hypogastric nerve (L2) -> Acts on bladder and internal sphincter
  • Somatic
    • Pudendal nerve (S2-S4) -> Acts on external sphincter
310
Q

Which parasympathetic nerve, including nerve roots, innervates the bladder? What receptors does it act on?

A
  • Pelvic nerve (S2-S3)
  • Acts on M3 receptors
311
Q

Which sympathetic nerve, including nerve roots, innervates the bladder? What receptors does it act on?

A
  • Hypogastric nerve (L2)
  • Acts on β3 receptors
312
Q

Which sympathetic nerve, including nerve roots, innervates the internal sphincter of the bladder? What receptors does it act on?

A
  • Hypogastric nerve (L2)
  • Acts on α1 receptors
313
Q

Which somatic nerve, including nerve roots, innervates the external sphincter of the bladder? What receptors does it act on?

A
  • Pudendal nerve (S2-S4)
  • Acts on nicotinic receptors
314
Q

Summarise the effects of parasympathetic and sympathetic stimulation of the urinary tract.

A
  • Parasympathetic stimulation leads to:
    • Contraction of the bladder
  • Sympathetic stimulation
    • Relaxation of the bladder
    • Contraction of the internal sphincter
315
Q

Which nervous system also involves sensory nerves that innervate the lower urinary tract? What is their function?

A
  • Pelvic nerves of the parasympathetic nervous system
  • Detect the extent of stretch in the walls of the bladder
316
Q

What effect does stimulation of the pudendal nerve have on the external sphincter of the bladder?

A

It causes it to contract (via nicotinic receptors).

317
Q

Describe the nervous response to an empty bladder.

A
  • The lack of stretch of the bladder is detected by sensory pelvic nerve fibres (parasympathetic), feeding back to the sacral spinal cord
  • This low level of firing ACTIVATES the a fibre that causes firing of the hypogastric nerve (sympathetic) at the lumbar level
  • This causes relaxation of the bladder detrusor muscle and contraction of the internal sphincter
  • The brain/pons are also aware of the lack of sensory firing from the bladder, so they stimulate the hypogastric nerve and the pudendal nerve, while inhibiting the pelvic nerve
318
Q

What is micturition?

A

The act of urinating.

319
Q

Describe the nervous response to a full bladder (micturition).

A
  • The stretch of the bladder is detected by sensory pelvic nerve fibres (parasympathetic), feeding back to the sacral spinal cord
  • This high level of firing ACTIVATES a fibre that feeds directly back to a micturition centre in the brain
  • The brain/pons inhibit the hypogastric nerve and the pudendal nerve, while stimulating the pelvic nerve
  • There is also stimulation of interneurons that supply the thalamus and cerebral cortex, so you become aware of the sensation of needing to urinate
320
Q

What is the voiding (micrurition) reflex?

A

The nervous reflex that allows for urination to continue.

321
Q

Describe how the voiding (micturition) reflex works.

A
  • The stretch of the bladder is detected by sensory pelvic nerve fibres (parasympathetic), feeding back to the sacral spinal cord
  • This activates interneurons that activate the pelvic nerve (parasympathetic)
  • This allows for mictrurition to continue

NOTE: This is reflex arc, but it can also be influenced by the micturition centres in the brain (as described in a previous flashcard).

322
Q

Describe how the micturition reflex is affected by the volume of urine in the bladder.

A
  • The micturition reflex starts when the bladder is filled with around 200ml of urine -> It is a reflex, but the brain has conscious control over it, and can over-power it.
  • If the external sphincter does not relax, the bladder progressively relaxes. An additional increase in bladder volume reinitiates the cycle.
  • If the volume of urine exceeds 500ml, the internal sphincter may be forced to open -> This also leads to a reflexive relaxation of the external sphincter.
323
Q

At what volume of urine in the bladder does the micturition reflex start?

A

200ml

324
Q

At what volume of urine in the bladder does the micturition reflex typically lead to uncontrollable urge to urinate?

A

500ml

325
Q

How much urine remains in the bladder after urination?

A

Less than 10ml

326
Q

Why do infants not have control over their urination?

A

The required cortico-spinal connections not yet established.

327
Q

What are the two main types of urinary tract disorders?

A
  • Incontinence
  • Urine retention
328
Q

What are some factors that can result in incontinence?

A
  • UTIs
  • Pelvic floor injury
  • Elderly individuals
  • Nerve damage
    • Atonic bladder
    • Automatic bladder
    • Uninhibited neurogenic bladder
329
Q

How can UTIs result in incontinence?

A

Chemical stimuli increase bladder activity and hence the urge to void.

330
Q

Why do elderly individuals often experience incontinence issues?

A
  • Generic loss of muscle tone
  • Detrusor overactivity leading to overactive bladder
331
Q

What is an atonic bladder and how can it result in incontinence?

A
  • Caused by damage to sensory nerve fibers (e.g. crush injury to the sacral region)
  • Associated with overflow incontinence
332
Q

What is an automatic bladder and how can it result in incontinence?

A
  • Caused by spinal cord damage above sacral region
  • Micturition reflex intact, but control by the brain is impaired
333
Q

What is an uninhibited neurogenic bladder and how can it result in incontinence?

A
  • Caused by lack of inhibitory signals from the brain (due to partial damage of spinal cord or brain stem that interferes with most of the inhibitory signals)
  • Frequent and poorly controlled micturition
334
Q

What are two factors that can cause urinary retention?

A
  • Enlargement of the prostate gland (constricts the urethra)
  • Kidney stones
335
Q

How can urinary retention caused by an enlarged prostate by treated?

A

Using an α1 antagonist, such as Tamsulosin.

336
Q

What is an overactive bladder?

A

Where an individual experiences frequent and uncontrolled need to urinate.

337
Q

What are some possible causes of overactive bladder?

A
  • Increased afferent activity (from the parasympathetic pelvic nerve that innervates the bladder muscle)
  • Decreased inhibitory control in the CNS
  • Increased detrusor sensitivity to efferent stimulation
338
Q

What is the goal of therapy for overactive bladder?

A

To reduce bladder overactivity without interfering with normal micturition and without affecting other systems.

339
Q

What are some effective drugs for overactive bladder? What are their limitations?

A
  • Antimuscarinic drugs (e.g. oxybutynin)
    • Side effects: dry mouth and constipation (M3 receptors in salivary glands and gut)
  • Botulinum toxin
    • Administration is difficult
  • Resiniferatoxin and capsaicin (target sensory nerves)
340
Q

What are some experimental drugs that could be used to treat an overactive bladder?

A
  • β3 adrenoreceptor agonists
  • Phosphodiesterase type 5 inhibitors
341
Q

What drugs can be taken for incontinence and outflow obstruction?

A
  • Incontinence -> Muscarinic antagonists
  • Outflow obstruction -> Alpha-1 antagonists

YEAR 1 - Physiology and Pharmacology (Anton) (13 decks)

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