S2: Renal Blood Flow and Glomerular Filtration

Question 1

Why do the kidneys receive 20% of cardiac output when they are only about 0.5% of our body weight?

Answer 1

The kidneys receive very high flow compared the size of the organ.

This large flow is not related to metabolic need but rather to the function of the kidneys (filtering blood).

Question 2

What are the main functions of the kidney?

Answer 2

• To control volume and composition of body fluids
• To get rid of waste material from the body
• Acid-base balance
• It is an endocrine organ - EPO, renin, vitamin D

Question 3

What is the functional unit of the kidney?

Answer 3

Nephron

Question 4

What are the two parts of a nephron?

Answer 4

Glomerulus and Tubule

Question 5

What is the glomerulus contained in?

Answer 5

Bowman’s Capsule

Question 6

Describe the artery structure around the glomerulus

Answer 6

It has an artery entering called afferent arteriole which is wider than the artery leaving called efferent arteriole. This then goes on the become the peritubular capillaries which surround the tubule.

Question 7

How does blood and tubule meet?

Answer 7

Through the peritubular capillaries which come from the efferent arteriole

Question 8

What are the 2 sets of capillaries that the nephron has?

Answer 8

Glomerulus and Peritubular

Question 9

How many nephrons does each kidney contain?

Answer 9

1 million

Question 10

What are the two stages that urine is formed in?

Answer 10

1. The glomeruli produce the liquid

2. The tubule modifies its volume and composition

Question 11

Briefly describe vascular supply of a nephron

Answer 11

Blood flows through the renal artery and enters into the afferent arteriole. This connects to the ball shaped glomerular capillaries where fluid is filtered out (ultrafiltration). Blood leaves the glomerulus via the efferent arteriole which then leads to the peritubular capillaries (reabsorption takes place here where most of the tubular filtrate is taken back into the blood).

Question 12

Explain glomerular filtration

Answer 12

This is the first stage of urine production and is formed by passive ultrafiltration of plasma across the glomerular membrane as decribed by starlings principle of capillary fluid filtration (pressure change).

The rate at which fluid is being formed (GFR- glomerular filtration rate) is set by 2 things:

• Autoregulation
• Renal sympathetic vasomotor nerve activity

Blood is going to flow into afferent arteriole, into the glomerular capillaries and out the efferent arteriole. As it flows through, fluid is forced out into the urinary space of the Bowman’s capsule.
Importantly, the glomerulus is completely enclosed by epithelium of the Bowman’s capsule, though they are specialised to form podocytes.

Question 13

Why is reabsorption so high (119 ml reabsorbed from 120 ml/min filtrate)?

Answer 13

To prevent excess water loss from blood.

Also useful molecules such as glucose and AA is reabsorbed.

Question 14

What did Ludwig (1844) do?

Answer 14

He realised that glomerular fluid is a passive ultrafiltrate of plasma i.e. it is plasma from which proteins have been filtered out (so has similar composition just without as many proteins)

Question 15

What are the features of ultrafiltrate?

Answer 15

1. Small solutes such as NaCl, glucose and urea concentration in the fluid should equal the concentration in the plasma
2. Plasma protein concentration in the glomerular fluid is almost zero.
3. Net pressure drop across glomerular membrane drives ultrafiltration process

Question 16

What is proteinuria?

Answer 16

It is excess protein in the urine. This is routinely tested on wards and is a sign of renal/urinary tract disease.

Question 17

What is proteinuria?

Answer 17

It is excess protein in the urine. This is routinely tested on wards and is a sign of renal/urinary tract disease.

It can occur when filtration slits or basement membrane are damaged

Question 18

Explain how an imbalance of starlings forces drives glomerular fluid formation (filtration)

Answer 18

The main force pushing fluid out in capillary blood pressure (Pc)

Forces opposing this try and drive fluid into the capillary. These are plasma oncotic pressure (Pp) due to plasma proteins in the blood and pressure in the Bowman’s capsule trying to push fluid in (Pu)

Pc is roughly 50mmHg
Pp 25 mmHg
Pu 10 mmHg

Net effect of GF formation:

Pc - (Pp + Pu)

Question 19

Explain how For ultrafiltration, the net pressure favours the movement of fluid out of the capillary.

Answer 19

For ultrafiltration, the net pressure favours the movement of fluid out of the capillary.

As the blood flows through the capillary there is a slight drop in pressure from the afferent end to the efferent end. The plasma also gets more concentrated as the blood flows along due to fluid loss, an unusual effect observed just in the kidneys compared to other capillaries
However, along the whole capillary, despite the oncotic pressure rising, it is always less than Pc, meaning we get fluid filtration throughout the whole capillary (net filtration more than net absorptive force).

Question 20

What is the filtration fraction?

Answer 20

The proportion of fluid that is being filtered from the volume of blood flowing through.

The glomerulus has a filtration fraction of 20% which is very large compared to most capillary beds of 1%.

Question 21

Explain starlings force balance is reversed in the peritubular capillaries (rebsorption)

Answer 21

As blood travels out of the glomerulus and into the efferent arteriole, pressure starts to drop of colloid osmotic pressure (in blood) rises due to the fluid being lost in filtrate and protein remaining becoming more concentrated. Therefore Pp exerts a greater pulling force. It rises above hydrostatic BP and reabsorption of fluid back into the blood and surrounding tissue occurs.

This occurs in the PCT

Question 22

Describe the structure of pedicels

Answer 22

The epithelium of the bowmans capsule is invaginated to coat over the outer surface of the capillaries forming podocytes.

The podocytes cover the glomerular capillaries and give of feet like processes called pedicels. In between pedicels there are filtration slits.

Glomerular filtration emerges from the filtration slits

Question 23

What are fenestrations and basal lamina in bowmans capsule?

Answer 23

In capillary there is fenestrated endothelium, sitting on a basement membrane.

The fenestrae are areas where there are no membrane. The basal lamina surrounds the outside and this also has little gaps in it as it is a protein matrix.

Question 24

Explain the size of filtration slits, basal laminar and fenestae

Answer 24

Fenestrae 50-100nm
Basal Lamina
Filtration Slit 30nm

Question 25

An albumin molecule is 4nm

How come it doesn’t pass through the filtration slit?

Answer 25

The filtration slits are further subdivided into even smaller slits, in the formation of a central spine with lateral rungs sticking out.

The subdivision is made out of proteins nephrin and podocin.

Question 26

What proteins make the subdivision of filtration slits?

Answer 26

Nephrin and Podocin

Question 27

What causes nephrotic syndrome?

Answer 27

Deficiency of nephrin and podocin

Question 28

Which layer is the molecular sieve at bowmans capsule?

Answer 28

The glomerular membrane is three sieves in series of increasing fineness

1. RBC are too large to get through the fenestrations
2. Fibrinogen can pass through the fenestrations but are turned back at the basement membrane
3. Albumin can pass through the basal lamina but not through filtration slits.
   Evidence for this is by injecting myeloperoxidase,

Substances like water, glucose, NaCl, Urea, creatinine can freely move through.

Question 29

Explain intrinsic control of GFR (intra-renal)

Answer 29

BP often changes in daily life but we want to keep GFR constant. The internal mechanism doing this is called autoregulation.

Autoregulation is the intrinsic property of the kidney. GFR and renal blood flow are held constant over a range of arterial pressure

There are 2 mechanisms:

1. The bayliss myogenic response: due to direct vasoconstriction of afferent arteriole with an increase in perfusion pressure
2. Tubuloglomerular feedback (TGF): flow dependent signal detected in the macula densa that alters the tone of the afferent arteriole

Question 30

What is the Bayliss Myogenic Response?

Answer 30

Bayliss noticed if we had a 50% increase in pressure we only got a very small increase in flow, the reason is due to the afferent arteriole.
We see that when there is an increase in perfusion pressure there is an immediate increase in the vessel radius for a few seconds and blood flow goes up briefly.

But then what happens, is blood flow then quickly drops back to what it normally is and that is because of stretch of the smooth muscle in the afferent arteriole results in it then contracting to reduce the diameter and increase resistance. So the change in BP was not transmitted to change in GFR. Flow returns to normal in 30s.

What the kidneys do in the afferent arteriole, is that there is protection of the capillary pressure, by contraction of the afferent arteriole meaning there is an increased pressure drop. This means the capillary pressure is kept more or less the same.

So, changes in afferent arteriole resistance (precapillary) prevent changes in arterial pressure affecting capillary filtration pressure!
When the afferent arteriole is wide we have low resistance and Pc is close to Pa (arterial pressure)
When it is constricted, we have high resistance, a greater pressure drop and so Pc is much less than Pa

Question 31

What happens if BP drops below range of autoregulation?

Answer 31

e.g. in hypertension or shock

It will lead to oliguria (low urine output)

Question 32

What is tubulo-glomerular feedback (TGF)?

Answer 32

TGF is a second mechanism contributing to autoregulation.

Macula densa are specialised cells when tubule comes in contact with glomerulus.

If GFR is increased, flow through tubule increases due to more fluid which changes concentration of NaCl and therefore osmolality of fluid. This is picked up by macula densa (from thick ascending limb) which ATP signals and increases tone in afferent arteriole (it will constrict).

Leading to an increased resistance an increase pressure drop and decreased hydrostatic pressure in the glomerulus thus decreasing GFR.

Question 33

What does the macula densa do (except ATP signalling)?

Answer 33

Activate the RAAS which combats the effect of increased filtration by absorbing more

Question 34

Explain extrinsic control of GFR (neurohumoral)

Answer 34

This is through the renal sympathetic nerves (vasocontrictor, NA)

So the renal sympathetic nerves can affect the afferent/efferent arteriole and reduce GFR by re-setting the autoregulation to a lower level.

The role here is to conserve body fluid volume during physical stress. In shock these sympathetic actions are aided by circulating vasoconstrictor hormones such as adrenaline, angiotensin and vasopressin.

Question 35

3 conditions for the extrinsic control of GFR

Answer 35

• standing upright (orthostasis)
• heavy exercise
• haemorrhage and other forms of clinical shock

Question 36

Two Major Clinical Disorders of the GFR

Answer 36

1. Nephrotic syndrome (where glomeruli is too leaky to plasma proteins)

This leads to

- Proteinuria
- Hypoproteinaemia (low protein in blood)
    - Oedema (decreased oncotic pressure)

This response well to steroids

2. GFR is too low (more common)

• Chronic glomerulonephritis; whole glomerulus is replaced by collagen
• Chronic renal failure