Renal blood flow and glomerular filtration

Question 1

The 2 kidneys which represent about 0.5% of body weight receive nearly a quarter of the resting cardiac output, which is an exceptionally high flow for organs their size.

Why?

Answer 1

This large blood flow is clearly not related to the metabolic needs of the kidney but is a function of the major role that the kidney plays in the regulation of ECF and blood volume regulation and rapid waste disposal.

Question 2

Main functions of the kidney are: (5)

Answer 2

1. Control volume & composition of body fluids
2. To get rid of waste material from the body
3. Acid-Base balance
4. As an endocrine organ – EPO, Renin & Vit D activation
   5) gluconeogenesis

Question 3

Functional unit of kidney is nephron

what are the 2 elements?
how many in a kidney?
can kidney regenerate new ones?

Answer 3

• Average nephron ~4cm long
• Nephron has 2 elements – Bowmans capsule and tubule
• 1 million nephrons per kidney
• The kidney CAN NOT regenerate new nephrons.
• Therefore, you can still be able to function with one kidney or even a reduced function kidney

Question 4

nephron is unusual in that it has 2 sets of capillaries

what is unusual about the glomerulus blood network?
what does it form afterwards?

Answer 4

Within the Bowman’s Capsule is a tuft of blood vessels known as the glomerulus, which has an unusual arrangement in that it enters as an artery (afferent arteriole) and also leaves as an artery (efferent arteriole), before forming the peritubular capillaries around to the tubule.

Blood and the tubule again meet up along the peritubular capillaries.

Hence nephron is unusual in that it has 2 sets of capillaries = glomerular & peritubular.

Question 5

Urine Formation
2 stages

what happens to most of the fluid that is filtered out?

what urine output is considered renal failure?

Answer 5

1. Glomeruli produce the liquid
2. Tubules modifies its volume & composition

Nearly all of the fluid (and everything dissolved in it) are filtered through the glomerulus is reabsorbed back from the tubule into the blood, with the remainder being excreted as urine at a rate of 1ml/min (equivalent to ~1440ml/day or ~1.5L/day).

However, if your urine output is <5ml/day then this equates to renal failure.

Question 6

Stage 1: Glomerular Filtration

how is it formed?

Answer 6

Glomerular fluid is formed by passive ultrafiltration of plasma across the glomerular membrane, as described by Starling’s principle of capillary fluid filtration.

Question 7

Stage 1: Glomerular Filtration
Why such a huge filtration rate, namely 180 litre/day?

what is the gfr value typically?

Answer 7

• A high rate of formation of glomerular fluid is needed to wash out the waste products fast enough to keep their blood level low.

• Example; a human produces 36 g urea per day:
o Yet normal plasma urea is only 0.2 g/litre.
o To wash 36 g urea into the urine, 180litre of plasma have to be filtered per day (because 180L x 0.2 g/L = 36g).
o This is a glomerular filtration rate (GFR) of 120 ml/min

Question 8

The glomerular filtration rate (GFR) is set by (2)

Answer 8

o Autoregulation

o Renal sympathetic vasomotor nerve activity

Question 9

The glomerulus consists

3 layers?

Answer 9

The glomerulus consists of a clump of capillaries & Bowman’s capsule

The glomerulus is also completely enclosed by epithelium of the Bowman’s Capsule, they are specialised to form podocytes.

Question 10

Mechanism of Glomerular Fluid Formation

what is glomerular fluid?

what passes through completely?
what doesnt? clinical importance of this?

what drives the filtration?

Answer 10

Glomerular fluid is a passive ultrafiltrate of plasma.

The key features of glomerular filtration are:
• For small solutes, such as NaCl, glucose and urea, concentration in glomerular fluid = concentration in plasma.

• For plasma proteins, concentration in glomerular fluid = almost zero. Hence, urine is routinely tested on wards for protein (proteinuria). Proteinuria is a sign of renal/urinary tract disease.
• A net pressure drop across the glomerular membrane drives the ultrafiltration process.

(Suggests that there is some sort of sieve that strains out larger molecules.)

Question 11

Proteinuria

Answer 11

Proteinuria is a sign of renal/urinary tract disease.

Question 12

An imbalance of starlings forces drives glomerular fluid formation (filtration)

what is unique about capillary pressure in the kidneys?

what 2 components act backwards on the driving force?
what is the net effect?

what happens to pressure from afferent to efferent end? and what happens to the plasma? does this change anything?

Answer 12

In the kidney the capillary pressure is highest compared to other arterioles in the body, hence have a pressure of ~50mmHg.

This results in an outward force i.e. pushing fluid out of the blood vessel.

There are 2 components of pressure acting in the opposite direction to this:
1. Colloid osmotic pressure exerted by proteins in the blood (25mmHg)
2. The other is the pressure in the Bowman’s space (10mmHg).
Hence the net effect is an outward force of approximately 15mmHg that drives fluid out of the capillary into the Bowman’s Capsule.

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, the net filtration force is always more than the net absorptive force resulting in a glomerular filtration rate of 20% which is colossal compared to 1% elsewhere in the body.

Question 13

filtration fraction equation

value?

Answer 13

filtration fraction =

GFR/plasma flow = 120/600 = 20%

Question 14

Starling force balancr is reversed (absorption) in peritubular capilaries

what happens at afferent end? result of this?

what happens at the efferent end? what drops and what rises? what effect does this have?

Answer 14

The blood pressure in the afferent arteriole is higher than the colloid osmotic pressure (COP) as you enter the glomerulus, resulting in a net filtration pressure out of the capillaries into the tubule.

As fluid travels out of the glomerulus into the efferent arteriole, the pressure begins to drop, and the COP rises because fluid is lost from capillaries, hence the protein is getting more concentrated thereby exerting a greater force driving fluid back from the tubule into the capillary i.e. Fluid is being absorbed back into the surrounding tissue and peritubular capillary where it comes into contact with the tubule wall.

Question 15

Glomerular Membrane

what 3 layers are there?
what does a molecule have to be smaller than to be found in filtrate?

where can albumin pass? when do you find albumin in urine?

Answer 15

Fenestrated endothelium end of capilarry
Basement membrane
Foot processes of podocytes with filtration slits

Therefore, in a normal situation you would not expect to have blood in your urine. However, anything smaller than the fenestrae can enter the capillaries and then through the filtration slits into the urine.

Albumin can pass through the fenestrae but cannot pass through the filtration slits hence we would not expect albumin in the urine. However, if you have a lack of nephrin and podocin it will lead to the presence of albumin in the urine.

Question 16

Ultra-high magnification of filtration slits

what does it look like?
what is it made up of?
defiency of these - what is that called?

Answer 16

Central spine with lateral rungs
subdivides filtration slit into pores 4nm wide
made of proteins nephrin and podocin

deficiency of these proteins causes nephrotic syndrome

Question 17

Which layer is the molecular sieve?

what reacts with ferritin to produce a black precipitate?

where does this freely pass and where does it line up?

what is the primary filtration barrier for albumin?

describe the 3 sieves

what happens if last layer is broken down? (condition)

Answer 17

• Ferritin has and iron (Fe) core so each black dot is an individual molecule held up at the basement membrane because of its size.

Myeloperoxidase produces a black precipitate in a positive reaction

Glomerular filtration after iv administration of myeloperoxidase (MPO) with a MW of 160,000-180,000 showed that it readily traverses the endothelial fenestrations and crosses the basement membrane.

It then piles up beneath the surface of overlying pedicels and at the slit junctions of adjacent pedicels.

This suggests that the primary filtration barrier to molecules of the size of albumin is the slit pore.

Therefore, the glomerular membrane is 3 sieves in series, of increasing fineness. If the filtration slits breakdown then albumin gets through = nephrotic syndrome

Question 18

Molecules that make it through to what point of sieve layers

all the way?
filtration slits?
basement membrame?
fenestrated endothelium?

Answer 18

water, glcuose, urea, creatinine, na, k all the way through

albumin stopped at filtration slits

fibrinogen stopped at the basement membrane

red cell stopped at fenestrated endothelium

Question 19

Control of GFR
Intrinsic control (intra-renal)

what rate is it held at constant at? why is this important?
what holds GFR constant?

what are chnages in urine production due to?

Answer 19

• GFR is in the main held constant (120ml/min)
• Important for capacity of tubules to reabsorb filtrate not be overwhelmed by excessive GFR
• The mechanism holding GFR constant is an internal one called ‘autoregulation’.
• Changes in urine production (diuresis, antidiuresis) are not usually due to changes in GFR, but due to changes in tubular reabsorption done by ADH.

In the normal range of renal arterial pressure even if BP changes up or down, GFR remains constant = autoregulation. (80 -180/200 bp)
If there was no autoregulation, then a relatively small increase in BP (from 100-125mmHg) would cause a similar 25% increase in GFR i.e. increasing from 180-225L/day.

If tubular reabsorption remained constant then urine flow would increase by 30-fold (difference between GFR and tubular reabsorption), thereby depleting blood volume very quickly.

Question 20

Control of GFR
Autoregulation
2 mechanisms

name and describe the 2 mechanisms

what is their primary role?
what do they both do?

how do they respond differently to BP?

Answer 20

• When kidney subject to acute increases in BP, the renal plasma flow (RPF) and GFR remain relatively constant. Termed intrinsic because even if you denervated the kidney and isolate the kidney the GFR would remain relatively the same.

• 2 mechanisms acting together are responsible for this:
o Bayliss myogenic response:
- Direct vasoconstriction of afferent arteriole which is done by an increase in perfusion pressure

o Tubuloglomerular feedback (TGF):
- Flow-dependent signal detected in macula densa, that alters tone of afferent arteriole.

The current view is that these two mechanisms act in concert and that their primary role is to stabilise renal function by preventing pressure-induced fluctuations in RBF, GFR and the delivery of filtrate to the distal tubule. Both alter the tone of afferent arteriole
• The myogenic response can prevent changes in RBO in response to BP fluctuations that occur in intervals greater than 3-4 secs, whereas the TGF responds to slower BP fluctuations, over intervals of 20sec or longer.

Question 21

Bayliss Myogenic Response

blood flow equation
how can you maintain flow and keep pressure down?

Answer 21

The relation between blood flow (F), the pressure difference that drives the blood from artery to vein (∆P) and resistance (R) is given by the equation F = ∆P/R.

• If the resistance was to remain constant i.e. the calibre of the vessels was not to change – a 50% increase in pressure would cause a 50% increase in flow.
• However, in the kidney and within a range of 80-180mmHg, a 50% increase in pressure only causes a 6-8% increase in flow.

• Resistance, therefore, increases with increasing pressure and this increase in resistance is localised entirely in the afferent arterioles.

Question 22

Bayliss Myogenic Response
Blood pressure increase and blood flow

what happens when there is an increase in perfusion pressure?
what detects change?
effect?
how long till flow returns back to control?

Answer 22

Increase in perfusion pressure → immediate increase in vessel radius (few seconds only) → blood flow goes up briefly

Bayliss observed that resulting stretch of smooth muscle in afferent arteriole quickly results in contraction → reduction in diameter & increase in resistance -> flow returns to control value in 30s

Therefore, if you paralyse smooth muscle via drugs it would stop autoregulation.

Question 23

Bayliss Myogenic Response
Blood pressure increase and bowman’s capsule pressure

what happens if BP rise? why?
what is maintained in parallel? so what happens if systemic pressure rises?

what also increases to balance rise in pressure?

Answer 23

If the blood pressure increases, then the vessels just upstream of the Glomerular capillaries contract resulting in a drop of pressure and keeping the pressure in the Bowman’s capsule (Pgc) still in the same range (constant at ~50mmHg).

Since the GFR and RPF are maintained in parallel, autoregulation must be mediated in part by changes in afferent arteriolar resistance.

As systemic pressure rises, for example, an increase in afferent arteriolar tone prevents the elevation in pressure from being transmitted to the glomerulus, allowing Pgc and GFR to remain unchanged.

The enhanced arteriolar resistance also increases total renal vascular resistance and this increase in vascular tone balances the rise in pressure and minimizes any change in RPF.

Question 24

Bayliss Myogenic Response
Drop in pressure

what will happen?
when does the ability to maintain renal haemodynamics becoome impaired? what happens then?

Answer 24

Conversely, as blood pressure decreases, afferent arteriolar dilation will initially protect both GFR and RPF. However, the ability to maintain renal Haemodynamics becomes impaired at mean arterial pressures below 70.

In this setting, GFR and RPF fall in proportion to the drop-in blood pressure and the GFR ceases when the systemic pressure reaches 40 to 50 mmHg.

Question 25

Bayliss Myogenic Response
Mechanism

what is the simplest hypothesis of the mechanism?

what will an elevation in renal perfusion pressure do? what will this promote and what mediates this?

describe the mechanism
what type of msucle?
responds to what?
what is involved?

Answer 25

The mechanism by which autoregulation is mediated is incompletely understood. The simplest hypothesis is that myogenic stretch receptors in the wall of the afferent arteriole are of primary importance.

An elevation in renal perfusion pressure, will increase the degree of stretch -> which will then promote arteriolar constriction; this effect is mediated in part by increased cell entry of calcium.

The myogenic mechanism involves an intrinsic smooth muscle response to increased transmural pressure. The underlying mechanisms, though not fully resolved, involve depolarisation, activation of voltage-gated L-type Ca+2 channels and Ca+2 entry triggering a rapid vasoconstriction.

Question 26

Oliguria - what is it?

Answer 26

Oliguria = decreased urine production (monitored on ward & ICU in patients in shock/hypotension)

Question 27

How does contraction of afferent arteriole regulate glomerular capilary pressure?

what happens when arterial pressure increases?
what happens which protects the capillary Pressure?

Answer 27

Direct effect of rise in arterial pressure would be to raise capillary pressure

HOWEVER, increased precapillary resistance will cause a bigger pressure drop which protects the capillary pressure. This is done via arteriolar resistance.

Question 28

summary of changes in afferent arteriole resistance and how they prevent chnages in arterial pressure from affecting capillary filtration pressure

What happens when vessel is wide? constricted?

what does it protect it against?

Answer 28

wide = low resistance -> Pc close to Pa
constricted = high resistance -> Pc much less than Pa

The unique properties of the afferent arteriolar myogenic response, that protects it against the oscillating systolic pressure.

The autoregulation range reflects the limits of vasodilation and vasoconstriction
(80 - 200)

Question 29

How is effect of TGF and auto-regulation super-imposed?

what is the primary mechanism of TGF and auto-regulation?
how is this superimposed?

Answer 29

The primary mechanism regarding TGF and auto-regulation is via increase in afferent arteriole resistance due to local release of vasoconstrictors.

Superimposed on this is the RAAS and sympathetic system

Question 30

TGF and control of GFR and RBF

change in RBF will chnage what in DCT?
what detects this? what is release?
effect?

Answer 30

change in RBF/GFR
Chnage in NaCl delivery to DCT
Macula densa sense the change 
paracrine vasoactive agents (+ RAAS)
afferent arterioles change in diameter therfore resistance
restoration of RBF/GFR

Question 31

Extrinsic Control of GFR: Neurohumoral

what nerves can reduce gfr?

what 3 situations does this happen in?

what is its role in this siuation?

what aides these actions in shock?

Answer 31

Renal sympathetic nerves (vasoconstrictor, noradrenergic) can reduce the GFR, by re-setting autoregulation to a lower level.

This happens in 3 conditions:

1. Standing upright (orthostasis)
2. Heavy exercise
3. Haemorrhage & other forms of clinical shock

The role 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 32

Clinical Disorders of the GFR

what 3 thimgs happen when glomeruli are too leaky to plasma protein? what is this condition called?

what does this respond well to?

when GFR too low? what is it called? when is it chronic renal failure?

Answer 32

1. Glomeruli too leaky to plasma protein: nephrotic syndrome (e.g. Filtration slit disordered by nephrin deficiency)

• Proteinuria*
• Hypoproteinaemia*
• Oedema*
• All these problems respond well to steroids.

2. GFR too low (more common)
   - Chronic glomerulonephritis -> non-functioning glomeruli
   - When GFR < 30 ml/min, this is chronic renal failure.

Question 33

Nephron: Tubular structure

describe structure pf PCT? desceding loop? ascending loop? Jg apparatus? DCT? Collecting duct

Answer 33

Proximal convoluted tubule [15 mm] 55 µm in diameter: Tall cells with numerous mitochondria, apical tight junction and numerous microvilli

Loop of Henle
-Descending – thin permeable cells
-Ascending - thick cells with numerous mitochondria
(cortical nephrons 85%; JG nephrons 15%)

JG apparatus: Macula Densa + Lascis
cells + Granular cells of Afferent arteriole = Juxtaglomerular apparatus

Distal convoluted tubule [5 mm] – fewer microvilli

Collecting ducts [20 mm]

• Principal cells – tall, responsible for sodium absorption and vasopressin action
• Intercalated cells – more microvilli, numerous mitochondrion and responsible for acid secretion

Question 34

Nephron: Corpuscle

what does it contain?

what are Mesangial cells (pericytes)?

Answer 34

Glomerulus size (220 µm)
Ball of capillaries supplied by afferent and efferent arterioles
Surrounded by Bowmans capsule which holds filtered fluid (urine)
Total area 0.8m2

Mesangial cells (pericytes)
Contract to reduce glomerular volume
Secretes extracellular matrix

Question 35

Glomerular filtration barrier
(sizes too)

layers?

Answer 35

Three layers: 
Endothelium
Basement membrane
Podocytes 
Endothelial fenestration size (70-90 nm)
Filtration slit (podocytes) (25 nm)

Glomerulus allows free movement
<4 nm and stops everything >8 nm

Question 36

Renal blood flow (2 systems)

the blood sequence circualtion

Answer 36

Interlobar artery →arcuate artery → interlobar artery →afferent artery →efferent arteriole →peritubular capillary →interlobular vein →arcuate vein →interlobar vein

Peritubularcapillary→Descending vasarecta (non fenestrated) → ascending vasa recta (fenestrated) →arcuate vein

Question 37

Renal blood flow; what drives movement of solutes and solvents

in glomuerulus?
in descending vasarecta?

Answer 37

In the glomerulus the capillary hydrostatic pressure drives the fluid out to make the filtrate

In the descending vasarecta the osmotic pressure drives solutes in

Question 38

Nerve supply of renal vessels

where is the sympathetic preganglion from?
where do postganglion lie?
where are the fibres distributed?

Answer 38

Sympathetic preganglionic is from T10-L2

Postganglionic neurons lie in superior mesenteric and renal artery ganglion

Sympathetic fibres are distributed through the afferent arterial efferent arterial and juxtaglomerular apparatus

Noradrenergic innovation also happens at the loop of Henle

Nociceptive afferents run parallel to sympathetic fibres

Question 39

Reno-renal-reflex

what is it?

Answer 39

ureteric obstruction -> Decrease efferent nerve -> Increase Na/Water excretion

Question 40

Renal autoregulation in systemic hypotension

what happens? what is it mediated by?
prevented by?

Answer 40

Afferent arteriolar vasodilatation
Mediated by Prostaglandin
Prevented in old age, diabetes, NSAIDS

Efferent arteriolar vasoconstriction
Mediated by Angiotensin II
Prevented by ACEi, ARB

Question 41

Factors affecting GFR

Answer 41

Changes in renal blood flow
Changes in systemic blood pressure
Afferent and efferent arteriolar constriction
Changes in hydrostatic pressure in the Bowmans space
Ureteral obstruction
Oedema of kidney in the tight capsule
Changes in concentration of plasma proteins (dehydration, hypoalbuminemia)
Changes in filtration barrier
Changes in effective filtration surface area

Question 42

Factors affecting filtration surface area

what descreases it? (3)
what increases it? (5)

Answer 42

Mesangial contraction ↓ surface area by

• Endothelin
• Angiotensin II
• Vasopressin

Mesangial dilatation ↑surface area by

• Atrial Natriuretic peptide
• Dopamine
• Prostaglandin E
• cAMP
• acetyl choline

Question 43

Measurement of renal blood flow

flow equation?
renal plasma flow equation?

Answer 43

Flow = substance removed /
arterial concentration - venous concentration

Flow = S / As-Vs

Renal plasma flow = UPAH x Urine Volume / Arterial PAH - Venous PAH

RPF = UPAH x V / Arterial PAH [venous PAH is zero as all of it is removed]