ECF Volume Regulation

Question 1

One of the most important aspects of the ECF regulated by the kidney is it’s what?

Answer 1

Volume

Question 2

Since H2O can freely cross all cell membranes, the body fluids are in osmotic equilibrium, so that the distribution of TBW between cells and ECF is determined by what?

Answer 2

The number of osmotically active particles in each compartment

Question 3

What are the 2 major ECF osmoles?

Answer 3

Na+ Cl-

Question 4

What is the major ICF osmole?

Answer 4

K+ salts

Question 5

Regulation of ECF volume =

Answer 5

Regulation of body Na+

Question 6

What fraction of 60% body water (42l) is ICF and what is ECF?

Answer 6

ICF = 1/3 (28l) ECF = 1/3 (14l) (plasma 3l; interstitial fluid 11l)

Question 7

Changes in Na+ content of the ECF will lead to what? Which will then affect what?

Answer 7

Changes in ECF volume and therefore will affect the volume of blood perfusing the tissues = effective circulating volume and therefore BP

Question 8

So what receptors does regulation of Na+ basically rely on?

Answer 8

High and low P baroreceptors

Question 9

What is hypovolaemia?

Answer 9

Decreased ECF volume

Question 10

What causes lowered ECF volume?

Answer 10

Increased salt and H₂O

Question 11

What causes salt and H₂O loss?

Answer 11

Vomiting, diarrhoea or excess sweating

Question 12

Describe how increased salt and H₂O loss leads to decreased blood pressure

Answer 12

= decreased plasma volume = decreased venous pressure = decreased venous return = decreased atrial pressure = decreased EDV = decreased stroke volume = decreased cardiac output = decreased blood pressure

Question 13

What does decreased blood pressure cause (to try and reverse itself)?

Answer 13

Decreased carotid sinus baroreceptor inhibition of sympathetic discharge (causing increased sympathetic discharge)

Question 14

What does increased sympathetic discharge cause?

Answer 14

Increased vasoconstriction = increased TPR (total peripheral resistance) = increased blood pressure towards normal

Question 15

What does increased atrial pressure and decreased carotid sinus baroreceptor discharge cause?

Answer 15

Increase in ADH release (to try n retain water) (may cause hypo-osmolarity)

Question 16

What effect does the increased sympathetic vasoconstriction (to increase BP) have on the kidney?

Answer 16

Increased renal arterial constriction

Increased renin

Question 17

What does increased renin lead to?

Answer 17

Increased angiotensin II

Question 18

What 2 effects does increased angiotensin II have in the kidney?

Answer 18

• Decreased peritubular capillary hydrostatic P (and increased oncotic pressure) which causes increased NaCl and H₂O reabsorption in the proximal tubule (due to changes in rate of uptake by peritubular capillaries)
• Increased aldosterone which causes increased NaCl and H₂O reabsorption in the distal tubule

(so less Na excreted!)

Question 19

Increase in Na+ reabsorption is because of what?

Answer 19

Greater reabsorptive forces in the peritubular capillaries

Question 20

If we have lost NaCl and H₂O (more of the ‘wet stuff’), then what does this mean for oncotic pressure?

Answer 20

Increased even more than normal

Question 21

What does the increased oncotic pressure mean can happen?

Answer 21

Can reabsorb up to 75% of the filtrate at the proximal tubule

Question 22

How is GFR affected in the case of fluid loss? Why?

Answer 22

Remains largely unaffected; autoregulation maintains GFR and the VC of afferent and efferent means little effect on GFR until volume depletion is severe enough to cause considerable decrease in MBP

Question 23

So to recap - how is hydrostatic pressure and oncotic pressure in peritubular capillaries affected during hypovolaemia (dehydration)?

Answer 23

Hydrostatic pressure is less than normal due to renal VC (less force driving water out of capillaries)

Oncotic pressure is higher than normal due to reduced volumes of available fluid (so have an even stornger oncotic force favouring reabsorption)

Question 24

So how would pressures be affected in hypervolaemia?

Answer 24

Less VC so increased hydrostatic pressure

Oncotic pressure would be decreased because more fluid available but same amount of plasma proteins

Question 25

What exactly maintains GFR during hypovolaemia?

Answer 25

Constriction of afferent due to sympathetic VC coupled with angiotenisn II mediated constriction of efferent

Question 26

What hormone is regulation of distal tubule Na+ reabsorption under the control of?

Answer 26

**Aldosterone** (v important in long-term regulation of Na+ and ECF volume)

Question 27

What is aldosterone secretion controlled by?

Answer 27

**Reflexes involving the kidneys themselves**

Question 28

Smooth muscle of media of afferent (just before enetering glom) is specialised and contains large epithelial cells with plentiful granules, what are the cells called?

Answer 28

**Juxtaglomerular cells** (JG)

Question 29

What are juxtaglomerular cells closely associated with? What do they form?

Answer 29

A histologically specialised loop of the distal tubule called the macula densa Together they form the juxtaglomerular apparatus

Question 30

What can the juxtaglomerular cells sense?

Answer 30

Pressures and salt content (BP drop if we have less blood flow - so cells of JG sense less pressure from afferent arterioles so as a result release renin)

Question 31

What hormone do JG cells produce?

Answer 31

**Renin**

Question 32

What is renin? What does it do?

Answer 32

A **proteolytic enzyme which acts on** a large protein in the alpha₂-globulin fraction of the plasma proteins = **angiotensinogen** Splits off the decapeptide **angiotensin I** which is then converted by enzymes in endothelium to active octapeptide **angiotensin II**

Question 33

Describe process of creating angtiotensin II

Answer 33

**Liver produces angiotensinogen** in the plasma Decrease in BP results in **kidney granular cells producing renin**, which then coverts angiotensinogen to **angiotensin I** in plasma **ACE enzyme** from blood vessel endothelium then converts it to **angiotensin II**

Question 34

What is the RATE-LIMITING step in the creation of angiotensin II?

Answer 34

*The relase of renin* (since angiotensinogen is constantly present and so is ACE)

Question 35

Where does the greatest proportion ACE converting angiotensin occur?

Answer 35

As blood passes through pulmonary circuit (but all of endothelium is important)

Question 36

What does angiotensin II stimulate?

Answer 36

Aldosterone-producing cells in the zona glomerulosa of the adrenal cortex

Question 37

What does the aldosterone do after being released?

Answer 37

Passes in the blood to the kidney where it stimulates distal tubular Na+ ion reabsorption

Question 38

What 5 things control renin release?

Answer 38

1. Decreased pressure in afferent arteriole at level of JG cells 2. Increased sympathetic nerve activity (via ß₁ effect) 3. Inversely proportional to rate of delivery of NaCl at macula densa (decreased Na delivery = increased renin) 4. Angiotensin II feeds back to inhibit renin 5. ADH inhibits renin release (osmolarity contorl) (JG decreased P + Na increase; symp nerves increase; angio II + ADH inhibit)

Question 39

Give the effect of angiotensin II on: arterioles, cardiovascular control centre in medulla oblongata, hypothalamus, adrenal cortex

Answer 39

Arterioles = vasoconstrict CVS control centre = increased CV response Hypothalamus = increased ADH, increased thirst Adrenal cortex = increased aldosterone = increased Na+ reabsorption (VC + CV respose = increased BP; ADH + thirst + Na reabsorption = increased vol + osmolarity maintained = increased BP)

Question 40

The close relationship between afferent arteriole with JG cells and macula densa provides mechanism for what?

Answer 40

Controlling input and output of tubules and basis of tubuloglomerular balance

Question 41

Give 4 reasons that angiotensin II is fundamentally important in body's response to hypovolaemia

Answer 41

1. Stimulates aldosterone = Na and H₂O retention 2. V potent constrictor = increased TPR 3. Acts on hypothalamus to stimulate ADH secretion = increased H₂O reabsorption from CD 4. Stimulates thirst mechanism and salt appetite (hypothalamus)

Question 42

Give the steps that would occur to ultimately decrease GFR when it has been increased above normal

Answer 42

1. GFR increases 2. Flow through tubule increases 3. Flow past macula densa increases (increased salt delivery to MD) 4. Paracrine released from macula densa to afferent arteriole 5. Afferent arteriole constricts 6. Resistance in afferent arteriole increases 7. Hydrostatic pressure in glomerulus decreases 8. GFR decreases

Question 43

Tubuloglomerular feedback contributes to GFR constancy

Answer 43

Question 44

Consider a person suffering from severe diarrhoea, who has lost 3L of salt and water (from ECF) and drinks 2L of pure water, where will be opposing inputs to ADH secreting cells, what will they be?

Answer 44

Decreased ECF osmolarity -\> inhibition of ADH via osmoreceptors Decreased ECF volume -\> increased ADH via baroreceptors

Question 45

When decreased ECF osmolarity and decreased ECF volume have opposing inputs to ADH secreting cells, what will take primacy?

Answer 45

**Volume considerations** - so that ADH will increase because of the baroreceptors, even tho this is associated with hypoosmolarity (not as dangerous as hypovolaemia)

Question 46

How ADH is affected by volume:

Answer 46

Uner 10% of normal = dramatic increase of ADH to make sure we compensate for hypovolaemia - more important

Question 47

Regulation of Na+ =

Answer 47

Regulation of ECF volume

Question 48

What hormone promotes Na+ reabsorption?

Answer 48

Aldosterone

Question 49

What hormone promotes Na+ excretion?

Answer 49

ANP (Atrial Natriuretic Peptide)

Question 50

What 3 stages would happen if aldosterone is given to normal subjects on an adequate Na+ diet?

Answer 50

1. There will be Na+ retention and K+ loss 2. There will be a weight gain of 2-3kg due to Na+ and H2O retention 3. After a couple of days, a spontaneous diuresis occurs secondary to volume expansion, although K+ loss persists

Question 51

How is ANP linked to aldosterone?

Answer 51

Aldosterone causes increased Na+ reabsorption and increased K+ secretion (at distal tubule) Then leads to increased weight due to Na and water retention Then leads to volume expansion Vol expansion then stimulates the release of ANP from atrial cells which leads to subsequent loss of Na+ and H2O = *NATRIURESIS*

Question 52

Summarise the link between ANP and aldosterone

Answer 52

**ANP overrides aldosterone effects on Na+ reabsorption because of vol expansion** = *ALDOSTERONE ESCAPE*

Question 53

How are patients with Conn's syndrome (primary hyperaldosteronisms) affected in terms of potassium and sodium?

Answer 53

They are K+ depleted, but NOT hypernatraemic (ANP is secreted by atrial cells in response to expansion of ECF volume and causes natriuresis, loss of Na+ and H2O in urine)

Question 54

ANP works on the hypothalamus, kidney, adrenal cortex and medulla oblongata - how does it affect each of these to aid increased NaCl and H2O excretion? (in terms of hormone release)

Answer 54

* Hypothalamus* = **decreased ADH** release * Kidney* = **increased GFR**; **decreased renin**; increase NaCl and H2O excretion * Adrenal cortex* = **less aldosterone** (Medulla oblongata = decreased BP (also from decreased renin)

Question 55

What situation is important to consider in terms of hypovolaemia and clinically in explaining the effects of uncontrolled DM in producing **hyperglycaemic coma**?

Answer 55

**Osmotic diuresis**

Question 56

In uncontrolled DM, where [BG] is not kept within strict control, the high plasma glucose level exceeds what in the proximal tubule?

Answer 56

The maximum rebasorptive capacity

Question 57

Glucose remaining in the tubule will exert what effect?

Answer 57

An osmotic effect to retain H2O in the tubule

Question 58

What does the osmotic effect exerted by glucose to retain H2O in the tubule lead to?

Answer 58

Decreased [Na+] in the lumen because H2O is present in a larger volume Since Na+ gains access to the proximal tubule cells by passive diffusion down a concentration gradient created by active transport out of basolateral surfaces, Na+ reabsorption will be decreased Therefore - decreased ability to reabsorb glucose since it shares a symport with Na+

Question 59

Illustration of decreased reabsorption of Na and glucose due to osmotic effect of increased water content in proximal tubule

Answer 59

Question 60

Moving through the tubule into the descending loop of Henle, why is movement of H2O out of tubule then reduced in hyperglycaemia?

Answer 60

Because the glucose and excess Na+ exert an osmotic effect to retain H20 and therefore fluid in descending limb is not so concentrated

Question 61

So moving to ascending limb - the fluid delivered there in hyperglycaemia is less concentrated; since NaCl pumps in ascending limb are gradient limited, the medullary interstitial gradient is much less, how does this affect NaCl and H2O reabsorption from loops of Henle? What does this then mean?

Answer 61

There is a considerable reduction in reabsorption **so a large volume of NaCl and H2O is delivered to the distal tubule AND interstitial gradient is gradually abolished** ADH mechanism is then also ineffectie because we dont have the gradient driving the reuptake of water

Question 62

Recap of osmolarity in normal kidney nephron - in hyperglycaemic coma this cannot happen countercurrent multiplier ability is reduced

Answer 62

Question 63

So under normal conditions what does the macula densa do when a large volume of Na and H2O is delivered to the distal tubule (meaning there is an excess ECF volume)? Why is this bad in hyperglycaemia?

Answer 63

The macula densa will detect high rate of delivery of NaCl and will want to get rid of NaCl and H2O so renin secretion will be suppressed and therefore Na+ reabsorption at distal tubule will be decreased - this is bad because this response is inappropriate and unnecessarily further increase water and salt

Question 64

Recap of reabsorption of NaCl of Na Cl + H2O in renal tubule; normal on left abnormal on right

Answer 64

Decreased reabsorption in proximal tubule (osmotic effect of glucose), then in loop of henle impaired reabsorption again, driven by increased osmotic pressures – also have decreased distal tubule reabsorption due to RAAS system being switched off Also because we have ruined medullary gradient as a result of glucose effect – we cant use ADH system to produce concentrated urine As a result we excrete HUGE amounts of water, so what we are experiencing in hyperglycaemic coma is malperfusion of brain Massively hypovolaemic, brain perfusion is affected and you keel over and slip into coma as its not easy to restore these fluids

Question 65

What is the result of a large volume of nearly isotonic urine being excreted in hyperglycaemia?

Answer 65

Decreased plasma volume

Question 66

What will the decreased plasma volume trigger? But what then happens?

Answer 66

Will stimulate **ADH release** via baroreceptors BUT this **cannot be effective because interstitial gradient has run down**

Question 67

How much urine can patients with uncontrolled DM produce per day?

Answer 67

Up to 6-8L - causes severe salt and water depletion

Question 68

What causes the hypoglycaemic coma?

Answer 68

Hypotension may be so severe that it causes coma This is due to **inadequate BF to the brain** (whereas hypoglycaemic coma is due to inadequate glucose to the brain)

Question 69

Any solute remaining in the tubule e.g. NaCl or urea can cause what? What is the benefit?

Answer 69

**Osmotic diuresis** This can help eliminate their excess (problem with DM is that the liver keeps producing glucose so the problem is not self-limiting)

Question 70

Why is it important to know that the active transport mechanism that operates on the luminal surface of the thick ascending loop of Henle, actually involves K+ ions as well as NaCl, ie Na+-K+-2Cl- co-transporter? ## Footnote (This is a passive process, energy is provided by active transport, Na+/K+ATPase on the basolateral membrane)

Answer 70

Makes no difference to story, but important to know because loop diuretics can cause K+ ion wasting.