ECF Volume Regulation Flashcards
One of the most important aspects of the ECF regulated by the kidney is it’s what?
Volume
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?
The number of osmotically active particles in each compartment
What are the 2 major ECF osmoles?
Na+ Cl-
What is the major ICF osmole?
K+ salts
Regulation of ECF volume =
Regulation of body Na+
What fraction of 60% body water (42l) is ICF and what is ECF?
ICF = 1/3 (28l) ECF = 1/3 (14l) (plasma 3l; interstitial fluid 11l)
Changes in Na+ content of the ECF will lead to what? Which will then affect what?
Changes in ECF volume and therefore will affect the volume of blood perfusing the tissues = effective circulating volume and therefore BP
So what receptors does regulation of Na+ basically rely on?
High and low P baroreceptors
What is hypovolaemia?
Decreased ECF volume
What causes lowered ECF volume?
Increased salt and H2O
What causes salt and H2O loss?
Vomiting, diarrhoea or excess sweating
Describe how increased salt and H2O loss leads to decreased blood pressure
= decreased plasma volume = decreased venous pressure = decreased venous return = decreased atrial pressure = decreased EDV = decreased stroke volume = decreased cardiac output = decreased blood pressure
What does decreased blood pressure cause (to try and reverse itself)?
Decreased carotid sinus baroreceptor inhibition of sympathetic discharge (causing increased sympathetic discharge)
What does increased sympathetic discharge cause?
Increased vasoconstriction = increased TPR (total peripheral resistance) = increased blood pressure towards normal
What does increased atrial pressure and decreased carotid sinus baroreceptor discharge cause?
Increase in ADH release (to try n retain water) (may cause hypo-osmolarity)
What effect does the increased sympathetic vasoconstriction (to increase BP) have on the kidney?
Increased renal arterial constriction
Increased renin
What does increased renin lead to?
Increased angiotensin II
What 2 effects does increased angiotensin II have in the kidney?
- 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!)
Increase in Na+ reabsorption is because of what?
Greater reabsorptive forces in the peritubular capillaries
If we have lost NaCl and H2O (more of the ‘wet stuff’), then what does this mean for oncotic pressure?
Increased even more than normal
What does the increased oncotic pressure mean can happen?
Can reabsorb up to 75% of the filtrate at the proximal tubule
How is GFR affected in the case of fluid loss? Why?
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
So to recap - how is hydrostatic pressure and oncotic pressure in peritubular capillaries affected during hypovolaemia (dehydration)?
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)
So how would pressures be affected in hypervolaemia?
Less VC so increased hydrostatic pressure
Oncotic pressure would be decreased because more fluid available but same amount of plasma proteins
What exactly maintains GFR during hypovolaemia?
Constriction of afferent due to sympathetic VC coupled with angiotenisn II mediated constriction of efferent
What hormone is regulation of distal tubule Na+ reabsorption under the control of?
Aldosterone
(v important in long-term regulation of Na+ and ECF volume)
What is aldosterone secretion controlled by?
Reflexes involving the kidneys themselves
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?
Juxtaglomerular cells (JG)
What are juxtaglomerular cells closely associated with? What do they form?
A histologically specialised loop of the distal tubule called the macula densa
Together they form the juxtaglomerular apparatus
What can the juxtaglomerular cells sense?
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)
What hormone do JG cells produce?
Renin
What is renin? What does it do?
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
Describe process of creating angtiotensin II
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
What is the RATE-LIMITING step in the creation of angiotensin II?
The relase of renin
(since angiotensinogen is constantly present and so is ACE)
Where does the greatest proportion ACE converting angiotensin occur?
As blood passes through pulmonary circuit (but all of endothelium is important)
What does angiotensin II stimulate?
Aldosterone-producing cells in the zona glomerulosa of the adrenal cortex
What does the aldosterone do after being released?
Passes in the blood to the kidney where it stimulates distal tubular Na+ ion reabsorption
What 5 things control renin release?
- Decreased pressure in afferent arteriole at level of JG cells
- Increased sympathetic nerve activity (via ß1 effect)
- Inversely proportional to rate of delivery of NaCl at macula densa (decreased Na delivery = increased renin)
- Angiotensin II feeds back to inhibit renin
- ADH inhibits renin release (osmolarity contorl)
(JG decreased P + Na increase; symp nerves increase; angio II + ADH inhibit)
Give the effect of angiotensin II on: arterioles, cardiovascular control centre in medulla oblongata, hypothalamus, adrenal cortex
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)
The close relationship between afferent arteriole with JG cells and macula densa provides mechanism for what?
Controlling input and output of tubules and basis of tubuloglomerular balance
Give 4 reasons that angiotensin II is fundamentally important in body’s response to hypovolaemia
- Stimulates aldosterone = Na and H2O retention
- V potent constrictor = increased TPR
- Acts on hypothalamus to stimulate ADH secretion = increased H2O reabsorption from CD
- Stimulates thirst mechanism and salt appetite (hypothalamus)
Give the steps that would occur to ultimately decrease GFR when it has been increased above normal
- GFR increases
- Flow through tubule increases
- Flow past macula densa increases (increased salt delivery to MD)
- Paracrine released from macula densa to afferent arteriole
- Afferent arteriole constricts
- Resistance in afferent arteriole increases
- Hydrostatic pressure in glomerulus decreases
- GFR decreases
Tubuloglomerular feedback contributes to GFR constancy
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?
Decreased ECF osmolarity -> inhibition of ADH via osmoreceptors
Decreased ECF volume -> increased ADH via baroreceptors
When decreased ECF osmolarity and decreased ECF volume have opposing inputs to ADH secreting cells, what will take primacy?
Volume considerations - so that ADH will increase because of the baroreceptors, even tho this is associated with hypoosmolarity (not as dangerous as hypovolaemia)
How ADH is affected by volume:
Uner 10% of normal = dramatic increase of ADH to make sure we compensate for hypovolaemia - more important
Regulation of Na+ =
Regulation of ECF volume
What hormone promotes Na+ reabsorption?
Aldosterone
What hormone promotes Na+ excretion?
ANP (Atrial Natriuretic Peptide)
What 3 stages would happen if aldosterone is given to normal subjects on an adequate Na+ diet?
- There will be Na+ retention and K+ loss
- There will be a weight gain of 2-3kg due to Na+ and H2O retention
- After a couple of days, a spontaneous diuresis occurs secondary to volume expansion, although K+ loss persists
How is ANP linked to aldosterone?
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
Summarise the link between ANP and aldosterone
ANP overrides aldosterone effects on Na+ reabsorption because of vol expansion = ALDOSTERONE ESCAPE
How are patients with Conn’s syndrome (primary hyperaldosteronisms) affected in terms of potassium and sodium?
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)
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)
- 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)
What situation is important to consider in terms of hypovolaemia and clinically in explaining the effects of uncontrolled DM in producing hyperglycaemic coma?
Osmotic diuresis
In uncontrolled DM, where [BG] is not kept within strict control, the high plasma glucose level exceeds what in the proximal tubule?
The maximum rebasorptive capacity
Glucose remaining in the tubule will exert what effect?
An osmotic effect to retain H2O in the tubule
What does the osmotic effect exerted by glucose to retain H2O in the tubule lead to?
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+
Illustration of decreased reabsorption of Na and glucose due to osmotic effect of increased water content in proximal tubule
Moving through the tubule into the descending loop of Henle, why is movement of H2O out of tubule then reduced in hyperglycaemia?
Because the glucose and excess Na+ exert an osmotic effect to retain H20 and therefore fluid in descending limb is not so concentrated
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?
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
Recap of osmolarity in normal kidney nephron - in hyperglycaemic coma this cannot happen
countercurrent multiplier ability is reduced
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?
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
Recap of reabsorption of NaCl of Na Cl + H2O in renal tubule; normal on left abnormal on right
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
What is the result of a large volume of nearly isotonic urine being excreted in hyperglycaemia?
Decreased plasma volume
What will the decreased plasma volume trigger? But what then happens?
Will stimulate ADH release via baroreceptors
BUT this cannot be effective because interstitial gradient has run down
How much urine can patients with uncontrolled DM produce per day?
Up to 6-8L - causes severe salt and water depletion
What causes the hypoglycaemic coma?
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)
Any solute remaining in the tubule e.g. NaCl or urea can cause what? What is the benefit?
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)
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?
(This is a passive process, energy is provided by active transport, Na+/K+ATPase on the basolateral membrane)
Makes no difference to story, but important to know because loop diuretics can cause K+ ion wasting.
