Week 9 Electrolyte Distribution Flashcards
What is the ECF compartment subdivided into ?
Plasma
Interstitial fluid
What is equivalence ?
Amount of substance dissolved in a solution relative to its molecular weight and stoichiometry
What is osmolality ?
Number of solute particles per kg of H2O
What is the importance of osmolality in the body ?
Determines the direction of water flow between compartments
What are the most important solutes in extracellular fluids ?
Na+
Cl-
HCO3-
What is oncotic pressure ?
Pressure generated by large molecules and proteins
What is tonicity ?
The effect of a solution on the volume of the adjacent cell.
What percentage of body weight is water ?
60% in males
50% in females
What is the distribution of water between extra and intra cellular compartments ?
~1/3 ECF
~2/3 ICF
What is the distribution of water in the EC compartment between the plasma and interstitial fluid ?
~3/4 interstitial
~1/4 plasma
What determines hydrostatic pressure ?
Arterial/venous pressure
Length of capillary
Pre and post capillary sphincters
What determines oncotic pressure ?
Permeability of the membrane to protein molecules
What affects the movement of fluid across a membrane ?
SA
Permeability to water
Permeability to proteins
What should the response be to immediate large losses of ECF fluid ?
Fluid resuscitation with appropriate fluid
What is the response to sustained losses of ECF over time ?
Regulation through thirst and kidney
What is the response to immediate and sustained gains of ECF fluid ?
Kidney regulation
What is the response to immediate and sustained gains of ECF fluid in the absence of kidneys ?
Dialysis
Determinants of effective circulating volume
Volume of ECF Volume of vascular space BP Cardiac output Intact sensors = baroreceptors
What percentage of cardiac output do the kidneys recieve ?
20%
What is a nephron ?
Functional unit of the kidneys
How many nephrons does each kidney have ?
~ 1 million
What is each nephron comprised of ?
Renal corpuscle (glomerulus + Bowman’s capsule) and its tubule
The nest of the glomerular capillary between the ______ and ______ _______ allows for precise regulation of the intraglomerular forces governing the GFR
Afferent, efferent arterioles
What is the first step in urine formation ?
Glomerular filtration
What is GFR the sum of?
Individual filtration rates of ~2 million glomeruli
What are podocyte foot processes linked by ?
Slit diaphragm
What is the glomerular filtration barrier ?
A size and charge selective sieve
What are the principle determinants of GFR ?
Starling forces
Glomerular capillary filtration coefficient
Glomerular plasma flow rate
How do Starling forces determine movement of fluid across glomerular capillaries ?
Movement occurs because of difference between trans capillary hydrostatic pressure (favours filtration) gradient and the trans capillary oncotic pressure (opposes filtration)
How is the glomerular capillary filtration coefficient determined ?
Hydraulic conductivity x SA
How does glomerular plasma flow (QA) effect GFR ?
Plasma flow increase —> increase GFR
What happens if glomerular capillary oncotic pressure increases ?
Decreases GFR
What is the minute to minute regulation of GFR is mostly by changes in what ?
PGC and QA
How are PGC and QA are controlled ?
By alterations in afferent and efferent arteriolar resistances
What happens to GFR and renal blood flow when afferent arteriole resistance increases ?
Both GFR and RBF decrease
What happens to GFR and renal blood flow as efferent arteriole resistance increases ?
GFR increases then decreases
RBF decrease
How does the kidney respond to changes in arterial blood pressure ?
Immediate vasoactive response
Mainly alters afferent arteriole resistance in direction that maintains GFR and RBF
What is the myotonic mechanism ?
Ability of arterial smooth muscle to contract (or relax) in response to increases (or decreases) in vascular wall tension
Prevents excessive increases in RBF and GFR when arterial pressure increases
Very rapid
Where does auto regulation occur and which part is most important ?
Preglomerular resistance vessels
Afferent arterioles
Describe tubuloglomerular feedback
Changes in [NaCl] at the end of the thick ascending limb of LOH affect afferent arteriolar resistance
Stabilizes the delivery of volume and solute to the distal nephron
Kidney uses JGA for this
What makes up the JG apparatus ?
JG cells
Macula densa
What do JG cells do ?
Secrete renin
What is the macula densa ?
Specialized cells at the end of thick ascending limb
Sends flow-related changes in NaCl delivery
Sends out vasoconstrictor signal (adenosine) that affects afferent arteriole tone
Describe TGF response to increase in arterial pressure (RBF)
Increase GFR —> increase tubular fluid flow rate —> increase Na and Cl delivery to macula densa —> increase vasoconstrictor signals —> increase afferent aretriolar constriction —> decreased RBF
When is TGF less sensitive ?
During volume expansion :
Allows for greater delivery of fluid and electrolytes to the distal nephron to allow for the correction of volume expansion
When is TGF more sensitive ?
During extracellular volume contraction: help conserve fluid and electrolytes
What mainly synthesizes and secretes renin ?
JG cells of AA
What is renin release stimulated by
Decreased effective circulating volume (decreased NaCl delivery at macula densa, decreased AA stretch) and increased SNS activity
Where is angiotensinogen synthesized ?
Proximal tubules
Where is ACE located ?
Proximal tubules
What is Ang II ?
A potent vasoconstrictor due to binding at the AT1 receptors especcialy affects the efferent arteriole
What does Ang II directly stimulate ?
Proximal tubular sodium absorption
Why does Ang II exert a greater vasoconstrictor on efferent arterioles than the afferent arterioles ?
Because vasodilatory prostaglandins dilate the afferent arteriole
What does decreased effective circulating volume and NSAID use often lead to ?
Acute kidney injury
Where is angiotensinogen mainly synthesized ?
The liver
Where is ACE mostly synthesized ?
Vascular endothelium in the lungs
What does Ang II stimulate the release of ?
Aldosterone from the adrenal glands
Salt hunger and thirst
—> increase ECF volume and increased arterial blood pressure
What is the effect of aldosterone ?
Increase sodium reabsorption by principle cells in distal nephron
What happens when effective circulating volume decreases and you take an ACE inhibitor or ARB ?
Acute kidney injury
Loss of Ang II mediated vasoconstriction results in dilation of efferent arteriole —> decreased GFR
What does mild activation of the SNS cause
Decreased sodium and water excretion due to renin release
What effect does mild to moderate activation of the SNS have on renal blood flow and GFR
Little effect
What happens with strong activation of the SNS ?
Constrict renal arterioles
Decrease renal blood flow and GFR
What is the effect if early diabetic nephropathy on GFR ?
Hyperfiltration —> increased GFR
Where does sodium intake come from ?
Ingested food and fluids
What is typical daily intake of NaCl
5-7 g
2-2.8 g Na (86-120 mmol) = output
How is the effective circulating fluid volume monitored/sensed?
Low pressure sensors in atria, ventricles and pulmonary circulation
High pressure sensors in arteries (aortic arch, carotid, renal arteries)
Others in CNS and hepatic circulation (not well characterized yet)
Where are low pressure sensors located
Areas of lower BP where changes in blood volume don’t cause large changes in BP.
Cardiac atria, right ventricle, pulmonary circulation
What stimulates low pressure sensors ?
Increasing pressure/stretch
What is the response when low pressure sensors are activated ?
Inhibition of ADH
Release of ANP and BNP
Net effect of low pressure sensor activation
Decrease ADH —> increase diuresis (more water excretion)
ANP and BNP —> increased natriuresis
—> shrink blood volume towards normal
What can higher levels of BNP be indicative of ?
Congestive heart failure
This test can help differentiate dyspnea from CHF from dyspnea caused by pulmonary problem (pneumonia)
Where are high pressure sensors located ?
Carotid artery, aortic arch, arterioles in the kidney
What stimulates high pressure sensors ?
Decrease in arterial pressure (more sensitive to pressure than volume)
What is the response when high pressure sensors are activated ?
Increase in SNS activity
Stimulation of ADH release
Activation of RAAS
Inhibition of ANP
What are the effects of increased SNS activity ?
Increased HR and CO Increased vascular tone Decreased GFR Increased renin secretion Increased renal Na+ reabsorption Decreased renal Na+ excretion
What is the renal sensor for effective circulating fluid volume
JG apparatus
What happens in initial filtration of sodium by the nephron ?
NaCl is in solution and freely filtered across the glomerular basement membrane
[Na+] at start of proximal tubule = serum [Na+]
What happens to sodium in the proximal tubule ?
Intracellular space is kept almost Na+ free by Na+ K+ ATPase pump
2/3 of filtered Na+ is reabsorbed here mostly via Na+H+ anti porter or Na+ glucose co-transporter, or Na+AA co-transporter
What happens further down the proximal tubule ?
Cl- gradient established —> passive reabsorption of NaCl
—> water follows as osmoles leave the proximal tubule lumen
What has been reabsorbed by the end of the proximal tubule ?
~60% if NaCl and ~60% of water reabsorbed
[Na+] is same as plasma
What happens to sodium in the loop of Henle ?
Important site for reabsorption of ~25% of filtered sodium, but less water
POwered by basolateral Na+K+ ATPase
Na+ K+ 2Cl- symporter allows entry of 1 Na, 1K and 2Cl down the concentration gradient for NaCl
What is the site of action for loop diuretics ?
NKCC2
What happens in the early part of the distal tubule ?
NaCl is reabsorbed without any water
NaCl symporter is main channel
Where do thiazide type dieuretics act ?
NCC symporter
Commonly used to treat hypertension
What happens in the collecting duct/tubule
Principle cells carry out NaCl reabsorption via Na+ channel (ENaC)
Where does aldosterone act ?
Collecting duct/tubule
Increase Na+ reabsorption in exchange for K+ excretion
What is the overall effect of prostacyclin ?
Afferent arteriolar vasodilation and natriuresis
How is prostaglandin formed and what signals this ?
Arachidonic acid is released from membrane phospholipids and is metabolized to PGs by cyclooxygenase (COX-1 and 2) in the presence of Na+ conserving and vasoconstricting stimuli
What is the main prostaglandin in the kidney?
Prostacyclin (PGI2)
What happens to prostacyclin in low ECFV states such as CHF or cirrhosis ?
PGI2 levels rise to maintain renal perfusion in the setting of high Ang II, SNS activity etc
What do NSAIDS do when PGI2 levels are high ?
Remove counter regulation —> sodium retention, hypertension, lower GFR
What does increasing SNS acitivity of renal sympathetic nerves lead to ?
Renin secretion
Increased Na+/H2O reabsorption
What are the effects of ANP and BNP ?
Increase GFR and natriuresis
Antagonism of most RAAS actions
What is uroguanylin ?
Produced in intestine in response to salt intake
Reduces renal sodium reabsorption
What happens with increased effective circulating fluid volume ?
Increase GFR Decrease renin secretion Decrease aldosterone secretion Decrease Na+ reabsorption Increase Na+ and H2O excretion
What is edema caused by ?
Sodium excess
Treat by causing a negative sodium balance
What is the most common cause of death in the world ?
Volume depletion
What does sodium regulation determine ?
ECF volume
What does water regulation determine ?
Body osmolality
What is the formula for tonicity ?
Tonicity = ECF solute + ICF solute / TBW = 2[Na] + 2[K] /TBW ~ 2[Na]/TBW
How is the plasma osmolality estimated ?
2 x [Na+K]
Clinically 2x[Na]
What are measured disorders of plasma osmolality primarily due to ?
Abnormalities in water handling not abnormal sodium handling
What are the two ways that nephrons can be classified ?
Location within the cortex
Length of their loop of henle
What are the primary 3 locations within the cortex ?
Superficial
Midcortical
Juxtamedullary
Where does the short loop of henle turn into ?
Outer medulla or cortex
Where does the long loop of Henle turn back into ?
Inner medulla
Juxtamedullary nephrons have ____ loops
Long
What are vasa recta ?
Major blood vessels that carry blood into and out of the renal medulla
What are the two basic requirements for forming concentrated urine ?
- Hypertonic medullary interstitium
- generates osmotic gradient necessary for water reabsorption - High levels of ADH
- increases water permeability of DCT and CD
What are the major factors that contribute to excess buildup of solute ?
- Thick ascending limb of Loop of Henle
- Collecting ducts
- Passive Urea diffusion/recycling
- Diffusion of only a small amount of water from medullary tubules into interstitium
How does the thick ascending limb of the loop of Henle contribute to excess buildup of solute ?
Active transport of Na+ ions out into the interstitium
Con transport of Cl- ions, K+ ions, and other ions into the interstitium
How do the collecting ducts contribute to excess buildup of solute ?
- active transport of ions out of the CD into the interstitium
How does passive urea diffusion/recycling contribute to excess buildup of solute ?
- from the inner medullary collecting ducts —> medullary interstitium —> loop of Henle
Where in the kidney is ADH particularly active ?
Cortical collecting tubule
Inner medullary collecting tubule
Distal tubule
Which limb is the concentrating limb ?
Descending limb
Which limb is the diluting limb ?
Ascending limb
What is impermeable to urea?
Thick ascending limb
Distal tubule
Cortical collecting duct
Urea is ______ reabsorbed from the tubule
Passively
What is urea recirculated between ?
CD and loop of Henle
Where is the urea transport route ?
Along the paracellular route in proximal tubule
Describe proximal tubule urea reabsorption
Na+ is reabsorbed with H2O following.
As H2O leaves tubule, urea is concentrated —> urea gradient across tubule
Urea passively diffuses down this gradient along the paracellular route
Describe Urea transport in Loop and collecting duct
Tight junctions are tight
Urea is transported along transcellular route via facilitated diffusion (urea uniporter)
Urea levels in renal medulla are very high
-gradient favours secretion into loop
- gradient favours reabsorption from CT
Renal handling of urea summary
Freely filtered
Reabsorbed from proximal tubule
Secreted into loop of Henle
Reabsorbed again from collecting duct
How does the renal medullary blood flow help prevent dissipation of the hyperosmotic medullary interstitium ?
Medullary blood flow is low
- accounts for only 1-2% of renal blood flow
Vasa recta serve as countercurrent exchangers
-minimizes wash out of solutes from interstitium
What makes the vasa recta highly permeable to solutes ?
Fenestrated endothelium
What do vasa recta have channels for ?
Urea and water (aquaporins )
What are the basic requirements for forming concentrated urine ?
Hypertonic medullary interstitium
High levels of ADH
What two systems is plasma osmolarity regulated by ?
Osmoreceptor-ADH system
Thirst mechanism
Where does water reabsorption happen ?
70% from proximal tubule
15% from descending limb of loop of Henle
0-15% from collecting duct depending on plasma ADH level
How much fluid does the glomerulus filter per day from the plasma ?
180L
Where is ADH synthesized
By specilized nuclei in the hypothalamus (magnocellular nuclei)
What type of hormone is ADH ?
A preprohormone
What is ADH released in response to ?
- Change in plasma osmolality
- detected by osmoreceptors in the anterior hypothalamus - Change in blood pressure or in the blood volume
- detected by arterial baroreceptors and arterial stretch receptors
Describe the osmotic stimuli for ADH release
Increase plasma osmolarity —> osmoreceptors shrink
—> AP —> SON and PVN —> tips of their axons in post pit —> influx of Ca2+ ions —> ADH release from secretory granules —> ADH is carried away in post pit capillaries —> systemic circulation —> ADH increases water permeability of kidney in late distal tubules, cortical collecting ducts and inner medullary collecting ducts
Signals from osmoreceptors induce thirst mechanism
Describe the hemodynamic AVP release
Late responder
Insensitive (>10% change in volume/pressure)
Baroreceptors are the sensors
What 3 receptors coupled to G proteins does ADH bind to ?
V1a
V1b
V2
Where is the V1a receptor found and what does its activation lead to ?
Vascular smooth muscle
Increase intracellular Ca2+, resulting in contraction
Where is the V1b receptor found and what does its activation lead to ?
Ant pit
Modulates ACTH release
Where is the V2 receptor found and what does its activation lead to ?
Basolateral membrane of principle cells from the late distal tubule through the entire collecting duct
Coupled by Gs protein to cAMP —> insertion of water channels (aquaporins)
Water reabsorption mechanism with ADH
ADH binds to membrane receptor
Receptor activates cAMP second messenger system
Cell inserts AQP2 water pores into apical membrane
Water is reabsorbed by osmosis into the blood
In the abscense of ADH the collecting duct is ______ to water and the urine is ______
Impermeable, dilute
What is the obligatory urine volume ?
Minimal volume of water needed to excrete ingested and waste produced osmoles
Signs of hypoosmolality
Edema Hypotension Fatigue Lethargy Anorexia Confusion Ataxia Seizures
Hyper osmolarity signs
Thirst Polyuria Fatigue Hypotension Confusion Seizures
When is renin secreted ?
Decreased BP
Decreased renal arterial pressure
Decreased NaCl at macula densa cells
Effect of furosemide on ions
Hypokalemia
Metabolic alkalosis
Loss of Mg2+ and Ca2+ reabsorption
Indications for furosemide
CHF
Acute pulmonary edema
Peripheral edema
Adverse effects of loop diuretics
Hyponatremia Hypovalemia Hypotension Hypokalemia Metabolic alkalosis Ototoxicity
Mechanism of action of thiazide diuretics
Block Na+/Cl- symporter at distal tubule - increase Na+ secretion -decrease blood volume —> prevents maximal dilution of urine Dilation of arterioles - decrease BP
Clinical use for thiazide diuretics (hydrochlorothiazide)
Hypertension
Edema
Main adverse effects of thiazide diuretics
Hyponatremia
Hypokalemia
Metabolic acidosis
Mechanism of K+ sparing diuretics
Interfere with reabsorption of Na+ and secretions of K+/H+ at the cortical collecting tubule
Clinical use of spironolactone, amiloride
Edema
Heart failure
Primary hyperaldosteronism
Main adverse effects of K+ sparing diuretics
Hyperkalemia
What are the 3 primary purposes of RAAS?
maintain extracellular volume
regulate systemic vascular resistance
control cardiac output and arterial BP
how is angiotensinogen converted to Ang II?
angiotensinogen + renin –> Ang I –> Ang I + ACE –> Ang II
characteristics of Renin
proteolytic enzyme
primarily synthesized, stored and secreted from the kidney
Hypovolemia stimulates renin release via what 3 inputs ?
- renal sympathetic activation
- intrarenal baroreceptors
- macula densa
what are intrarenal baroreceptors ?
JG cells in afferent arteriole walls sensitve to BP
How are intrarenal barorecptors stimulated and what is the result ?
Low BP –> reduced stretch –> increase renin
How is the macula densa stimulated and what is the result ?
senses sodium conc in tubular fluid
low sodium beyond renal sympathetic nerves –> reduced GFR –> reduced tubular flow –> further renin secretion
what are non-ACE pathways that concert Ang I to Ang II
Chymase: produced in heart and vascular tissues
Cathepsins
Limited role under physiologic conditions
what do AT1 receptors mediate ?
most effects classically associated with RAAS
classification of aldosterone
Mineralocorticoid
where is aldosterone primarily found ?
zona glomerulosa adrenal cortex
what is the plasma half life of aldosterone ?
20 minutes
how much aldosterone is secreted daily ?
50-200 mg
what is aldosterone release stimulated by ?
Ang II and Ang III, ADH, endothelin
what is aldosterone inhibited by ?
ANP dopamine
what are the physiological actions of aldosterone ?
Na+ and water reabsorption
K+ and H+ excretion
Na+ and water reabsorption from gut, salivary glands and sweat glands
how does ang II alter peripheral resistance and what is the end result ?
i. direct vasoconstriction
ii. enhancement of peripheral noradrenergic neurotransmission
a. increased NE release
b. decreased NE reuptake
c. increased vascular responsiveness
iii. increased sympathetic discharge
iv. release of catecholamines from adrenal medulla
- -> rapid pressor response
how does ang II alter renal function and what is the end result ?
I. direct effect to increase Na+ reabsorption in proximal tubule
ii. release of aldosterone from adrenal cortex
iii. altered renal hemodynamics
a. direct renal vasoconstriction
b. enhanced noradrenergic neurotransmission in kidney
c. increased renal sympathetic tone
- -> slow pressure response
how does ang II alter cardiovascular structure and what is the end result ?
i. non-hemodynamically mediated effects
a. increased expression of proto-oncogenes
b. increased production of growth factors
c. increased synthesis of EC matrix proteins
ii. hemodynamically mediated effects
a. increased afterload
b. increased wall tension
- -> vascular and cardiac hypertrophy and remodelling
how does Ang II cause vasoconstriction ?
acts on AT1 receptor
increases intracellular Ca2+ –> vasoconstriction
how does SNS activation cause vasoconstriction?
ang ii mediated
increased NE release, decreased NE reuptake
____ arterioles are more sensitive than _____
efferent, afferent
Where in the kidney does aldosterone act ?
in distal and collecting duct to simulate Na+ reabsoprtion and K+ secretion
aldosterone negative outcomes
remodelling (hypertrophy, fibrosis)
arrhythmia
ischemia
volume (Na+ retention)
ACE 2 effects
AII –> Ang 1-7
opposes Ang II effects
side effects of ACE Inhibitor?
renal impairment hyperkalemia hypotension cough angioedema teratogenicity
contradictions to start ACE inhibitor
serum K+>5 mM serum creatinine > 200 uM critical aortic stenosis bilateral renal artery stenosis history of angioedema
how to use ACE inhibitor
check renal/electrolytes, initiate, recheck 1 week
up-titrate 2-4 weeks to maximum tolerated dose
recheck renal/electrolytes 7-10 days after increase
recheck renal/electrolytes at 3 months
renal/electrolytes 6 monthly once stable
Causes of exercise associated hyponatremia
excessive intake of hypotonic fluids
impaired renal water excretion due to ADH/AVP
sweat loss of sodium
inability to mobilize sodium stores
incidence of assymptomatic hyponatremia in endurance events
13-18 %
predisposing factors to exercise induced hyponatremia
exercise duration > 4 hours or slow running / exercise pace female low body weight excessive drinking during the event pre-exercise overhydration abundant avaliabily of drinking fluids at the event NSAIDs extreme hot or cold
Major classes of diuretics
carbonic anhydrase inhibitors (acetazolamide)
loop diuretics (furosemide)
thiazide diuretics (hydrochlorothiazide)
potassium sparing diuretics (spironolactone, amiloride)
action of acetazolamide (carbonic anhydrase inhibitor)
inhibits carbonic anhydrase–> renal loss of Na+ and HCO3-
- diuresis of an alkaline urine
- mild metabolic acidosis
major clinical use of acetazolamide
prevention of acute mountain sickness
treatment of open-angle glaucoma
how can acetazolamide help prevent acute mountain sickness ?
stimulating respiration through renal loss of Na+HCO3- –> metabolic acidosis of cerebrospinal fluid and hyperventilation
how can acetazolamide help treat open angle glaucoma ?
inhibit action of carbonic anhydrase –> reduce intraocular pressure.
topical application
mechnism of action of furosemide
inhibits Na+/K+/2Cl- at:
ascending loop of Henle –> reduce Na+ reabsorption, blood volume and BP
macula densa cells: inhibits detection of Na+ at distal tubule
dilates veins –> reduce venous pressure