Week 9 Electrolyte Distribution Flashcards
1
Q
What is the ECF compartment subdivided into ?
A
Plasma
Interstitial fluid
2
Q
What is equivalence ?
A
Amount of substance dissolved in a solution relative to its molecular weight and stoichiometry
3
Q
What is osmolality ?
A
Number of solute particles per kg of H2O
4
Q
What is the importance of osmolality in the body ?
A
Determines the direction of water flow between compartments
5
Q
What are the most important solutes in extracellular fluids ?
A
Na+
Cl-
HCO3-
6
Q
What is oncotic pressure ?
A
Pressure generated by large molecules and proteins
7
Q
What is tonicity ?
A
The effect of a solution on the volume of the adjacent cell.
8
Q
What percentage of body weight is water ?
A
60% in males
50% in females
9
Q
What is the distribution of water between extra and intra cellular compartments ?
A
~1/3 ECF
~2/3 ICF
10
Q
What is the distribution of water in the EC compartment between the plasma and interstitial fluid ?
A
~3/4 interstitial
~1/4 plasma
11
Q
What determines hydrostatic pressure ?
A
Arterial/venous pressure
Length of capillary
Pre and post capillary sphincters
12
Q
What determines oncotic pressure ?
A
Permeability of the membrane to protein molecules
13
Q
What affects the movement of fluid across a membrane ?
A
SA
Permeability to water
Permeability to proteins
14
Q
What should the response be to immediate large losses of ECF fluid ?
A
Fluid resuscitation with appropriate fluid
15
Q
What is the response to sustained losses of ECF over time ?
A
Regulation through thirst and kidney
16
Q
What is the response to immediate and sustained gains of ECF fluid ?
A
Kidney regulation
17
Q
What is the response to immediate and sustained gains of ECF fluid in the absence of kidneys ?
A
Dialysis
18
Q
Determinants of effective circulating volume
A
Volume of ECF Volume of vascular space BP Cardiac output Intact sensors = baroreceptors
19
Q
What percentage of cardiac output do the kidneys recieve ?
A
20%
20
Q
What is a nephron ?
A
Functional unit of the kidneys
21
Q
How many nephrons does each kidney have ?
A
~ 1 million
22
Q
What is each nephron comprised of ?
A
Renal corpuscle (glomerulus + Bowman’s capsule) and its tubule
23
Q
The nest of the glomerular capillary between the ______ and ______ _______ allows for precise regulation of the intraglomerular forces governing the GFR
A
Afferent, efferent arterioles
24
Q
What is the first step in urine formation ?
A
Glomerular filtration
25
What is GFR the sum of?
Individual filtration rates of ~2 million glomeruli
26
What are podocyte foot processes linked by ?
Slit diaphragm
27
What is the glomerular filtration barrier ?
A size and charge selective sieve
28
What are the principle determinants of GFR ?
Starling forces
Glomerular capillary filtration coefficient
Glomerular plasma flow rate
29
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)
30
How is the glomerular capillary filtration coefficient determined ?
Hydraulic conductivity x SA
31
How does glomerular plasma flow (QA) effect GFR ?
Plasma flow increase —> increase GFR
32
What happens if glomerular capillary oncotic pressure increases ?
Decreases GFR
33
What is the minute to minute regulation of GFR is mostly by changes in what ?
PGC and QA
34
How are PGC and QA are controlled ?
By alterations in afferent and efferent arteriolar resistances
35
What happens to GFR and renal blood flow when afferent arteriole resistance increases ?
Both GFR and RBF decrease
36
What happens to GFR and renal blood flow as efferent arteriole resistance increases ?
GFR increases then decreases
| RBF decrease
37
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
38
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
39
Where does auto regulation occur and which part is most important ?
Preglomerular resistance vessels
| Afferent arterioles
40
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
41
What makes up the JG apparatus ?
JG cells
| Macula densa
42
What do JG cells do ?
Secrete renin
43
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
44
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
45
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
46
When is TGF more sensitive ?
During extracellular volume contraction: help conserve fluid and electrolytes
47
What mainly synthesizes and secretes renin ?
JG cells of AA
48
What is renin release stimulated by
Decreased effective circulating volume (decreased NaCl delivery at macula densa, decreased AA stretch) and increased SNS activity
49
Where is angiotensinogen synthesized ?
Proximal tubules
50
Where is ACE located ?
Proximal tubules
51
What is Ang II ?
A potent vasoconstrictor due to binding at the AT1 receptors especcialy affects the efferent arteriole
52
What does Ang II directly stimulate ?
Proximal tubular sodium absorption
53
Why does Ang II exert a greater vasoconstrictor on efferent arterioles than the afferent arterioles ?
Because vasodilatory prostaglandins dilate the afferent arteriole
54
What does decreased effective circulating volume and NSAID use often lead to ?
Acute kidney injury
55
Where is angiotensinogen mainly synthesized ?
The liver
56
Where is ACE mostly synthesized ?
Vascular endothelium in the lungs
57
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
58
What is the effect of aldosterone ?
Increase sodium reabsorption by principle cells in distal nephron
59
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
60
What does mild activation of the SNS cause
Decreased sodium and water excretion due to renin release
61
What effect does mild to moderate activation of the SNS have on renal blood flow and GFR
Little effect
62
What happens with strong activation of the SNS ?
Constrict renal arterioles
| Decrease renal blood flow and GFR
63
What is the effect if early diabetic nephropathy on GFR ?
Hyperfiltration —> increased GFR
64
Where does sodium intake come from ?
Ingested food and fluids
65
What is typical daily intake of NaCl
5-7 g
| 2-2.8 g Na (86-120 mmol) = output
66
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)
67
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
68
What stimulates low pressure sensors ?
Increasing pressure/stretch
69
What is the response when low pressure sensors are activated ?
Inhibition of ADH
| Release of ANP and BNP
70
Net effect of low pressure sensor activation
Decrease ADH —> increase diuresis (more water excretion)
ANP and BNP —> increased natriuresis
—> shrink blood volume towards normal
71
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)
72
Where are high pressure sensors located ?
Carotid artery, aortic arch, arterioles in the kidney
73
What stimulates high pressure sensors ?
Decrease in arterial pressure (more sensitive to pressure than volume)
74
What is the response when high pressure sensors are activated ?
Increase in SNS activity
Stimulation of ADH release
Activation of RAAS
Inhibition of ANP
75
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
```
76
What is the renal sensor for effective circulating fluid volume
JG apparatus
77
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+]
78
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
79
What happens further down the proximal tubule ?
Cl- gradient established —> passive reabsorption of NaCl
| —> water follows as osmoles leave the proximal tubule lumen
80
What has been reabsorbed by the end of the proximal tubule ?
~60% if NaCl and ~60% of water reabsorbed
| [Na+] is same as plasma
81
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
82
What is the site of action for loop diuretics ?
NKCC2
83
What happens in the early part of the distal tubule ?
NaCl is reabsorbed without any water
| NaCl symporter is main channel
84
Where do thiazide type dieuretics act ?
NCC symporter
| Commonly used to treat hypertension
85
What happens in the collecting duct/tubule
Principle cells carry out NaCl reabsorption via Na+ channel (ENaC)
86
Where does aldosterone act ?
Collecting duct/tubule
| Increase Na+ reabsorption in exchange for K+ excretion
87
What is the overall effect of prostacyclin ?
Afferent arteriolar vasodilation and natriuresis
88
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
89
What is the main prostaglandin in the kidney?
Prostacyclin (PGI2)
90
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
91
What do NSAIDS do when PGI2 levels are high ?
Remove counter regulation —> sodium retention, hypertension, lower GFR
92
What does increasing SNS acitivity of renal sympathetic nerves lead to ?
Renin secretion
| Increased Na+/H2O reabsorption
93
What are the effects of ANP and BNP ?
Increase GFR and natriuresis
| Antagonism of most RAAS actions
94
What is uroguanylin ?
Produced in intestine in response to salt intake
| Reduces renal sodium reabsorption
95
What happens with increased effective circulating fluid volume ?
```
Increase GFR
Decrease renin secretion
Decrease aldosterone secretion
Decrease Na+ reabsorption
Increase Na+ and H2O excretion
```
96
What is edema caused by ?
Sodium excess
| Treat by causing a negative sodium balance
97
What is the most common cause of death in the world ?
Volume depletion
98
What does sodium regulation determine ?
ECF volume
99
What does water regulation determine ?
Body osmolality
100
What is the formula for tonicity ?
Tonicity = ECF solute + ICF solute / TBW = 2[Na] + 2[K] /TBW ~ 2[Na]/TBW
101
How is the plasma osmolality estimated ?
2 x [Na+K]
| Clinically 2x[Na]
102
What are measured disorders of plasma osmolality primarily due to ?
Abnormalities in water handling not abnormal sodium handling
103
What are the two ways that nephrons can be classified ?
Location within the cortex
| Length of their loop of henle
104
What are the primary 3 locations within the cortex ?
Superficial
Midcortical
Juxtamedullary
105
Where does the short loop of henle turn into ?
Outer medulla or cortex
106
Where does the long loop of Henle turn back into ?
Inner medulla
107
Juxtamedullary nephrons have ____ loops
Long
108
What are vasa recta ?
Major blood vessels that carry blood into and out of the renal medulla
109
What are the two basic requirements for forming concentrated urine ?
1. Hypertonic medullary interstitium
- generates osmotic gradient necessary for water reabsorption
2. High levels of ADH
- increases water permeability of DCT and CD
110
What are the major factors that contribute to excess buildup of solute ?
1. Thick ascending limb of Loop of Henle
2. Collecting ducts
3. Passive Urea diffusion/recycling
4. Diffusion of only a small amount of water from medullary tubules into interstitium
111
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
112
How do the collecting ducts contribute to excess buildup of solute ?
- active transport of ions out of the CD into the interstitium
113
How does passive urea diffusion/recycling contribute to excess buildup of solute ?
- from the inner medullary collecting ducts —> medullary interstitium —> loop of Henle
114
Where in the kidney is ADH particularly active ?
Cortical collecting tubule
Inner medullary collecting tubule
Distal tubule
115
Which limb is the concentrating limb ?
Descending limb
116
Which limb is the diluting limb ?
Ascending limb
117
What is impermeable to urea?
Thick ascending limb
Distal tubule
Cortical collecting duct
118
Urea is ______ reabsorbed from the tubule
Passively
119
What is urea recirculated between ?
CD and loop of Henle
120
Where is the urea transport route ?
Along the paracellular route in proximal tubule
121
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
122
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
123
Renal handling of urea summary
Freely filtered
Reabsorbed from proximal tubule
Secreted into loop of Henle
Reabsorbed again from collecting duct
124
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
125
What makes the vasa recta highly permeable to solutes ?
Fenestrated endothelium
126
What do vasa recta have channels for ?
Urea and water (aquaporins )
127
What are the basic requirements for forming concentrated urine ?
Hypertonic medullary interstitium
| High levels of ADH
128
What two systems is plasma osmolarity regulated by ?
Osmoreceptor-ADH system
| Thirst mechanism
129
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
130
How much fluid does the glomerulus filter per day from the plasma ?
180L
131
Where is ADH synthesized
By specilized nuclei in the hypothalamus (magnocellular nuclei)
132
What type of hormone is ADH ?
A preprohormone
133
What is ADH released in response to ?
1. Change in plasma osmolality
- detected by osmoreceptors in the anterior hypothalamus
2. Change in blood pressure or in the blood volume
- detected by arterial baroreceptors and arterial stretch receptors
134
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
135
Describe the hemodynamic AVP release
Late responder
Insensitive (>10% change in volume/pressure)
Baroreceptors are the sensors
136
What 3 receptors coupled to G proteins does ADH bind to ?
V1a
V1b
V2
137
Where is the V1a receptor found and what does its activation lead to ?
Vascular smooth muscle
| Increase intracellular Ca2+, resulting in contraction
138
Where is the V1b receptor found and what does its activation lead to ?
Ant pit
| Modulates ACTH release
139
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)
140
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
141
In the abscense of ADH the collecting duct is ______ to water and the urine is ______
Impermeable, dilute
142
What is the obligatory urine volume ?
Minimal volume of water needed to excrete ingested and waste produced osmoles
143
Signs of hypoosmolality
```
Edema
Hypotension
Fatigue
Lethargy
Anorexia
Confusion
Ataxia
Seizures
```
144
Hyper osmolarity signs
```
Thirst
Polyuria
Fatigue
Hypotension
Confusion
Seizures
```
145
When is renin secreted ?
Decreased BP
Decreased renal arterial pressure
Decreased NaCl at macula densa cells
146
Effect of furosemide on ions
Hypokalemia
Metabolic alkalosis
Loss of Mg2+ and Ca2+ reabsorption
147
Indications for furosemide
CHF
Acute pulmonary edema
Peripheral edema
148
Adverse effects of loop diuretics
```
Hyponatremia
Hypovalemia
Hypotension
Hypokalemia
Metabolic alkalosis
Ototoxicity
```
149
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
```
150
Clinical use for thiazide diuretics (hydrochlorothiazide)
Hypertension
| Edema
151
Main adverse effects of thiazide diuretics
Hyponatremia
Hypokalemia
Metabolic acidosis
152
Mechanism of K+ sparing diuretics
Interfere with reabsorption of Na+ and secretions of K+/H+ at the cortical collecting tubule
153
Clinical use of spironolactone, amiloride
Edema
Heart failure
Primary hyperaldosteronism
154
Main adverse effects of K+ sparing diuretics
Hyperkalemia
155
What are the 3 primary purposes of RAAS?
maintain extracellular volume
regulate systemic vascular resistance
control cardiac output and arterial BP
156
how is angiotensinogen converted to Ang II?
angiotensinogen + renin --> Ang I --> Ang I + ACE --> Ang II
157
characteristics of Renin
proteolytic enzyme
| primarily synthesized, stored and secreted from the kidney
158
Hypovolemia stimulates renin release via what 3 inputs ?
1. renal sympathetic activation
2. intrarenal baroreceptors
3. macula densa
159
what are intrarenal baroreceptors ?
JG cells in afferent arteriole walls sensitve to BP
160
How are intrarenal barorecptors stimulated and what is the result ?
Low BP --> reduced stretch --> increase renin
161
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
162
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
163
what do AT1 receptors mediate ?
most effects classically associated with RAAS
164
classification of aldosterone
Mineralocorticoid
165
where is aldosterone primarily found ?
zona glomerulosa adrenal cortex
166
what is the plasma half life of aldosterone ?
20 minutes
167
how much aldosterone is secreted daily ?
50-200 mg
168
what is aldosterone release stimulated by ?
Ang II and Ang III, ADH, endothelin
169
what is aldosterone inhibited by ?
ANP dopamine
170
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
171
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
172
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
173
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
174
how does Ang II cause vasoconstriction ?
acts on AT1 receptor
| increases intracellular Ca2+ --> vasoconstriction
175
how does SNS activation cause vasoconstriction?
ang ii mediated
| increased NE release, decreased NE reuptake
176
____ arterioles are more sensitive than _____
efferent, afferent
177
Where in the kidney does aldosterone act ?
in distal and collecting duct to simulate Na+ reabsoprtion and K+ secretion
178
aldosterone negative outcomes
remodelling (hypertrophy, fibrosis)
arrhythmia
ischemia
volume (Na+ retention)
179
ACE 2 effects
AII --> Ang 1-7
| opposes Ang II effects
180
side effects of ACE Inhibitor?
```
renal impairment
hyperkalemia
hypotension
cough
angioedema
teratogenicity
```
181
contradictions to start ACE inhibitor
```
serum K+>5 mM
serum creatinine > 200 uM
critical aortic stenosis
bilateral renal artery stenosis
history of angioedema
```
182
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
183
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
184
incidence of assymptomatic hyponatremia in endurance events
13-18 %
185
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
```
186
Major classes of diuretics
carbonic anhydrase inhibitors (acetazolamide)
loop diuretics (furosemide)
thiazide diuretics (hydrochlorothiazide)
potassium sparing diuretics (spironolactone, amiloride)
187
action of acetazolamide (carbonic anhydrase inhibitor)
inhibits carbonic anhydrase--> renal loss of Na+ and HCO3-
1. diuresis of an alkaline urine
2. mild metabolic acidosis
188
major clinical use of acetazolamide
prevention of acute mountain sickness
| treatment of open-angle glaucoma
189
how can acetazolamide help prevent acute mountain sickness ?
stimulating respiration through renal loss of Na+HCO3- --> metabolic acidosis of cerebrospinal fluid and hyperventilation
190
how can acetazolamide help treat open angle glaucoma ?
inhibit action of carbonic anhydrase --> reduce intraocular pressure.
topical application
191
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
