1
Q
What is the homeostatic set point for plasma urine concentration?
A
285-295 mosmol.l
2
Q
How is constant plasma osmolality maintained?
A
- urine formation
- thirst
kidneys can generate hyperosmotic/ hypoosmotic urine with high/low volume
3
Q
Plasma urine concentration when it is concentration urine?
A
> 300mosmol/l
4
Q
How much waste products are we obliged to eliminate each day?
A
600mosmol
5
Q
What is the maximum urinary concentration possible?
A
1400 mosmol.l
6
Q
Equation for obligatory water loss
A
obligatory water loss= (waste generated)/(max urine conc)
(600mosmol)/(1400mosm.l)= 0.428l
7
Q
What is oliguria?
A
Urine output <0.428l/day
8
Q
Why is there no fixed value for water loss?
A
- dependent on physiological state of the person e.g. fasting, tissue trauma
- ^ additional metabolic products are produced which must be eliminated, therefore there is an increased water loss
9
Q
Plasma urine concentration when it is dilute urine?
A
<300mosmol/l
10
Q
Lowest urine concentration possible?
A
50mosmol/l
11
Q
What is normal urine output?
A
1-2L/day
12
Q
What is polyuria?
A
excessive urine output
13
Q
What is maximum urine output?
A
23l/day
bladder can cope but eliminating so much urine would mean the patient would have to empty their bladder every 30 minutes
14
Q
Capacity of bladder?
A
500mL
15
Q
What does ideal urine look like?
A
Clear/ slightly straw coloured with no odour or bubbles
completely clear urine is not a sign of good health e.g. water diabetes or water intoxication
16
Q
Equation for osmolar clearance?
A
Cosm= (Uosm x V)/ Posm
Cosm= ml/min
V= urine flow rate (ml/min)
Uosm= urine osmolarity (mosm/ml)
Posm= plasma osmolarity (mosm/mL)
17
Q
Definition of osmolar clearance?
A
Volume of plasma cleared of osmotically active substances per unit time
(fictive flow of urine that would have resulted in a urine which was isomolar to plasma)
18
Q
Value for fasting osmolar clearance?
A
2-3mL/min
19
Q
What is free water clearance?
A
- reflects the ability of the kidneys to excrete dilute or concentrated urine
- used to assess renal function
20
Q
Equation for free water clearance
A
CH2O= V- ((Uosm * V )/ Posm)
CH2O > 0: hypo-osmotic urine (dilute)
CH2O = 0 isomotic urine with respect to plasma
CH2O < O hyperosmotic urine (concentrated)
Possible CH2) rangeL -1.3- 14.5 ml/min
- 14.5ml/min is in the complete absence of ADH
- -1.3 ml/min is maximum diuresis
21
Q
Where are osmoreceptors found?
A
OVLT- organum vasculosum lamina terminalis
MPN- medium preoptic nucleus
SFO- subfornical organ
22
Q
How is ADH released?
A
- Osmoreceptors signal to the magnocellular neurosecretory cells in the paraventricular and supraoptic nuclei in the hypothalamus
These cells produce and release ADH into the blood through the pituitary - Precursor molecule of ADH is passed along the axon to the posterior pituitary
As it is passed along, it is cleaved to form ADH (9 amino acids)
At the posterior pituitary, ADH released into blood of the internal carotid artery where it can go onto act at the level of the collecting duct
23
Q
Why is ADH very effective?
A
- short plasma half-life of 10-20 minutes
- rapid release
24
Q
At what plasma level of osmolality are thirst sensations stimulated?
When are ADH concentrations stabled and what is the threshold point?
A
295mosm/kg
osmolality reaches 295mosm/kg
- Below 280mosm/kg: ADH concentrations are stable
- Above 280mosm/kg: threshold point
Above threshold, there is a linear relationship between plasma ADH concentration and plasma osmolality
Even within normal range of plasma osmolality (285-295mosm/kg) there are changes in ADH concentration in the blood
25
What other factors affect ADH (vasopressin) secretion?
- blood pressure
- blood volume
ADH is most sensitive to changes in blood plasma osmolality
1% change in plasma osmolality: change in ADH
5% decrease in blood volume: change in ADH
10% change in BP: change in ADH
26
What increases and decreases ADH secretion?
angiotensin II increases ADH secretion
natriuretic peptides decreases ADH secretion
27
What other factors control ADH levels other than osmoreceptors?
```
Alcohol (inhibits ADH)
Nicotine (stimulates)
Nausea (stimulates)
Pain (stimulates)
Stress (stimulates)
```
28
Diabetes insipidus/ water diabetes
- Characteristics:
Polyuria (excessive urination eg. > 2L/day)
Polydispsia (thirst)
Nocturia (urination throughout night)
- Types:
1. Neurogenic: No ADH is secreted (problem at level of brain)
o Congenital (from birth)
o Head injury eg. trauma, brain tumour
2. Nephrogenic: problem at the level of the nephron
o Inherited ie. Mutated V2 receptor or AQP2 channel
o Acquired ie. Infection or side effect of drug such as lithium
29
Osmotic diuresis
- Characteristics:
Polyuria (urination >2L/day)
o Due to small molecules eg. glycerol, mannitol and excess glucose in the renal tube of lumen (and in urine)
o Typical of untreated diabetes mellitus
Polydipsia (thirst due to water lost)
- Mechanism:
1. Increased blood glucose
2. Increased glomerular filtration of glucose (not bound to protein)
o Concentration of glucose in filtrate is same as plasma, and since there is increased concentration there will be increased filtration of glucose
3. Increased osmolality in filtrate
4. Decreased water reabsorption from proximal tubule
5. Later portions of nephron cannot compensate as most water reabsorption occurs in PCT
30
concentration of sodium in extracellular fluid
5mM ECF
major cation is sodium
31
concentration of potassium in ICF
150mM
major cation is potassium
32
What is the excitable nature of cells dependent on?
Potassium permeability and potassium gradient
33
What is K+ intake in the diet?
It is variable with diet
40-120 mmoles/day
34
How does body control additional source of potassium?
via urine excretion
35
How much potassium does the kidney filter?
How much of this is reabsorbed?
800mmoles/day
(not bound to protein)
95% is reabsorbed
36
How does K reabsorption occur in PCT?
65% reabsorbed passively at the proximal tubule (majority- passive process following movement of sodium and water passively between cells)
There are no potassium reabsorption transporters expressed on luminal membrane (no specific transporter- passive)
- Higher concentration of K+ outside than inside the epithelial cell
Na+/K+ ATPase pump expressed at the basolateral membrane of PCT
Sodium is moving out of cell against concentration gradient whilst potassium moves into the cell
Potassium concentration inside cell is maintained by pump leak mechanism:
Potassium enters cell via pump and moves down out concentration gradient via potassium channel (leak)
37
K+ transport pathways in thick ascending limb?
- 30% reabsorbed here
- Na+:K+:2Cl- cotransporter (NKCC2 transporter)
Luminal membrane
38
K+ transport pathway on distal tubule?
- 5% reabsorbed in the distal tubule
K+/H+ exchanger: transporter on distal tube is the same one as the one found in intercalated cells of the collecting duct
39
K+ transport pathway in CD?
- K+ reabsorbed by intercalated cells (& distal cells) in exchange for H+
- Outweighed by:
K+ secretion by principal cells from Na+/K+ ATPase pump found on basolateral membrane
Exit routes
- Exit routes include:
Potassium channels
o ROMK: renal outer medullary K+ channel
o BK: Ca2+ activated big-conductance K+ channel
K+:Cl- cotransporter
40
Factors affecting K+ secretion by principal cells
- any factors affecting entry through ENaC channels
(removal of Na+ changes electrochemical gradient driving potassium movement)
- aldosterone stimulates K+ channels + stimulate activity of Na/K/ATPase pump
(increased secretion + excretion into urine)
- tubular flow rate (high flow rates favour excretion/ washing away electrochemical gradient due to high flow rate drives more K to be secreted through K channels)
- acid base balance
acidosis inhibits whilst alkalosis
(alters electrochemical gradient/ acidosis has more hydrogen ions, therefore inhibiting secretion since potassium is positively charged and therefore hydrogen is +ve)
41
How is potassium removed?
Renal excretion (kidney is main regulator)
From extracellular fluid by redistributing potassium into cells
Via faecal losses (GIT)
42
Mild, moderate and severe levels of hypokalaemia plasma [K+]
<3.5mM
Mild: 3-3.5 mM
Moderate: 2.5-3mM
Severe: <2.5mM
43
What is hypokalaemia caused by?
1) Increased external losses (most common)
GiT eg. vomiting, diarrhoea
Kidney eg. diuretics, osmotic diuresis, hyperaldosteronism, transporter mutations eg. ENaC, alkalosis **
Skin eg. burns, intense sweating
2) Redistribution into cells
Metabolic alkalosis**
Insulin excess**
3) Inadequate K intake (rare)
Starvation and prolonged fasting (must persist for several weeks before hypokalaemia develops)
44
How do loop diuretics and thiazide diuretics inhibit potassium reabsorption?
- Loop diuretics acting on the thick ascending limb (Na+/K+ cotransporter)
Inhibiting sodium reabsorption inhibits water reabsorption
Increase tubular flow rates
Inhibit potassium reabsorption increases the potassium concentration in the filtrate and so more excreted leading to hypokalaemia
- Thiazide diuretics acting on the distal tubule (Na+/Cl- cotransporter)
Inhibiting sodium reabsorption inhibits water reabsorption, which again increases tubular flow rates
- Summary: these inhibit sodium (and potassium) reabsorption and increase tubular flow rates (inhibits water reabsorption too)
45
How do transporter mutations favour K+ secretion?
Inhibit sodium reabsorption and increase tubular flow rates
Mutation on the epithelium sodium reabsorption transporter inhibits water reabsorption, again increasing tubular flow rates
- Osmotic diuresis (increased urine production)
Increases tubular flow rates
Increases potassium secretion
- Summary: High flow rates favour K+ secretion
46
How does hyperaldosteronims stimulate potassium secretion and excretion?
Stimulates activity of Na+ channel, K+ channel and Na+-K+ ATPase pump
Stimulates potassium secretion and excretion
47
Alkalosis plasma pH
> 7.45 (associated with hypokalaemia)
48
Acidosis plasma pH
< 7.35 (associated with hyperkalaemia)
49
Metabolic alkalosis
| Kidney increased external losses
- K+ secretion in principal cells increased by alkalosis (less H+ in filtrate)
- Related to changes in electrochemical gradient and secretion of K+ through K+ channels
50
Redistribution into cells
- Alkalosis means there is a higher pH and too few hydrogen ions in the extracellular fluid
- H+ ions bound to intracellular proteins (buffer) will leave intracellular protein to return plasma pH to normal (enter extracellular proteins)
- Potassium will take their place inside cells
Redistribution of potassium inside the cells leads to hypokalaemia
NB: skeletal muscle has largest volume of intracellular fluid in the body
51
Insulin
- Insulin excess: redistribution of potassium into cells
Stimulates the activity of Na+/K+ ATPase pump
Removes potassium from extracellular fluid into the cells
Hypokalaemia
52
Signs/ symptoms of hypokalaemia
- Mild: asymptomatic
- Moderate: confusion and muscle weakness
- Severe: affect organ systems (shown on right)
Affects resting membrane potential
Cells become hyperpolarised (more negative) and so nerves must depolarise more to achieve AP firing
In addition, Repolarisation is slower, therefore cells closer to threshold for longer, making them more excitable
53
How to treat hypokalaemia?
- Eat foods rich in potassium eg. bananas, spinach
- KCl administration (oral/iv)
- Alkalosis correction
- Use of potassium sparing diuretics (prevent secretion)
eg. spironolactone (inhibits aldosterone), amiloride (inhibits principal cell sodium channels
54
Causes of hyperkalaemia?
- Doesn’t often persist unless there is renal problems
Can be caused by:
1) Decreased external losses
Renal failure
Hypoaldosteronism
Action of drugs
2) Redistribution out of cells
Acidosis (exacerbated by lack of insulin in diabetic ketoacidosis)
Tissue destruction/cell lysis eg. rhabdomyolysis
NB: potassium is a major intracellular cation so any cell damage can cause potassium to leak into the fluid
55
Signs/ symptoms of hyperkalaemia
- Mild: [K+] 5.5 – 6.5mM
- Moderate: 6.5 – 7.5mM
- Severe: >7.5mM (can be fatal)
- Resting membrane potential is mainly determined by the potassium gradient
In hyperkalaemia, the resting membrane potential is shifted closer to the threshold for action potential firing (depolarises excitable cells)
56
Treatment of hyperkalaemia
- Short term: stabilise cardiac membrane
Calcium IV: antagonise effect of K+ on heart muscle to return membrane potential to normal
- Intermediate term: shifting potassium into the cells
Insulin administered with glucose to shift potassium into cells
Excess insulin stimulates Na+/K+ ATPase pump to shift
- Long term: remove potassium from the body
Increase K+ excretion with diuretics eg. loop diuretics and thiazides
Treat for renal failure
CVR
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