Physiology: Tubular Function Flashcards
At what regions of the tubule does reabsorption occur?
All regions
Reabsorption of substances is non-specific/specific?
Filtration of substances is non-specific/specific?
Reabsorption = specific
Filtration = relatively non-specific (substance just needs to be able to bypass filtration barriers)
GFR is ~…?
Plasma is filtered ~ how many times per day?
GFR: ~125 ml/min
Plasma is filtered ~65x per day
Match the following substances with how they are reabsorbed from the filtrate in the kidney:
- Majority reabsorbed
- All reabsorbed
- Partially reabsorbed
- Not reabsorbed
Substances: creatinine, amino acids, urea, glucose, salt, fluid
- Majority reabsorbed: fluid + salt (~99% reabsorbed)
- All reabsorbed: amino acids + glucose (100% reabsorbed)
- Partially reabsorbed: urea (50% reabsorbed)
- Not reabsorbed: creatinine (0% reabsorbed)
Glomerular filtrate is a modified version of plasma. Why is it not identical?
The barriers to filtration prevent rbc’s and large plasma proteins from entering the Bowman’s capsule and contributing to the tubular fluid
What is the rate of flow of the filtrate entering the proximal tubule?
125 ml/min (GFR)
Why does the flow rate decrease by the time the tubular fluid reaches the Loop of Henle?
Because ~80ml/min of the filtrate is reabsorbed in the proximal tubule
What is the flow rate of tubular fluid entering the loop of Henle?
~45ml/min
125-80
What is the osmolarity of the tubular fluid along the proximal tubule?
It remains constant at ~300 mOsmol/L
Why does the osmolarity of tubular fluid not change along the proximal tubule?
Because equal amounts of salt and H2O are reabsorbed, the fluid remains iso-osmotic with the filtrate (~300 mOsmol/L)
List…
- 5 substances which are reabsorbed in the proximal tubule
- 7 substances which are secreted in the proximal tubule
Reabsorbed: sugars, amino acids, phosphate, sulphate, lactate
Secreted: H+, hippurates, neurotransmitters, bile pigments, uric acid, toxins, drugs e.g., penicillin, atropine, morphine
Describe the steps of the transcellular route of reabsorption
- Substance in the filtrate in the tubular lumen crosses the luminal membrane of a cell in the single epithelial cell wall of the nephron
- Substance moves through the epithelial cell and out of the basolateral membrane
- Substance is now in the interstitial fluid
- Substance is reabsorbed into the peritubular capillary/vasa recta
What 2 factors does the paracellular route of reabsorption depend on?
- Transcellular reabsorption (which drives simultaneous paracellular reabsorption of different substances)
- How tight the tight junctions between the adjacent cells of the tubular epithelium wall are (this varies at different segments of the proximal tubule)
Transcellular reabsorption is unique to each substance due to carrier-mediated membrane transport mechanisms. Name 3 types of transport mechanism
- Facilitated diffusion
- Primary active transport
- Secondary active transport
Describe the following mechanisms of carrier-mediated transport:
- Facilitated diffusion
- Primary active transport
- Secondary active transport
- Facilitated diffusion: passive carrier-mediated transport of a substance down its concentration gradient
- Primary active transport: carrier moves the substance across the membrane against its concentration gradient using energy from ATP hydrolysis
- Secondary active transport: the substance is transported coupled to the concentration gradient of an ion (usually Na+)
Na+ reabsorption is driven by…?
The basolateral Na+/K+ ATPase
Describe 3 ways in which Na+ can enter the apical membrane of the tubular epithelium before it exits the basolateral membrane via Na+/K+ ATPase
1) The Na+-dependent glucose transporter
2) The Na+-dependent amino acid transporter
3) The Na+/H+ countertransporter
Trancellular reabsorption of Na+ drives paracellular reabsorption of X and Y due to…?
Cl- and H2O
Cl-: due to the electrochemical gradient
H2O: due to the osmotic gradient (osmosis)
How do Na+ and H2O, now in the interstitial fluid, get pulled into the peritubular capillaries/vasa recta?
By oncotic drag of the peritubular plasma
i.e., water is attracted to the plasma proteins in the blood which pulls H2O and therefore water from the interstitial space into the capillaries
How are glucose and amino acids reabsorbed in the proximal tubule?
- They cross the luminal membrane of the tubular epithelium cell by Na+-dependent transporters
- They leave the basolateral membrane by facilitated diffusion
- Normally, 100% of glucose and amino acids from the filtrate are reabsorbed in the proximal tubule
What is meant by the…
- Transport maximum (Tm)
- Renal threshold
… of a substance?
- Transport maximum (Tm): the maximum rate at which a particular substance can be reabsorbed when all of the transport mechanisms for reabsorption have been saturated
- Renal threshold: the plasma concentration of the substance at its transport maximum, after which the kidneys will begin to excrete it in the urine
What is the renal threshold of glucose?
~10-12 mmol/L
Describe the appearance of a graph relating rates of filtration, reabsorption and excretion of glucose to plasma glucose concentration
- Increasing plasma glucose increases rates of glucose filtration
- Rate of filtration and reabsorption remain equal and rising as 100% of glucose is reabsorbed
- Once the renal threshold is reached at ~10-12 mmol/L, reabsorption levels off while filtration continues to rise
- Rate of excretion begins to rise from 0 at the renal threshold
Why is excess glucose excreted in the urine in diabetes?
Plasma glucose concentration increases above the renal threshold
Transport mechanisms for reabsorption are saturated and so excretion of glucose by the kidneys begins
Tubular secretory mechanisms can also become saturated. T/F?
True e.g., for PAH used to clinically determine renal plasma flow
Clearance of reabsorbed or secreted substances is constant once the transport maximum is reached. T/F?
False
Clearance is not constant. It continues to rise as plasma conc. rises
What proportion of.. - Salt - Water - Glucose - Amino acids ... are reabsorbed in the proximal tubule (not the entire length of the tubule)?
Salt + water: ~67% (2/3rds)
Glucose + amino acids: 100%
What is the function of the Loop of Henle?
To work together with the vasa recta to generate a cortico-medullary solute concentration gradient
What is meant by the cortico-medullary solute concentration gradient?
The progressively increasing osmolarity of the interstitial fluid surrounding the nephron as we move from the cortex and down into the medulla
What feature of the Loop of Henle sets up the cortico-medullary concentration gradient?
The ascending and descending limbs have differing permeabilities to salt and water
Describe the permeability of the…
- Descending limb
- Ascending limb
… of the Loop of Henle to salt and water
- Descending limb: no NaCl reabsorption, highly permeable to water so reabsorbed
- Ascending limb: Na+ and Cl- are reabsorbed, relatively impermeable to water so little or no reabsorption
How are Na+ and Cl- reabsorbed in the ascending limb of the Loop of Henle?
The Na+/K+/Cl- triple transporter takes them from the tubular lumen and across the luminal membrane of the tubular epithelium cell
They exit the basolateral membrane via the…
- Na+/K+ ATPase
- K+/Cl- co-transporter
(K+ is recycled across the same membrane it is absorbed so there is no net change in conc.)
How does this Na+ and Cl- reabsorption affect the osmolarity of the…
- Tubular fluid in the ascending limb
- Interstitial fluid
…?
- Tubular fluid in the ascending limb: becomes more diluted (as it is losing salt)
- Interstitial fluid: becomes more concentrated (as it is gaining salt)
As the interstitial fluid has become more concentrated, how does this affect filtrate being pumped down the descending limb?
Passive water efflux occurs as the filtrate moves down the descending limb
This means the filtrate becomes more concentrated as it moves down the descending limb
Summarise the concentrations of the tubular fluid and interstitial fluid throughout the loop of Henle
- Tubular fluid becomes progressively more concentrated as it moves down the descending limb and loses H2O
- Tubular fluid becomes progressively more dilute as it moves up the ascending limb and loses salt (NaCl)
- The interstitial fluid has a vertical gradient, becoming more concentrated as you move deeper into the medulla and further from the cortex
What is meant by countercurrent multiplication?
The cortico-medullary concentration gradient which is formed by the movement of NaCl and H2O through the different segments of the loop of Henle
What is the function of the countercurrent multiplication system?
To concentrate the medullary interstitial fluid, enabling the kidneys to produce urine of different volume and concentration according to hydration status/ADH levels
What are the... - Average - Lowest range - Highest range ... values for rate of urine excretion (Vu)?
Average: ~1 ml/min
Low e.g., in dehydration: 0.3 ml/min
High e.g., in over-hydration: 25 ml/min
What does the value of osmolality range from from the start of the descending limb to the end of the descending limb?
300 -> 1,200 mOsmol/L
Tubular fluid in the descending limb is hyper-/iso-/hypo- osmotic?
Iso-osmotic (as it has the same osmolarity as the tubular fluid)
Tubular fluid in the ascending limb is hyper-/iso-/hypo- osmotic?
Hypo-osmotic (as it has a lower osmolality than the interstitial fluid)
What does the value of osmolality range from from the bottom of the ascending limb to the top of the ascending limb?
1,000 -> 100 mOsmol/L
What is meant by ‘the two-solute hypothesis’?
NaCl and urea both work together to form the cortico-medullary concentration gradient
How does urea contribute to the cortico-medullary concentration gradient?
It adds solute to the interstitium
The X acts as a Y and forms a countercurrent system with the Loop of Henle
X - vasa recta
Y - countercurrent exchanger
How do the vasa recta of juxtamedullary nephrons act as a countercurrent exchanger?
- The capillary blood equilibrates with the interstitial fluid across its ‘leaky’ endothelium
- It runs alongside the loop of Henle and so…
- Blood osmolality rises as the vasa recta dips down into the medulla. This is because the permeable epithelium loses water and gains solute
- Blood osmolality falls as the vasa recta rises back up into the cortex. This is because the permeable epithelium gains water and loses solute
Normal blood flow from the cortex and through the medulla would wash away NaCl and urea. How do the vasa recta avoid this problem? (3)
- They follow hairpin loops back out into the cortex
- They are freely permeable to NaCl and water
- Blood flow to the vasa recta is low
Why is there no change in the osmolality of the blood between the efferent arteriole and the renal venules?
Because they are connected by the vasa recta which follow a hairpin loop through the medulla
This means that osmolality will rise back to 300 mOsmol/L as the vasa recta follows the loop of Henle back out into the cortex
So what is the function of the countercurrent exchanger formed by the vasa recta?
To…
- Preserve the cortico-medullary concentration gradient
- Ensure the salt and urea are not washed away
Summary: Which structures make up... - Countercurrent multiplication - Countercurrent exchanger - Countercurrent system ...?
- Countercurrent multiplication: Loop of Henle
- Countercurrent exchanger: Vasa recta
- Countercurrent system: Loop of Henle + vasa recta
Summary:
- The A and the B create the cortico-medullary concentration gradient
- The C preserves the cortico-medullary concentration gradient
- The high medullary osmolarity allows for the production of Y urine in the presence of Z
A - loop of Henle/countercurrent multiplier
B - urea cycle
C - vasa recta/countercurrent exchanger
Y - hypertonic/concentrated
Z - ADH
What is the osmolality of the tubular fluid entering the distal tubule? How does this compare to the surrounding interstitial fluid?
100 mOsmol/L (hypo-osmotic)
The surrounding interstitial fluid of the renal cortex is 300 mOsmol/L
The distal tubule empties into the collecting duct. What is the osmolarity of the interstitial fluid surrounding the collecting duct?
Osmolarity of the interstitial fluid surrounding the collecting duct progressively increases (from 300-1200 mOsmol/L) as it descends through the medulla
> 95% of filtered ions are reabsorbed in the distal tubule. T/F?
FALSE
> 95% of filtered ions have been reabsorbed before the filtrate reaches the distal tubule
Why is the small, residual load of ions in the filtrate (<5%) important?
It is essential for salt balance in the body
What is the function of the distal tubule and the collecting duct?
They are the major sites for the regulation of ion and water balance in the body
Why are the distal tubule and collecting ducts the major sites for the regulation of ion and water balance in the body?
The hormones that regulate ion and water balance in the body act on the cells of the distal tubule and collecting ducts to have their effect
What is the main hormone involved in regulating water balance?
Antidiuretic hormone (ADH, aka vasopressin)
What effect does ADH action have on the distal tubule and collecting duct?
ADH decreases the rate of urine production by stimulating water reabsorption by cells of the distal tubule and collecting duct
Name 3 hormones involved in regulating ion balance
Aldosterone Atrial natriuretic hormone/peptide (ANP) Parathyroid hormone (PTH)
How do the following hormones affect ion balance? Aldosterone Atrial natriuretic hormone/peptide (ANP) Parathyroid hormone (PTH)
Aldosterone:
- increases Na+ reabsorption
- increases H+/K+ secretion
Atrial natriuretic hormone/peptide (ANP):
- decreases Na+ reabsorption
Parathyroid hormone (PTH):
- increases Ca2+ reabsorption
- decreases phosphate reabsorption
Why is urea concentrated in the tubular fluid in the distal tubule?
Because the distal tubule usually has a low permeability to water and urea
When might the distal tubule have a higher permeability to water and urea?
Higher circulating ADH increases their permeability
Why is it important for urea to be concentrated in the distal tubular fluid?
To help establish the osmotic gradient within the medulla (remember the two-solute hypothesis with NaCl and urea)
The distal tubule can be divided into an early and a late segment.
Describe the ion transport that occurs in the early distal tubule
NaCl reabsorption (via the Na+/K+/2Cl- triple transporter)
The distal tubule can be divided into an early and a late segment.
List the ion transports that occurs in the late distal tubule
Ca2+ reabsorption
H+ secretion
Na+ reabsorption
K+ reabsorption (in the basal state)
When might K+ secretion, as opposed to reabsorption, occur in the late distal tubule?
When aldosterone acts on the cells, K+ is secreted instead
The collecting duct is also split into early and late segments.
The early collecting duct is similar to the early/late distal tubule?
Late distal tubule
The collecting duct is also split into early and late segments.
The late collecting duct has a low/high ion permeability?
Low
The collecting duct is also split into early and late segments.
The late collecting duct is permeable to X and Y, which is influenced by ADH
Water and urea
ADH is the main hormone involved in the control of water balance. Describe how it is…
- Synthesised
- Stored
- Released
- Synthesised: as an octapeptide by clusters of nerves in the hypothalamus
- Stored: in granules in the posterior pituitary
- Released: into the blood by Ca2+-dependent exocytosis when action potentials arise
Describe when and how ADH is released
- Increased plasma osmolarity e.g., during dehydration
- This is detected by hypothalamic osmoreceptors
- These signal to nerve cells in the hypothalamus to stimulate AP’s to the posterior pituitary
What is the plasma half-life of ADH?
10-15 mins
Describe the steps involved when ADH increases the water permeability of the distal tubule and collecting duct cells
- ADH binds to type 2 vasopressin receptors on the basolateral membrane (interstitial fluid side) of the cells
- Cell signalling response is stimulated, which increases cAMP
- Increased cAMP causes intra-cellular vesicles containing type 2 aquaporins to fuse
- These vesicles fuse with the apical membrane (tubular lumen side) and insert the aquaporins into the membrane
- Permeability of the membrane to water is now increased, so water reabsorption occurs
How does the permeability of the distal tubule and collecting duct cells to water change when ADH decreases again?
Vesicles take the aquaporins back into the cell and so water permeability decreases
How does high ADH (e.g., during dehydration) drive the formation of hypertonic urine?
Maximal plasma ADH conc. increases the permeability of the collecting duct to water as aquaporins are added to the membrane
Water moves from the collecting duct lumen into the interstitial fluid of the medulla by osmosis
This results in a smaller volume of concentrated urine
How does low ADH (e.g., during over-hydration) drive the formation of hypotonic urine?
Minimal plasma ADH conc. decreases the permeability of the collecting duct to water as aquaporins are removed from the membrane
The collecting duct is now impermeable to water, and so no water is reabsorbed into the interstitial fluid of the medulla
This results in a larger volume of dilute urine
Collecting duct tubular fluid equilibrates with the interstitial fluid via X in the presence of maximal/minimal plasma ADH conc.
X - aquaporins
In the presence of maximal plasma ADH conc.
Describe the effect of increasing plasma ADH on…
- Urine osmolarity
- Urine volume
- Total solute excretion
As plasma ADH increases,…
- Urine osmolality increases
- Urine volume decreases
- Total solute excretion stays the same (as ADH has no effects on salt excretion)
ADH is released in response to increased plasma osmolarity which is detected by hypothalamic osmoreceptors. Why does ADH cause H2O reabsorption as a response?
Increased H2O reabsorption…
-Reduces plasma osmolarity
-Increases plasma volume
… which reduces plasma osmolarity and increases ECF volume
As well as increasing water reabsorption, what else does ADH release trigger? (2)
- Increased thirst
- Arteriolar vasoconstriction
How does ADH cause vasoconstriction?
What effect does this have?
By acting on type 1 vasopressin receptors on arteriolar smooth muscle cells
Arteriolar vasoconstriction reduces arterial blood pressure and ECF volume
ADH release is normally triggered by hypothalamic osmoreceptors.
What other receptor may trigger its release and when?
Left atrial stretch receptors
This only occurs when there is a large decrease in arterial blood pressure and ECF volume
Why does a patient with diabetes insipidus produce large volumes of dilute urine?
Due to the inability to produce/secrete ADH (cranial DI) or failure of the kidneys to respond to ADH (nephrogenic DI)
Lack of ADH action means that the collecting duct has little or no permeability to water, and so water is retained in the collecting tubule lumen and not reabsorbed
How do... - Nicotine - Alcohol - Ecstasy ... affect ADH release?
- Nicotine: stimulates ADH release (so you pee less)
- Alcohol + ecstasy: inhibit ADH release (so you pee more)
Describe the feedforward inhibition of ADH by the upper GI tract
When drinking a large fluid load, stretch receptors of the upper GI tract are stimulated
This feeds forward to reduce ADH secretion which increases urine output
What is aldosterone?
A steroid hormone (a mineralocorticoid) secreted by the zona glomerulosa of the adrenal cortex
When is aldosterone secreted? (3)
In response to…
- Increasing plasma K+ conc.
- Decreasing plasma Na+ conc.
- Activation of the renin-angiotensin-aldosterone system (RAAS)
Rising plasma K+ directly/indirectly stimulates aldosterone release from the adrenal cortex?
(if indirectly, then state how)
Directly
Falling plasma Na+ directly/indirectly stimulates aldosterone release from the adrenal cortex?
(if indirectly, then state how)
Indirectly via the juxtaglomerular apparatus which activates the RAAS system
What affect does aldosterone release have? (2)
It acts on cells in the distal tubules and collecting ducts to stimulate…
- Na+ reabsorption
- K+ secretion
How does Na+ reabsorption lead to increased blood volume and pressure?
Because H2O follows Na+ and so is retained by the body
Normally, how much K+ is reabsorbed in the nephron and how much is excreted?
- ~90% reabsorbed in the early regions of the nephron (mainly the proximal tubule)
- The remainder is reabsorbed in the distal tubule
- No K+ is excreted in the urine (so 100% reabsorbed)
The presence of aldosterone still does not result in K+ being excreted in the urine. T/F?
False
Aldosterone stimulates K+ secretion which means that some K+ is excreted in the urine
Falling plasma Na+ indirectly causes aldosterone release via the juxtaglomerular apparatus which activates the RAAS system.
Which cells in the juxtaglomerular apparatus release renin?
Granular cells
What 3 stimuli cause granular cells in the JGA to release renin?
- Reduced pressure in the afferent arteriole (detected by granular cells)
- Reduced NaCl content in the distal tubular fluid (detected by macula densa cells)
- Increased sympathetic activity (as a result of reduced arterial blood pressure)
How does aldosterone increase Na+ reabsorption in the distal tubule and collecting duct? (2)
- Increases expression of apical Na+ channels which allows more Na+ to enter the cells
- Increases no. and activity of Na+/K+ pumps on the basolateral membrane which increases Na+ loss across the basolateral membrane
Abnormal increase in the RAAS system can cause…?
Hypertension and fluid retention
due to reabsorption of Na+ driving reabsorption of water
List 3 treatment options for abnormal increase in RAAS activity
- Low salt diet (less Na+ can be retained)
- Loop diuretics (increase urine output so decrease ECF volume)
- ACEIs (inhibit the RAAS system)
What is atrial natriuretic peptide (ANP)?
A hormone which is produced and stored in atrial myocytes in the heart
When is ANP released?
When atrial myocytes are mechanically stretched due to an increase in circulating plasma volume
How does ANP act to reduce blood pressure, plasma volume and Na+ reabsorption? (4)
ANP inhibits…
- Na+ reabsorption in the tubules
- The RAAS system
- The smooth muscle of afferent arterioles
- The sympathetic nervous system
What effect does ANP inhibiting each of these actions have?
- Na+ reabsorption in the tubules
- The RAAS system
- The smooth muscle of afferent arterioles
- The sympathetic nervous system
- Na+ reabsorption in the tubules and the RAAS system: increased Na+ and H2O excretion in urine
- The smooth muscle of afferent arterioles: increased GFR so increased Na+ and H2O excretion
- The sympathetic nervous system: decreased arterial blood pressure
The urine is stored in the bladder until it is appropriate for micturition (urination) to occur.
What are the 2 mechanisms that govern micturition?
- The micturition reflex (reflex control)
2. Voluntary control
Describe the micturition reflex (reflex control of urination)
- The bladder fills
- Stretch receptors in the bladder wall are activated once 250-400ml of urine accumulates
- Parasympathetic nerves are stimulated to cause the bladder to contract
- The internal urethral sphincter mechanically opens when the bladder contracts
Describe voluntary control of urination
- The cerebral cortex senses activation of stretch receptors in the bladder
- Cerebral cortex stimulates motor neurons to the external urethral sphincter to keep it constricted
- This prevents urination
- When it is appropriate to urinate, the motor neuron to the external sphincter is inhibited
- This allows the external urethral sphincter to relax and open, allowing for urination to occur
Voluntary control of urination overrides the micturition reflex. T/F?
True
