Renal Physiology Flashcards
1
Q
How much Ca2+ and phosphate do the kidneys excrete in comparison to the amount entering the body via the GI tract?
A
The same amount
2
Q
Which metabolite and hormone can increase intestinal Ca2+ and phosphate absorption?
A
Vitamin D can help to activate the hormone calcitriol, and this hormone increases absorption of Ca2+ and phosphate.
3
Q
Which enzyme activates Vitamin D3?
A
1a-hydroxylase
4
Q
Where is 1a-hydroxylase produced?
A
The proximal convoluted tubule
5
Q
What regulates the levels of 1a-hydroxylase enzyme?
A
Parathyroid hormone
6
Q
How does calcium levels affect the levels of parathyroid hormone?
A
Calcium sensing receptors on the parathyroid gland release parathyroid hormone.
7
Q
What does PTH do to the concentration of Ca2+ and phosphate?
A
1) Increased Ca2+ and phosphate reabsorption from the bone.
2) Increased Ca2+ and decreased phosphate reabsorption from the kidneys
3) Increases calcitriol production in the kidney which increases Ca2+ and phosphate absorption.
All increases plasma Ca2+ levels.
8
Q
Outline how PTH increases Ca2+ reabsorption in the proximal convoluted tubule
A
1) Binding of PTH to the PTH receptor increases levels of intracellular cAMP.
2) Increased cAMP down regulates 2 phosphate dependant transporters, so more phosphate excretion from the PCT cells occurs.
9
Q
Outline how PTH increases Ca2+ reabsorption in the distal convoluted tubule
A
1) PTH regulates the transient receptor potential channel (TRPV5).
2) Increased levels of cAMP up regulates TRPV5, so more Ca2+ is reabsorbed from the lumen.
3) Plasma membrane calcium ATPase channels (PMCA) transports the Ca2+ into the bloodstream, so overall more Ca2+ reabsorption.
10
Q
In the body is calcium or phosphate regulation prioritised?
A
Calcium balance is prioritised over phosphate balance.
11
Q
When is erythropoietin produced?
A
When the blood pO2 decreases
12
Q
Where is erythropoietin produced from?
A
Interstitial fibroblasts in the kidney
13
Q
Where does erythropoietin act?
A
It acts on the bone marrow
14
Q
Where is renin secreted from in the kidney?
A
The granular cells of the afferent arteriole
15
Q
List 3 reasons why renin is released from the kidneys
A
1) Reduced pressure in the afferent arteriole - sensed by macular densa cells
2) Increased sympathetic activity
3) Decreased levels of Na+ in the DCT - sensed by macular densa cells
16
Q
What is the function of renin?
A
To cleave angiotensin to angiotensin 1.
17
Q
What happens when angiotensin 1 travels through the capillary endothelial cells in the lung?
A
The angiotensin converting enzymes on the surface of these cells convert angiotensin 1 to angiotensin 2.
18
Q
Which substance is only excreted in those with diabetes?
A
Glucose will be excreted in the urine also by those patients who have diabetes
19
Q
What is diabetic neuropathy?
A
When there is scarring and an expanded interstitium of the kidney, which severely affects kidney function.
20
Q
What is polycystic kidney disease?
A
When cysts appear throughout the kidney from the nephron tubules.
It is an autosomal dominant disease.
21
Q
What are the two routes/pathways a substance can take when crossing a cell membrane?
A
Paracellularly (between the tight junctions of cells)
Transcellularly (across the cell)
22
Q
Which organ has the highest blood flow per unit mass?
A
The kidneys
23
Q
Which substances pass from the glomerular capillaries to the Bowman’s capsule?
A
Water, urea, salts, ions.
These are at roughly the same concentration as they are in the plasma.
Large blood proteins do not pass across the filtration barrier.
24
Q
Define the glomerular filtration rate
A
This is the sum of the filtration rates of all the nephrons in the body.
25
What happens to the GFR if the number of functioning nephrons is reduced?
The GFR will decrease, thereby resulting in chronic renal failure.
26
What properties does a substance have to have in order to be used to measure the GFR?
1) Substance has to be freely filtered from the glomerular capillaries.
2) Substance should not be reabsorbed into the capillaries
3) Substance should not further be excreted into the tubules from the capillaries
27
Which 2 substances are commonly used to calculate the GFR?
Inulin and creatinine
28
What is the equation for GFR?
Conc of inulin in urine x flow rate in the kidneys
÷
Conc of inulin in the plasma
29
What are podocytes?
Podocytes are cells that wrap around the glomerular capillaries.
Between their primary processes there is the filtration slit, which is spanned by the protein nephron.
30
List 3 structural elements of the basement membrane
1) Endothelial pores - usually plugged by glycocalyx to prevent large proteins passing through.
2) Basement membrane that connects the podocytes and endothelial cells.
3) Filtration slits, fenestrations that allow substances to pass across the membrane.
31
What does a mutation in the nephron protein result in?
Cogenital nephrotic syndrome, there is an abnormal or absent filtration slit diaphragm.
32
What does a mutation in the type IV collagen result in?
Alport syndrome, affects the basement membrane in the Bowman's capsule
33
Which 2 factors affect how effectively a substance is freely filtered from the glomerular capillaries?
1) Molecular weight -> if molecule is large it may not be able to pass between the filtration slits.
2) Charge -> glomerular filtration barrier is negative, so large negatively charged molecules will be repelled from the surface.
34
What kinds of molecules can get through the glomerular filtration barrier?
Filterability suddenly decreases when molecular diameter increases past 3 nm.
Anions filterability decreases faster at a smaller diameter than neutral molecules, as the negative charge repels so it blocked from being filtered more quickly.
(small, neutral/positive molecules)
35
Which 4 forces are acting on the glomerular capillaries, and controls filtration?
1) Hydrostatic pressure in glomerular capillary from the systolic blood pressure.
2) Hydrostatic pressure in the Bowman's capsule
3) Oncotic pressure in the glomerular capillary due to the large plasma proteins being left in the capillary.
4) Oncotic pressure in the Bowman's capsule - this is negligible as the flow removes filtrate along the tubules quickly.
36
How do you calculate the net ultrafiltration pressure?
Net ultrafiltration pressure = Net hydrostatic pressure - Net oncotic pressure
37
How does the filtration rate change from the afferent arteriole to the efferent arteriole?
The oncotic pressure in the glomerular capillary increases in the the efferent end.
This means the net ultrafiltration pressure decreases, so filtrate rate decreases.
38
Which changes to 3 factors will reduce the GFR?
1) Decrease in hydrostatic pressure in capillary
2) Increase in hydrostatic pressure in the Bowman's capsule
3) Increase in oncotic pressure in the capillaries.
39
How does the renal plasma flow affect the filtration rate?
Increase in renal plasma flow increases the filtration rate.
40
Which drug can cause afferent arteriole constriction?
Adenosine
41
What does afferent arteriole constriction cause?
It decreases the hydrostatic pressure and decreases renal blood flow.
Decreases GFR.
42
Which drug can cause efferent arteriole constriction?
Angiotensin 2
43
What does efferent arteriole constriction cause?
It increases hydrostatic pressure and decreases renal blood flow.
Increases GFR.
44
Which drug can cause afferent arteriole dilation?
Prostaglandins and NO
45
What does afferent arteriole dilation cause?
Increases hydrostatic pressure and increases renal blood flow.
Increases GFR.
46
What can cause efferent arteriole dilation?
Blocking of angiotensin 2 receptors
47
What does efferent arteriole dilation cause?
Its decreases hydrostatic pressure and increases renal blood flow.
Decreases GFR.
48
What is the difference between inulin and creatinine as a substance used to calculate GFR?
Inulin is not secreted or excreted from the bloodstream, however some creatinine is secreted back into the tubules.
49
What is the equation for filtration fraction?
Glomerular filtration rate
÷
Renal plasma flow
50
What occurs in auto regulation as the blood pressure increases?
The vascular resistance also increases.
51
Which part of the kidney is affected by blood pressure changes?
Only the afferent arteriole will vasoconstrict depending on the change in blood pressure.
52
What is the autoregulatory renal plasma flow range in human?
90-180mmHg
53
Outline the myogenic mechanism of the afferent arterioles
An increase in blood pressure increases the stretch in the afferent arteriole.
This stretch opens non specific cation channels within the arteriole, which therefore causes depolarisation of those cells.
The Ca2+ channels then open, which causes the afferent arteriole to contract.
Vasoconstriction of the afferent arteriole decreases hydrostatic pressure and renal blood flow, thereby decreasing the GFR.
54
Outline the mechanism of tubuloglomerular feedback
An increase in blood pressure increases the filtration rate in the glomerulus.
This delivers more NaCl and water into the DCT.
The macula densa cells surrounding the DCT detect this increase in NaCl by taking up Na+. This causes ATP release, which then initiates a Ca2+ release in the mesangial cells which is in the gap junction between macula densa cell and smooth muscle cell. This leads to afferent arteriole constriction.
Adenosine can also lead to the vasoconstriction of the afferent arterioles.
In turn this will decrease the GFR and renal blood flow so less NaCl is filtered and more is reabsorbed.
55
What can override the auto regulatory system when the blood pressure is below 90mmHg or above 200mmHg?
Nerves, hormones (extrinsic factors)
56
How can the sympathetic nervous system override auto regulation?
Sympathetic activity can cause afferent and efferent arteriole constriction.
This particularly occurs during haemorrhage, when the sympathetic nervous system diverts blood flow away from other vital organs.
57
Which hormone causes vasoconstriction of the afferent arteriole?
Adrenaline
58
How does adrenaline override auto regulation?
Adrenaline increases sympathetic activity, which then increases afferent arteriolar constriction.
Increased afferent arteriolar constriction decreases the hydrostatic pressure and decreases the renal blood flow, resulting in a decreased glomerular filtration rate.
59
What is the purpose of the SGLT2 transporter?
These glucose transporters have a low affinity and high capacity for glucose, and cotransport glucose into the PCT cells with Na+.
60
What do SGLT2 transporter inhibitors do?
1) These decrease glucose uptake therefore decrease the blood glucose concentration and HbA1c levels.
2) Less glucose reabsorption causes unintentional weight loss.
3) Less glucose in blood reduces blood pressure.
4) It is cardiovascular protective.
5) It is renal protective.
61
How does diabetes mellitus affect the function of SGLT2?
When diabetic, more glucose is transported to the nephron. This means more SGLT2 transporters have to be transcribed in order to increase the glucose uptake.
This indirectly also increases the Na+ uptake into he capillaries.
This prevents the tubuloglomerular feedback mechanism from occurring (this is stimulated by an increase in Na+ in the tubule).
Means that the filtration of glucose cannot be decreased.
62
What happens when an SGLT2 inhibitor is given to a diabetic person?
The inhibitor prevents more SGLT2 transporters from being transcribed.
This means more glucose (and Na+) remains in the tubule, therefore the tubuloglomerular feedback mechanism can be stimulated to reduce glucose reabsorption overall.
63
Define renal clearance
The volume of plasma that would be required to supply that amount of the substance excreted per unit.
64
Can renal clearance be measured using any compound?
Yes! But the value obtained will depend on how the substance is handled by the kidneys.
65
When is the clearance equal to the the glomerular filtration rate of that substance?
When the substance is freely filtered, and is not reabsorbed or secreted.
66
If the clearance is less than inulin what has happened?
More reabsorption of that substance has occurred
67
If the clearance is greater than inulin what has happened?
More secretion from the capillaries has occurred.
68
What has happened if the renal clearance is 0?
Either it is completely reabsorbed or not filtered at all.
69
What is one drawback of renal clearance methods?
Does not provide information about a specific substance or precise sites or mechanisms of transport.
70
The clearance of which specific substance gives the renal plasma flow?
Para amino hippurate
71
Outline how inulin is used as a measure of renal clearance
It is a polysaccharide of fructose which has to be infused intravenously.
Requires continuous blood sampling every 10-20 minutes.
72
Outline how creatinine is used as a measure of renal clearance
It is an endogenous by product of muscle metabolism that is released into the blood at a constant rate.
Only requires one blood sample, but because there is some secretion from the capillaries use of creatinine overestimates GFR by 10-20%.
73
What happens to the urinary excretion when the GFR decreases?
The urinary excretion also decreases as the GFR decreases.
74
What happens to plasma creatinine when the urinary excretion decreases?
The plasma creatinine will increase as it is not being filtered.
However this then reverses and leads to higher plasma creatinine excretion in the urine.
Means that a decrease in GFR is proportional to an increase in plasma creatinine.
75
Does a small or large change in plasma creatinine concentration have large effects on GFR?
Small changes in plasma creatinine has large effects on the GFR.
76
What is the normal range for GFR?
90-140 ml/min
77
Why is PAH used to calculate plasma renal flow?
PAH is secreted from peritubular capillaries (from a Tm dependant mechanism) into the PCT.
At low plasma concentrations, almost all the PAH arriving in the renal plasma is excreted in the urine.
78
List 4 factors that can affect the normal range of GFR?
1) Age
2) Sex
3) Racial group
4) Body size
79
Define what Tm (transport maximum) means
Tm = The point where an increase in concentration does not result in an increase in movement of a substance across a membrane. Applies to both absorptive and secretory processes.
80
Describe the flow of PAH through the tubules and peritubular capillaries
20% of PAH is filtered in the Bowman's capsule. The rest is secreted into the tubules in the PCT. Means that all PAH is excreted.
Results in a high renal flow but zero renal clearance.
81
Does the flow of PAH have a high or low Tm saturation?
The filtration of PAH has a Tm at high plasma concentration.
| This means the clearance is not representative of the renal plasma flow.
82
What is Fick's principle regarding PAH entering the kidney?
The amount of PAH entering the kidneys per minute is equal to the amount of PAH leaving the kidneys per minute.
83
What is the equation for renal plasma flow?
Excreted load of PAH
÷
Arterial PAH conc - Venous PAH conc
84
How do you calculate the excreted load of PAH?
This is the conc of PAH in the urine x the flow rate
85
What happens to the plasma clearance as the concentration of inulin increases?
The plasma clearance stays the same.
86
What happens to the plasma clearance as the concentration of PAH rises?
Above a certain concentration the plasma clearance starts to decrease.
87
Why does plasma clearance decrease when PAH conc rises?
Because the clearance process becomes saturated - the Tm has been reached.
Means that only when there is a low PAH conc the clearance of PAH is equal to the renal plasma flow.
88
How do you convert Renal Plasma Flow to Renal Blood Flow?
RBF is the RPF ÷ (1-haematocrit)
89
Define the filtration fraction
This is the ratio of the GFR to the RPF - the fraction of plasma that is actually filtered across the glomerular capillaries.
90
What could cause an increase in the filtration fraction?
Severe haemorrhage
91
What happens when the filtration fraction is increased?
The hydrostatic pressure decreases and the oncotic pressure in the peritubular capillaries increases.
Overall this results in increased reabsorption.
92
What happens when the filtration fraction is decreased?
The hydrostatic pressure increases and oncotic pressure in the peritubular capillaries decreases.
Overall this results in decreased reabsorption.
93
What is glycosuria?
Presence of glucose in the urine
94
Why does glycosuria occur in those with diabetes mellitus?
The excessive amount of glucose in the blood cannot all be filtered, as the number of transporters on the cell membranes is limited.
This means the transporters become saturated and the Tm is reached. Results in some glucose having to be excreted.
95
What is the relationship between glucose clearance and glucose plasma concentration?
As the glucose plasma concentration increases above 200 mg/dL (when the Tm of the glucose transporters has been reached) the clearance of glucose also increases.
96
Which glucose transporter becomes saturated in diabetes?
SGLT2 transporters
97
Which glucose transporter is present in the proximal straight tubule?
SGLT1 transporter, for remaining 3% of glucose.
98
List 3 drugs used to treat diabetes
1) Dapagliflozin
2) Canagliflozin
3) Empagliflozin
99
Define the meaning of 'splay' in regards to SGLT2 glucose transporters
When plasma glucose increases, the glucose transporters reach the transport maximum gradually.
This is because different nephrons have different levels of expression of SGLT2, so saturation will also be gradual.
100
What is the equation for the calculating the transport maximum?
Tm = Filtered rate - Excreted rate
101
How do you calculate the filtered rate for glucose?
The conc of plasma glucose x GFR
102
How do you calculate the excreted rate of glucose?
The amount of glucose in the urine x The rate at which the urine is produced
103
If the transport rate of a solute is close to zero what does this mean?
This means there is no reabsorption or secretion of that solute.
104
If the transport rate of a solute is negative what does this mean?
The solute is secreted
105
If the transport rate of a solute is positive what does this mean?
The solute is reabsorbed
106
List the 5 main ways in which renal function can be measured
1) GFR -> inulin, creatinine
2) RPF -> PAH
3) RBF -> RPF ÷ (1-haematocrit)
4) Filtration fraction
5) Changes in tubular transport rates
107
How many stages are in the Chronic Kidney Disease quality initiative?
5
108
What is the GFR level below if a patient is stage 5 Chronic Kidney Disease?
Less than 15 ml/min
109
What is the RIFLE criteria for AKI?
```
Risk
Injury
Failure
Loss
ESRD
```
110
What should be carried out if ESRD persists for more than 3 months?
RRT -> renal replacement therapy
111
Where are the sites of Na+ reabsorption in the nephron?
PCT, Descending loop of Henle, Thick ascending loop of Henle, DCT and collecting tubule (regulated by aldosterone)
112
Where are the sites of water reabsorption in the nephron?
PCT, Descending loop of Henle, collecting tubule (regulated by ADH)
113
Which transporter reabsorbs water?
Aquaporins
114
What percentage of Na+ and water is reabsorbed in the PCT?
70%
115
What are the vasa recta?
These are the peritubular capillaries that travel alongside nephrons to allow reabsorption and secretion between blood and the inner lumen of the nephron.
116
By which process are very small proteins reabsorbed from the PCT?
Endocytosis
117
What is proteinuria?
Condition where the DCT is damaged, so hormonal proteins like ADH are lost in the urine.
118
How does the retention of large proteins in the peritubular capillary affect reabsorption?
The colloid oncotic pressure is lower, paired with a lower hydrostatic pressure = more is retained and reabsorbed in the capillaries.
119
How are glucose, amino acids , phosphates and water transported across the luminal membrane in the PCT?
1) The Na+/K+ ATPase exchanger on the basolateral membrane creates a diffusion gradient of Na+ into the PCT cell.
2) K+ channels on the basolateral membrane allow K+ to leave the cell down its concentration gradient, and also allows it to be recycled.
3) This Na+ concentration gradient allows glucose, amino acids and phosphate to be cotransported across the luminal surface.
4) H+ ions are exchanged with the Na+ ions - this is seen in gastric parietal cells in the production of HCl.
5) Cl- is transported paracellularly across tight junctions and into the interstitial fluid.
6) AQP 1 channels are also present on the luminal and basolateral membrane of PCT cells, allowing water to freely be reabsorbed.
120
What are the 2 types of Na+/glucose cotransporters present on the PCT?
There are some cotransporters that are coupled to only 1 Na+ -> these transport most of the glucose into the cell
Some cotransporters are coupled to 2 Na+ -> these transport the remaining glucose into the cell even when glucose concentration in the lumen is low.
121
How many different Na+/amino acid cotransporters are there on the PCT lumen?
There are 8 different luminal cotransporters for each type of amino acid.
122
How do you calculate the amount of glucose filtered through the kidneys?
Amount of glucose filtered = GFR x Plasma conc of glucose
123
Do Na+ coupled glucose transporters have limited capacity?
Yes, they do have a Tm. However this is hardly ever exceeded, so a high Tm value is not needed.
124
Would defective SGLT1 transporters cause renal glycosuria?
No, because these transport a minimal amount of glucose into the capillaries so it would not make a big difference.
125
How does presence of glucose in the urine also cause osmotic diuresis?
Glucose particles are osmotically active, so greater content of glucose in tubules increases colloid oncotic pressure inside the tubule. Results in movement of water into the tubules from the capillaries, which can result in dehydration.
126
What are the 2 parts of the loop of Henle?
The thin descending limb
| The thick ascending limb
127
How is water and Cl- transported across the luminal and basolateral membranes of the thin descending loop of Henle?
1) AQP 1 is expressed on the luminal membrane, allowing water to be freely reabsorbed.
2) Cl- channels are also expressed on the apical and basolateral membrane, so that the tubular fluid has a similar concentration as the interstitial surrounding the loop of Henle.
128
How are cations of K+, Na+ and 2Cl- reabsorbed from the lumen of the thick ascending loop of Henle?
1) The Na+/K+ ATPase exchanger on the basolateral membrane creates a diffusion gradient of Na+ into the cell.
2) The K+ channels on the basolateral membrane help to maintain polarisation of the cell even with an influx of negative Cl- ions.
3) The ROMK K+ channels on the luminal surface allow K+ to be recycled for the Na+/K+/Cl- cotransporter.
4) The NKCC2 transporter on the apical surface cotransports Na+(down conc gradient from ATPase), K+(against conc gradient) and Cl-(down conc gradient).
5) The Cl- channel on the basolateral membrane allows Cl- to move into the vasa recta capillaries.
6) The cells of the thick ascending limb of the loop of Henle are impermeable to water.
129
What is the Cl- specific channel in the thick ascending loop of Henle made up of?
It is made up of CLC-Kb and Barttin subunits.
130
How does the lumen of the cells in the thick ascending loop of Henle obtain a lumen positive transepithelial potential?
The presence of the NKCC2 transporter means that more negative Cl- ions are transported into the cells than the positive Na+ or K+.
This means the luminal surface of the cells has lumen-positive transepithelial potential.
131
What is the purpose of the lumen-positive transepithelial membrane in the thick ascending loop of Henle?
This allows the paracellular shunts to attract positively charged cations of Na+, K+ and Ca2+(they are repelled by the luminal membrane).
132
Why is paracellular shunting of positive cations in the thick ascending loop of Henle usefull?
Prevents any back leak of Cl- from the paracellular pathway, as the channels are only specific to cations.
133
The graph of Cl- uptake into the cells of the thick ascending loop of Henle is sigmoidal. What does this explain about the way Cl- is taken up through NKCC2?
Means that Cl- enters through positive cooperativity.
| This also means that at low concentrations the NKCC2 transporter is not fully saturated.
134
What are the equilibrium potentials on the basolateral membrane of the cells of the thick ascending loop of Henle?
The equilibrium potential of K+ is -90mV.
| The equilibrium potential of the Cl- is -30mV.
135
What is the equilibrium potential on the luminal membrane of the cells of the thick ascending loop of Henle?
The equilibrium potential of K+ is -90mV.
136
What trans cellular voltage is generated in the thick ascending loop of Henle to transport cations paracellularly?
+8mV
137
How many Na+ is transported across the membrane of the thick ascending loop of Henle for one ATP hydrolysis?
6 Na+
138
How many Na+ is transported across the membrane in the DCT for one ATP hydrolysis?
3 Na+
139
How is Na+ and Cl- reabsorbed in the DCT?
1) The Na+/K+ ATPase exchanger creates a diffusion gradient for Na+ into the cell.
2) K+ channel on the basolateral membrane allows the recycling of K+ for the ATPase exchanger.
3) The Na+/Cl- cotransporter on the apical membrane allows Na+ and Cl- to enter the cell.
4) Cl- channel on the basolateral membrane allows Cl- to enter the vasa recta.
5) The cells of the DCT are impermeable to water.
140
Why does hydrolysis of one ATP move less Na+ into cells of DCT than the thick ascending loop of Henle?
Because in the DCT the concentration of Na+ is so low that more energy from ATP is required to move the same amount Na+.
141
How is water and Na+ reabsorbed in the principle cells of the collecting tubule?
1) The Na+/K+ ATPase exchanger creates a diffusion gradient of Na+ into the principle cell.
2) K+ channels on the basolateral membrane allow the recycling of K+ for the ATPase exchanger to continue function.
3) Na+ enters the cells down ts conc gradient through ENaC channels.
4) ROMK channels for K+ on the apical membrane ensures the membrane potential doesn't get too close to the Na+ equilibrium. Restores voltage.
5) Water is reabsorbed across the luminal surface by AQP 2 which is regulated by ADH.
6) Water is reabsorbed into he capillaries across the basolateral membrane by AQP 3 and 4.
142
How are ENaC channels regulated in principle cells?
ENaC channels are responsive to aldosterone - produced from the renin-angiotensin pathway.
More aldosterone increases expression of ENaC.
If the intake of Na+ is too high then ENaC is degraded by the ubiquitin pathway to reduce the intake.
143
How does ADH regulate the reabsorption of water in principle cells of the collecting duct?
Increased levels of ADH increase the levels of cAMP through adenyl cyclase through a G protein pathway, by binding to the V2 vasopressin receptor. This activates protein kinase A, which is made up of 2 catalytic and 2 regulatory subunits. When cAMP binds to the regulatory subunit it dissociates and releases active protein kinase A, which directly phosphorylates AQP 2 channels. ADH also increases exocytosis of AQP2 vesicles onto the luminal membrane.
AQP 3 and 4 are constantly active on the basolateral membrane for trans cellular water transport.
144
Which cells in the collecting duct are responsible for controlling acid base balance?
Alpha intercalated cells
145
Outline the processes by which alpha intercalated cells control acid base balance
1) The reaction of H2O and CO2 and dissociation of the carbonic acid results in H+ and HCO3- being produced in the cell.
2) H+ is then removed from the cell through a H+/K+ ATPase exchanger and a singular H+ ATPase exchanger into the luminal membrane.
This allows the kidney to excrete more H+ when needed.
3) HCO3- is moved into the capillaries across the basolateral membrane by a HCO3-/Cl- exchanger.
4) Cl- channels on the basolateral membrane allow the recycling of Cl- into the HCO3- exchanger.
146
What is the Cl- specific channel on the basolateral membrane of alpha intercalated cells made up of?
They are made up of CLC-K and Barttin
147
Name another cell type other than alpha intercalated cell that controls acid base balance in the collecting duct
Beta intercalated cells
148
What is the function of beta intercalated cells?
These cells are able to move HCO3- into the lumen and H+ into the bloodstream
149
What is the function of alpha intercalated cells?
These cells are able to move H+ into the lumen and HCO3- into the bloodstream
150
In which state would the body want to move more bicarbonate into the lumen of the collecting duct and more H+ into the bloodstream?
Hyperventilation
151
In which state would the body want to move more H+ into the lumen of the collecting duct and more bicarbonate into the bloodstream?
Hypoventilation
152
Which 3 transporters can Bartter's syndrome affect?
NKCC2 -> in the thick ascending limb of Henle
ROMK -> in the thick ascending limb of Henle, and in the principle cells of the collecting tubule
CLC-Kb Bartinn -> in the thick ascending limb of Henle
153
Outline what happens when ROMK is affected by Bartter's syndrome
Only some reabsorption can occur of Na+, causing fluid to accumulate.
This can be seen clinically as lots of fluid in the womb due to the embryo urinating.
154
Outline what happens when CLC-Kb Barttin is affected by Bartter's syndrome
CLC-Kb is mostly expressed in the ear so lack of Cl- reabsorption in the bloodstream can lead to deafness in children.
BUT CLC-Ka is also present on the membrane and this can transport the Cl- instead.
155
Which transporter does Gitelman's syndrome affect?
Affects the Na+/Cl- transporter in the DCT, so less Na+ is reabsorbed.
Can be corrected by increasing salt intake.
156
Is Gitelman's syndrome symptomatic?
It is only symptomatic when the conc of Mg2+ is low.
Less Mg2+ reabsorbed so neuronal membrane voltage cannot be stabilised.
Can result in epileptic seizures.
157
Which transporter does East syndrome affect?
Affects the K+ channel on the basolateral membrane on the DCT.
Means that the function of the Na+/K+ ATPase exchanger is reduced, leading to increased Na+ uptake.
This can result in hypertension.
158
What are some symptoms of East syndrome?
Mutation of channel 10 -> epileptic shock, renal tubulopathy
Mutation of channel 16 -> affects K+ handling
159
Which transporter does Liddle syndrome affect?
ENaC Na+ channel transporters
160
What is a result of Liddle syndrome?
Overactivation of Na+ reabsorption from excessive ENaC activation close to the collecting duct means loss of Na+.
= pseudohypoaldosteronism, body is behaving as if there is no aldosterone present.
161
How does diabetes insipidus affect water handling of the nephron?
Nephrogenic -> body does not respond to ADH stimulation due to V2 receptors being misfolded
Central -> lack of ADH or mutation of ADH receptors (eg with pituitary tumours, head surgery/trauma)
162
How does inappropriate antidiuresis affect water handling of the nephron?
Patient has a gain of the V2R receptor that retains water in the tubules.
Means serum Na+ conc becomes very low and osmolarity is very low.
163
How does the nephron maintain a hypertonic medulla for a concentration gradient of water out of the collecting duct and descending loop of Henle?
The active salt transport out of the thick ascending limb of Henle is greater than the water reabsorption into the capillaries in the descending loop of Henle.
Majority of water is then reabsorbed in the collecting duct through AQP 2, using the hypertonic environment of the medulla (from salt transport).
164
What properties of the loop of Henle allows for more water reabsorption in the descending loop and more NaCl reabsorption in the thick ascending limb?
The descending loop of Henle is impermeable to solutes (salts) but is permeable to water. This allows water to move into the medullary space, and countercurrent flow means the tubular fluid becomes increasing hypertonic.
The thick ascending loop of Henle is impermeable to water but is permeable to solutes (salts). This makes the tubular fluid hypotonic and the interstitium becomes hypertonic.
165
Which organelle allows the active transport of salts out of the thick ascending limb of the loop of Henle?
Mitochondria
166
What occurs in the vasa recta in comparison to the ascending loop of Henle?
The descending part of the vasa recta is adjacent to the ascending limb of loop of Henle.
This means Na+ is actively transported into the descending vasa recta, which makes the blood hypertonic.
167
What occurs in the vasa recta in comparison to the descending loop of Henle?
The ascending part of the vasa recta is adjacent to the descending limb of the loop of Henle.
This means water is transported into the ascending vasa recta, which makes the blood iso osmotic.
168
What is the purpose of the mechanism of vasa recta and the loop of Henle?
It allows the water and salt to be reabsorbed without changing the osmolarity of the blood itself.
169
What is ADH produced by in the hypothalamus?
2 nuclei: Supraoptic nucleus and Paraventricular nucleus
170
Where is ADH secreted from when there are changes in plasma osmolarity?
Posterior pituitary gland
171
What are the 2 methods by which ADH secretion is determined by?
1) Detecting plasma osmolarity -> very sensitive method
| 2) Detecting plasma volume -> less sensitive
172
How is plasma osmolarity detected for ADH secretion?
Osmoreceptors detect increases in osmolarity. This results in secretion of ADH.
This causes more aquaporins to be regulated to produce a hypertonic urine.
173
How is plasma volume detected for ADH secretion?
Baroreceptors detect decreases in plasma volume. This results in secretion of ADH,
This causes more aquaporins to be regulated to produce a hypertonic urine.
174
At what plasma osmolarity does the secretion of ADH begin to increase?
280 mosm/L
175
What happens in a person that has Syndrome of Inappropriate Antidiuretic (SIADH)?
This is when ADH is secreted at higher levels than normal.
| This means blood osmolarity is kept at lower level than what it normally should be - blood is slightly more hypotonic.
176
Why is some urea reabsorbed into the capillaries from the tubule?
Urea reabsorption into the vasa recta from the collecting tubule allows the osmolarity in the medulla to remain high, so that more reabsorption of water from the collecting tubule can take place.
177
What is the concentration of the fluid in the tubule when maximal ADH is secreted?
Maximal ADH means that the maximum amount of water is reabsorbed from the tubular lumen, and there is the greatest saturation of AQP2.
In addition there is more reabsorption of salt in the thick ascending limb, also making the medulla more hypertonic.
178
Why do animals in the desert have along loop of Henle?
A longer loop of Henle means reabsorption of water into the vasa recta and rebabsorption of salt to make the medulla more hypertonic can occur for a greater length.
Means the animal can retain more water.
179
What is the concentration of the fluid in the tubule when minimal ADH is secreted?
Minimal ADH means that aquaporin channels are not activated.
Means that filtrate that already has a low osmolarity goes through more salt reabsorption in the DCT and collecting duct, further making the filtrate hypotonic.
Means the urine is very dilute.
180
How can central diabetes insipidus be treated?
Treated with ADH analogue nasal sprays and carbamazepine.
181
How can nephrogenic diabetes insidious be controlled?
Treated with high affinity pharmacophores that have a strong agonistic effect to artificially fold the misfolded proteins.
182
What is a symptom of nephrogenic and central diabetes insipidus?
Very little water reabsorption, resulting in large volumes of dilute urine.
183
What is a symptoms of SIADH? (syndrome of inappropriate ADH secretion)
Too much water reabsorption in the collecting duct.
| Low urine output despite marked hyponatraemia. (less salt)
184
How can SIADH be controlled?
Treated with water restriction, CAVE rapid correction.
185
How can NSIAD be controlled? (nephrogenic syndrome of inappropriate antidiuresis)
Treated with water restriction.
186
What occurs in NSIAD?
V2 receptor for ADH continually activates adenyl cyclase producing cAMP without a bound agonist.
187
What does ADH also control the excretion of apart from water?
ADH also controls urea excretion in the collecting tubule, which dictates by how much urea contributes to the osmolarity of the medulla interstitium.
188
What determines the water content and volume of the extracellular volume?
The content of osmotically active solute (Na+) in the filtrate determines the volume of extracellular fluid.
189
Through which mechanism is there uncontrolled output of Na+?
Sweating through skin and faeces is uncontrolled output of Na+.
190
Through which mechanism is there controlled output of Na+?
Urine excretion is where there is controlled output of Na+.
191
What is the definition of the effective circulating volume?
The effective circulating volume is an indication of the fullness of the circulatory system.
Normally this is proportional to the extracellular volume.
192
In which conditions is the effective circulating volume decreased but the total extracellular volume is not decreased?
Heart failure
Liver cirrhosis
Ascites
Oedema
193
What mechanism can help to increase the effective circulating volume when it has decreased?
Increased Na+ reabsorption to the capillaries can help to increase the effective circulating volume. (creates a diffusion gradient for water from high water potential to low water potential in the capillaries, which will increase the effective circulating volume).
194
Which 3 pressures are monitored in calculating the effective circulating volume?
1) Arterial pressure
2) Venous pressure
3) Juxtaglomerular apparatus pressure
195
Which receptors detect changes in arterial pressure?
Baroreceptors
196
Which receptors detect changes in venous pressure?
Atrial receptors, Pulmonary vasoreceptors
197
What detects changes to the pressure in the juxtaglomerular apparatus?
The cells surrounding the macula densa around the afferent arteriole.
These are also controlled by renal nerves that stimulate the secretion of renin.
198
What is the body's reaction to a decrease in effective circulating volume?
Decreased in arterial/venous pressure -> increased renal sympathetic nervous activity(alpha 1 receptors) -> causes afferent arteriole constriction -> decrease in renal blood flow -> decrease in glomerular filtration rate(increased reabsorption) -> stimulates reabsorption in PCT -> stimulates renin release from juxtaglomerular apparatus in the nephron
199
What 2 factors cause increased renin secretion from the juxtaglomerular apparatus?
1) Increased renal sympathetic activity
| 2) Decreased renal perfusion pressure
200
What occurs after renin is produced in response to renal sympathetic activity and decreased renal perfusion pressure?
Renin converts angiotensin from the liver into angiotensin 1.
Angiotensin converting enzyme from the pulmonary endothelium converts angiotensin 1 to angiotensin 2.
201
What are the 3 effects of angiotensin 2 in the body?
1) Causes increased reabsorption of Na+ from the proximal convoluted tubule.
2) Causes increased secretion of aldosterone from the renal gland.
3) Increases thirst
202
What is the effect of aldosterone in the collecting duct?
Aldosterone binds to DNA in the nucleus through a receptor and increases transcription of regulatory proteins and ENaC.
This results in the up regulation of Na+/K+ ATPase pumps and ENaC channels, which allows for increased uptake of Na+.
It also negatively targets ubiquination of ENaC which targets ENaC for degradation.
203
What is the body's reaction to an increase in the effective circulating volume?
Increase in atrial/venous pressure -> Decrease in renal sympathetic activity -> Reduced vasoconstriction of afferent arteriole -> Increased GFR (less reabsorption) -> Decreased angiotensin 2 -> Decreased aldosterone
Increase in release of atrial natriuretic peptide -> decreased Na+ reabsorption
204
What is the function of ANP?
It dilates the afferent arteriole, increases GFR, decreases ENaC activity and inhibits renin secretion.
205
What is the effect of dopamine on the GFR?
Dopamine increases vasodilation of the afferent arteriole.
| This increases the GFR and the renal plasma flow, which decreases water absorption.
206
What is a major function of albumin in the blood vessels?
It contributes to the colloid oncotic pressure inside the blood vessels so it can offset the hydrostatic and blood pressure.
Means the net filtration in the capillary bed is close to zero.
207
Is albumin present in extracellular fluid?
No, it is an effective osmole so cannot pass across the membrane
208
What are the short term changes made my the ANS that allow circulation to meet the body's metabolic needs?
Heart rate and vascular tone.
209
What are the longer term changes made by ANS to allows circulation to meet body metabolic needs?
Altering NaCl excretion by the kidneys
210
Which is more important to maintain, circulation or constant osmolarity?
Circulation takes precedence.
211
How much of plasma osmolarity does Na+ contribute?
Na+ contributes 270 mosm from 290 mosm
212
What are the function of WNK kinases?
These regulate transporters associated with Cl- and K+
213
What does the renal clearance of Na+ depend on?
It depends on the amount of Na+ in the body, NOT Na+ conc in extracellular fluid
214
How does weight change as NaCl intake increases?
As NaCl increases, weight increases until it reaches a constant
215
Can you measure effective circulating volume?
No, it is a functional volume that indicates the fullness of the circulation
216
What is an example of a change in effective circulatory volume?
Compared to when standing, the urinary Na+ output is higher when immersed in warm water.
This is because hydrostatic pressure of being in the water increases the venous return.
217
What is an example of when Na+ excretion doesn't affect the effective circulatory volume?
In oedemic states such as congestive heart failure, hepatic cirrhosis, nephrotic syndrome.
This is when there is high extracellular volume but low Na+ excretion.
218
Which blood vessels sense the effective circulatory volume the best and why?
Thoracic low pressure vessels are isolated from pressure changes due to being in the negative pressure of the thoracic cavity.
This means they can sense the effective circulatory volume very well.
219
Where are the low pressure sensors for effective circulating volume?
The cardiac atria
The pulmonary vasculature
220
Where are the high pressure sensors for effective circulating volume?
The carotid sinus
The aortic arch
The juxtaglomerular apparatus (afferent arteriole)
221
Are there also sensors for effective circulating volume in the CNS and liver?
Yes!
222
Outline the mechanism of angiotensin II how it increases effective circulating volume?
1) Angiotensin II stimulates release of noradrenaline, thereby increasing the sympathetic effects.
2) This causes vasoconstriction of the afferent and efferent arterioles.
3) This reduces the GFR and reduces the RBF.
4) This causes a decrease in the hydrostatic pressure in the capillary and increases the colloid osmotic pressure.
5) This makes Na+ reabsorption increase in the PCT.
6) Overall results in decreased Na+ excretion and decreased H2O excretion.
223
Where is angiotensin synthesised?
The liver
224
Where is renin produced and stored?
It is produced bu the juxtaglomerular apparatus in the kidney and is stored in granules by the granular cells in the juxtaglomerular apparatus.
225
What is the function of renin?
To cleave angiotensin to angiotensin I
226
What cleaves angiotensin I to angiotensin II?
Angiotensin converting enzyme (ACE), which is present on vascular endothelia (lungs and kidneys especially).
227
In what 3 circumstances is renin released by the kidney?
1) Lowered systemic blood pressure
2) Decreases NaCl conc at the macula densa
3) Decreased renal perfusion pressure
228
How does lowered systemic blood pressure cause renin release?
1) Baroreceptors detect low effective circulating volume and low blood pressure.
2) This stimulates the medullary control centres to increase sympathetic outflow to the juxtaglomerular apparatus.
3) This results in renin release.
229
How does decreased NaCl conc in the macula densa cause renin release?
1) A decrease in effective circulating volume results in a decreased GFR.
2) This means there will be less NaCl being filtered so the conc of NaCl will be lowered in the macula densa.
3) This results in renin release.
230
How does decreased renal perfusion pressure cause renin release?
1) The granular cells in the receptors of afferent arterioles detect decreased stretch due to a lower effective circulating volume.
2) Decreased stretch lowers the conc of Ca2+.
3) This results in the release of renin.
231
Name a drug that can inhibit the renin response (prevent vasoconstriction)
Propanlol
232
What is the result of WNK1 and 4, Cullin-3 mutations that overactive NCC channels in the DCT?
Results in more reabsorption of NaCl, so will cause hypertension.
233
What could be the result of reduced effective circulating volume?
Heart failure, severe haemorrhage shock, hypovolaemic shock, septic shock.
234
What causes hyperaldosteronism?
More aldosterone means there will be a greater number of ENaC channels in the collecting duct.
This results in hypernataemia and chronic volume expansion due to more water also being reabsorbed.
235
What happens to plasma osmolarity when pregnant?
The osmolarity decreases by 8-10 mosm.
236
How does alcohol and opiate antagonists affect concentration of urine?
These drugs inhibit ADH release, resulting in increased excretion of water.
237
What can organs use locally to control blood flow and pressure within them?
Vasodilators and vasoconstrictors
238
List some examples of vasoconstrictors
Prostaglandins
Products from activated platelets
Leukocytes
Endothelins
239
List some examples of vasodilators
```
Increased O2
Increase metabolic acids (lactate)
Increase in NO
Increase in K+ conc
Increase in H+ conc
Inflammation
Increase in body temperature
```
240
What are the main functions of PTH?
1) Increase Ca2+ reabsorption
2) Bone resorption of Ca2+
3) Stimulate production of calcitriol (vitamin D)
241
List 6 factors affecting plasma potassium concentration
1) Insulin levels (stimulates K+ uptake)
2) Aldosterone (decreases K+ in plasma)
3) Diuretics (increases K+ excretion)
4) Acid base status (alkalosis increases K+ excretion, acidosis increases K+ absorption unless being compensated)
5) Cell lysis/trauma (increases K+ concentration)
6) Renal failure (K+ cannot be excreted properly)
242
Are non volatile acids handled by the lungs or the kidneys?
Handled by the kidneys
243
What is the main anion associated with being a chemical buffer?
The bicarbonate ion.
| All other buffer systems are in equilibrium, so this is the only system that can be controlled.
244
What are 2 methods by which the body can replenish bicarbonate in the body?
1) Hypoventilation takes in more CO2
| 2) Kidneys can dissociates more carbonic acid
245
How can the Henderson Hasselbach equation be rearranged to calculate the pH of the buffer?
pH = 6.1 + log10 ([HCO3-] ÷ sxpCO2)
246
What does the s stand for in the rearrangement of the Henderson Hasselbach equation?
The s is the multiplication factor to obtain the CO2 concentration proportionally.
247
How is bicarbonate reabsorbed in the PCT?
1) Na+ gradient is set up by the Na+/K+ ATPase exchanger.
2) Means symporter on luminal membrane can move Na+ into cell and H+ out into lumen.
3) In lumen the H+ joins with HCO3- to form carbonic acid. This then forms CO2 and H2O using carbonic anhydrase.
4) This can enter the PCT through AQP 2/3/4 then dissociate again.
5) HCO3- can move tot he capillaries through a Na+/HCO3- symporter on the basolateral membrane.
248
How is bicarbonate reabsorbed in the alpha intercalated cells?
1) Both ATPase channels - one only moves H+ out, one moves H+ out and K+ into cell.
2) The H+ in the lumen combines with the HCO3- to form carbonic acid with forms CO2 and H2O with carbonic anhydrase.
3) HCO3- anions can then exit the cell from the basolateral membrane through the HCO3-/Cl- Bartinn exchangers.
249
How is new bicarbonate added to the bloodstream? (acid phosphate)
1) CO2 and H2O inside the cell dissociates with carbonic anhydrase.
2) The H+ then exits the luminal surface through the Na+/H+ exchanger.
3) The bicarbonate then leaves the basolateral membrane through the Na+/HCO3- symporter, resulting in new bicarbonate ions being added the blood.
This can either neutralise the blood or make the blood more alkaline.
250
How is bicarbonate added to the bloodstream in the PCT cells? (ammonia excretion)
1) Amino acid metabolism produces NH3, which can move into the lumen of kidney tubules via Na+/NH3 exchangers.
2) H+ also moves into the lumen via Na+/H+ exchangers from the dissociation of carbonic acid from carbonic anhydrase.
3) The HCO3- can then leave the cell via a Na+/HCO3- symporter on the basolateral membrane so that new bicarbonate ions can be present in the bloodstream.
251
What is excreted and what is reabsorbed from tubular lumen when in acidosis?
HCO3- is not excreted in acidosis.
HCO3- is reabsorbed as much as possible and new HCO3- is added to the bloodstream. This results in more excretion of acid phosphate and ammonium.
252
What is excreted and what is reabsorbed from tubular lumen when in a normal state?
HCO3- is not excreted in the normal state.
| New bicarbonate that has been absorbed is added to the bloodstream, which means acid phosphate and ammonium is excreted.
253
What is excreted and what is reabsorbed from tubular lumen when in alkalosis?
HCO3- is excreted in alkalosis.
| It does not need to be reabsorbed or any new bicarbonate added, so no acid phosphate or ammonium is excreted.
