Renal tubule function Flashcards
1
Q
PCT reabsorbs what % of Na
A
65
2
Q
PCT reabsorbs what % of water
A
65%
3
Q
PCT reabsorbs what % of chloride
A
60%
4
Q
PCT reabsorbs what % of amino acids
A
100%
5
Q
PCT reabsorbs what % of glucose
A
100%
6
Q
PCT reabsorbs what % pf urea
A
50-60%
7
Q
PCT reabsorbs what % of K
A
55%
8
Q
What intrinsic factors to the PCT anatomy/histology facilitate absorption
A
micorvilli
9
Q
What factors limit reabsorption
A
Gradient limited - basolateral transit to capillaries and removal
Diffusion limited - ability to diffuse paracellualrly or transcelluarlly
- Tubular maximum/saturated transporters
10
Q
Glucose reabsorption occurs where ? Via? What transporters are there? Where are each located?
A
ranscellular reabsorption (PCT) via SGLUT (sodium dependent glucose symporter) via secondary active transport. Two types of transporter
◦ Low affinity - high capacity - rapidly absorbs glucose but ineffective at low concentrations (early PCT) and reabsorbs 90% of filtered glucose
◦ High affinity low capacity - slowly reabsorbs, remains effective at low concentrations, late PCT (i.e. usually when most glucose has already been reabsorbed) and reabsorbs 10% of glucose filtered
11
Q
Draw a graph outlining relationship between glucose concentration and plasma glucose indicating filtered and urine concentratinos
A
12
Q
Glomerular tubular balance is?
A
As GFR increases the filtered load increases and can saturate transporters and reabsorption increasing excretion
13
Q
What is the threshold of glycosuria or renal threshold for glucoe
A
11-12mmol/L
14
Q
Why is glycosuria a problems
A
Osmotic diuretic - reduced Na reabsorption, increases solute load in filtrate and urinary flow rates –> reducing water and later electrolyte reabsorption due to higher flow rates. Increased K excretion due to increased Na/K exchange in DCT and aldosterone release
ADH release
Risk of urianry tract infection
15
Q
How is the PCT implicated in glucose control
A
Reabsorption
Also in severe starvation can be responsible for 40% of gluconeogenesis
16
Q
What is PAH and why does it matter?
A
PAH or paramino hippuric acid is a protein 90% protein bound, 10% free
But in the kidney 20% filtered and 80% secreted in PCT–> i.e. complete clearance
When PAH concentration is low all the plasma perfusing the kidney is being cleared
Effective renal blood flow = effective renal plasma flow / (1- haematocrit)
17
Q
How do you use PAH to calculate renal blood flow
A
Effective renal blood flow = effective renal plasma flow / (1- haematocrit)
As renal clearance = 100%
Renal clearance = effective renal blood flow
So U x V/P = effectvie plasma flow /(1- haematocrit)
18
Q
Normal urine protein content per day
A
100mg
19
Q
What waste products are secreted by the kidney
A
Organ anions
- Urate, bile salts, fatty acids, PG, drugs
Organic cations
- Creatinine, ACh, catecholamines, histamine
Uncharged waste
- Urea
- Uric acid
- Bilirubin
20
Q
What is glomerular tubular balance
A
Sodium reabsorption is adjusted to match filtration/GFR - so a constant FRACTION of sodium is reabsorbed in the PCT
◦ Increased filtered glucose and amino acids with elevated filtration –> increased sodium re-absorption
◦ Increased GFR increases the protein concentration in the glomerular cpiallary plasma which increases the oncotic pressure in the peritubular capillaries enhancing the movement of solutes and water into the capillary . Thus a constant fraction of sodium is reabsorbed of GFR
21
Q
Freee water clearance refers to?
A
Any water present that is in excess of what is required to produce iso-osmotic water to the plasma
i.e. low osmolality = excess free water
High osmolality = negative free water
22
Q
How would you calculate free water clearance
A
Urine volume, urine osmolality and plasma osmolality
23
Q
Chloride intake per day
A
1.5mmol/kg
24
Q
Chloride reabsorption via
A
Paracellular and transcellular tied to Na reabsroption
Collecting duct intercalated B cells exchange it with HCO2 dpeendent on basolateral H+ ATPase
25
What is the osmolality of glomerular filtrate
292mosmol/L
26
Which SGLT receptor is responsible for most glucose reabsorption
SGLT2 90%
27
How does glucose move across basolateral membranes in PCT
GLUT 2 faciliate diffusion --> later GLUT1 faciliated diffusion in late PCT
28
How to AT2 affect PCT
Increased Na/H countertransport
29
How to PTH act in the PCT
Decreased phosphate absorption
30
What is the osmolality at the end fo the PCT
300mosm/L
31
What % of water remains at the end of the LOH
25%
32
What is the osmolality of fluid n the lumen of the tubule at the end of the LOH
100mosm/L
33
How much water is reabsorbed in the descending loop of Henle
10-20%
34
What % of Na is reabsorbed in the ascending LOH
25%
35
What % of K is reabsorbed in the ascending loop of Henle
30%
36
What % of chloride is reabsorbed in the ascending LOH
25%
37
What is a leaky K channel called?
ROMK channel
38
What is the purpose of a ROMK channel in the ascending LOH?
“Leaky channels” allow K+ to move outside the cell —> create a luminal positive potential as K+ moves down its concentration gradient. Positively charged lumen repels diva lent cations pushing them paracellularly (PTH independent). Loop diuretics which interfere with luminal absorption and this gradient can reduce Ca and Mg reabsorption
25% Ca reabsorption
60% Mg absorption
39
What can take the place of an ion in the NaKCL2 transporter in the ascending LOH?
Ammonium can take the place of K
40
What produces the osmolality of the inner medulla?
Na , Cl 60% of osmolality
urea 40% of osmolality
41
What is the osmolality of the inner medulla of the kidney
1200mosm/L
42
Draw a DCT cell and explain the absorption of Ca and Na/Cl in this region
43
What effect do thiazides have on Calcium
◦ Reduce urinary calcium excretion as sodium concentration intracellularlyu drops with Na/Cl blockade meaning the Na/Ca exchanger ono the basolateral membrane becomes more active (chemical gradient) increasing calcium reabsorption.
◦ This effect is utilised with thiazide treatment in familial hypercalciuria
44
What % of Na reaches the DCT? What % is reabsorbed at this location?
10%
6% reasbrobed in th DCT leaving 4%
45
What does PTH do in the DCT?
GPCR --> adenylate cuclase --> cAMP increase --> protein kinase A --> increased Ca receptor activation and insertion for reabsorption at the basolateral membrane
46
What is the action of aldosterone
* Aldosterone —> binds to intracellular aldosterone receptors leading to mRNA production for Na and K+ channels luminally and increased Na/K ATPase. Increases Na and H20 reabsorption as well as K+ loss --> as loss of Na+ from the tubular fluid produces a negative charge + there is a concentration gradient
47
Where are aquaporins inserted?
Usually in basolateral membrane
Giving ADH causes insertion of aquaporin 2 into apical membrane
48
What does a principle cell do?
Regulated water excretion and reabsorption as well as K and Na
Aldosterone and ADH primary regulators at this point
49
Which is the most abundant cell in the colecting duct
Principal ell
50
Distal tubule osmoallity
100mosm/L
51
What secretion occurs in the collecting duct and DCT
K
H+
52
How low can the osmolality get inthe collecting duct
50mosm/L
53
What 2 things does ADH affect
Water reabsorption
Urea reabsorption
54
What is the volatile acid load of the body per dayu
13-20mol/day
55
Normal concentrations of CO2 in mmol/L and HCO3
◦ Normal concentration of CO2 is 1.2mmol/L (0.03 x 40mmHg) and normal HCO3 is 24mmol/L
56
What is the Henderson Hasselbach equation
pH = pKa + Log (HCO3-)/(CO2)
ForCO2 and HCO2= 7.4
57
Fixed non voltaile acid production per day includes what?> How much>
* Fixed e.g. lactate, sulphate, phosphate and ketones
◦ 10mmol/kg/day produced and eliminated by the kidney. AN exceedingly small amount of H+ is free in the blood and therefore a small amount is filtered and cannot comprise the required amount of acid to be excreted each day.. whereas loads of base is filtered and needs reabsorption
58
3 mechanisms of acid base control in the kidney
Reabsorbed bicarbonate
Ammonium
Buffers
59
What is the lowest the urine pH can get
4.4
60
Average urinary pH
6
61
Where is bicarbonate reabsorbed
90% PCT
Thick ascneding limb, DCT and CT for the final 10%
62
How is H+ secreted in the kidney 3
◦ Primary H+ ATPase in the PCT and DCT
◦ H+/Na+ anti porter in the PCT and ascending limp
◦ H+/K+ ATPase in the CT
63
How is ammonia produced in the kidney
From glutamine
64
Where does glutamine come from
Amino acid
Filtered and absorbed from circulation by PCT cells
65
What is glutamine metabolised to
NH4+ and HCO3
66
How is ammonia moved into the filtrate
◦ NH4+ is secreted (NH4+/Na+ anti porter)
◦ HCO3- is reabsorbed (diffusion)
67
What is the pKa of NH3
9.2
So it all sits as NH4+
Not an effective urinary buffer but is a sink for H+
68
What are the important buffer systems of the Kidney
PO4(3-)\About 36mmol of H_ is eliminated each day by binding here
as proteins stop functioning below pH 4.4 it is essential to buffer the excreted acid
Hydrogen ions bufferred early in the nephron by bicarbonate
69
How is H+ secreted in the DCT and CT?
Type A intercalated cells
H+/K+ antiport
H+/CL cotransport
H+ ATPase
Bicarbonate and K reabsorbed
70
How is the activitiy of HCO3 reabsorption regulated
Carbonic anhydrase is regualated based on aciditiy --> more acid = more active
71
What does a type B intercalated cell secrete?
HCO3
K
Reabsorbs Cl and H+
72
How does the kidney respond to respiratory acidosis
◦ Respiratory acidosis —> bicarbonate reabsorption increased due to raised CO2 tension and raised extra cellular hydrogen stimulation hydrogen and ammonium secretion
73
How does the kidney respond to metabolic acidosis
◦ Metabolic acidosis —> filtered bicarbonate reduced so secreted acid allows for full reabsorption of bicarbonate in addition to increased glutamine(ammonium) excretion and phosphate bound hydrogen ion secretion
74
Average daily intake of sodium
450mmol
75
Where do we lose Na per day
11mmol sweat
11mmol faeces
435mmol in urine
76
How much waste product is produced per day which needs to be renally excreted
600mosm
77
What is the maximim concentrating capacity of the kidney
1400mosm/L
78
What is the minimum volume of urine per day to maintain homeostasis with waste removal
460mls
79
How is urea filtered
Completelely
80
How is urea treated along the tubule
50% reabsorbed in PCT
50% secreted back into ascneing LOH via UT uniporters so luminal concentration becomes much greater due to the reabsorption of water
50% ahain reasborbed in medullary collecting duct
81
Where in the collecting duct is urea permeable
Medullary collecting duct
82
What happens tothe urea concentration in the LOH
It is increased in the descending loop of Henle compared to filtration as:
1/ only 50% reabsorbed, whereas 65% of water reabsrobed in the PCT
2/ Further water reabsorption in the descending LOH
83
What has happened to urea concentration by the time you reach the medullary collecting duct
100x plasma concentration
84
What % of urea filtered is excreted
40-60%
85
Explain the counter current multiplier
Juxtamedullary nephrons ONLY
* Thick ascending limb pushes solutes into the interstitium increasing intersittium concentration --> from 300mosm/L --> 400 mosm/L leaving the tubular fluids 200mosm/L
* The descending limb now has a concentration gradient which pushes fluid out into the intersititum
* The thick ascending limb pumps area able to work against a concnetration gradient of approximately 200milliosmol/L difference and so start pushing solutes out as water makes the interstitium less concentrated
* But now the fluid in the tubule travelling around to the ascending area is more concentrated enhancing this concentration difference
* This cycle continues until a maximum concentration of 1200 milliosmol/L is reached in the medulla
86
Explain the counter current exchange
* freely permeable to water and solute, therefroe osmolarity mirrors the surrounding interstitium, therefore when the vasa recta enters and exits it has virtually the same osmolarity.
* This also prevents washing away of solutes and maintains graded hyperosmolarity.
* Blood flow in cortical areas is faster and more prevalent, blood flow to medullary areas is slow and less further preserving the high concentrations in the medulla as solute concnetrations equalise at each level fo the loop
* The exchange works as the vasarecta surrounds the loop of Henle of juxtamedullary nephrons and folllow it into the medulla
* In hypovolaemic situations - renal blood flow falls and vasarecta flow decreases —> reducing washout
* When renal blood flow is high —> vasa recta flow increases and washes out part of the concentration gradient
87
How much water is ingested per day
2.5L per day for a 70kg male
1000mL in food
350mL prudced from metabolic processes
Drinking 1.2L
Minimum draily water intake 25-30ml/kg
88
Excretion of water per day at baseline
900mL insensible losses skin and lung
50ml sweaat
faeces 100ml
Urine output 1.5L
89
In the absence of ADH how much water is lsot per day
20% of filtered --> 30L
90
What is the daily mandatory solute load composed of?
Urea 400mmol/day
Cr 12mmol/day
Na 100-150mmol/day
K 70-100mmol/day
Cl 150mmol/Day
91
How does a body respond to changes in osmolality and toniciity with aldosterone and ADH? Why does it make sense to have both systems?
‣ Body system seeking to maintain osmolarity AND increase volume --> Aldosterone only
‣ Seeking to increase volume regardless of osmolarity --> both
‣ Decrease osmolarity regardless of volume --> ADH only
‣ Decrease osmolarity BUT maintain volume --> reduced aldosterone + increased ADH
i.e. BOTH are require
92
How is urea produced
Nitrogenous waste product from the liver
Glutamate --> de-amination --> ammoniam (toxic) --> carbomyl phosphatase to urea cycle --> urea
93
what % of urea entering the kidney is excreted?
25% cardiac output to kidney
93% of renal perfusion to renal cortex
Filtration fraction 0.2 (freely filtered)
40-60% of filtered urea excreted
4-10% of urea entering the kidney is excreted
94
Draw the RAAS system
95
What causes the liver to release angiotensinogen
GC
Thyroid hormones
Oestrogen
Angiotensin 2
Inflammation
96
Renin trigggered by
Macula densa
Hypotension
B1
97
Angiotensin 2 actions
Thirst
Aldosterone and ADH
Drives Na/Cl absorption
Increased SNS repsonsiveness
Direct vasoconstriction in peripheral vessels
Mesangial cell contraction
Efferent and afferent arteriole constriction
98
Describe the pattern of absorption or ssecretion of potassium along the renal tubule
* Potassium excreted = filtered + secreted - reabsorbed
* Filtration and reabsorption fairly stable
◦ PCT 55% reabsorbed passively
◦ Ascending loop of Henle 30% reabsorbed
◦ Medullary collecting duct always reabsorbs potassium
* Principal cells of DCT and collecting ducts cortically secrete potassium while type A intercalated cells reabsorbed potassium
◦ The balanced effect depends dietary intake —> normal intake net effect is secretion; reduced intake net effect reabsorption
◦ Cortical collecting duct secretion > DCT secretion
99
pottasium excretion is therefore primary affected by
secretion
100
Principal cell potassium secretion is regulated primarily by what factors
Plasma potassium concentration --> egulates NaK basolateral pump and aldosterone release
Aldosterone
Tubular flow - increased flow = increased loss
101
How does body sodium content affect plasma pottasium
It does not
◦ High body sodium = less aldosterone (less K lost) but flow rate of renal tubules is higher (more K lost) (and vice versa)
102
How does body water content affect potassium secretion
Equalisation of effects so does not affect secretion
◦ High body water = reduced ADH promoted K secretion but higher flow rate at renal tubules results in balance loss
103
How does alkalosis affect potassium secretion
Urniary excretion of K is increased by alkalosis
Na/K exchange is stimulated in principle cells by low H+
104
How much bicarbonate is filtered per day
* 4000-5000mmol HCO3 filtered by glomerulus per day
105
How is bicarbonate absorption increased
* More bicarbonate resorbed when:
◦ Higher filtered HCO3-
◦ Higher PaCO2
◦ Lower luminal flow rate
◦ Angiotensin 2
106
How does an intercalated cell secreted acid
H+/K+ ATPase on apical membrane
Stimulated by aldosterone
CO2 from lumen or blood
107
Phosphate buffer in the urine pKa
6.8
108
Minimum urine pH
4.5
109
When is the phosphate buffer active
Once bicarbonate has been reabsobed
110
Draw an equation for the phosphate buffer
* Phosphate (HPO4 (2-)): HPO4(2-) + H+ ⇄ H2PO4-
111
What is the phosphate buffer generally eliminated as
H2PO4
112
What does most phosphate in the blood move around as
HPO4
113
What amount of hydrogen ions are eliminated per day due to the phsopahte buffer
36mmol
114
What is glutamine used for in the liver? What is it converted to?
* Filtered Glutamine from catabolism of protein and oxidation of amino acids in the liver is broken down (after being reabsorbed from filtratea and absorbed from blood) in PCT tubular epithelia cells to two NH4+ and two HCO3-
115
How is bicarbonate reabsorbed through the NH4 system?
* Filtered Glutamine from catabolism of protein and oxidation of amino acids in the liver is broken down (after being reabsorbed from filtratea and absorbed from blood) in PCT tubular epithelia cells to two NH4+ and two HCO3-
Na/HCO3 cotransport on basolateral membrane
116
How does NH4 enter the lumen
NH4/Na antiport
117
What happens to ammonia in the tubule>?
* It is resorbed in the thick ascending limb as ammonia, moves through the medulla to re-enter the collecting duct “ammonia recycling”- concentrated in the inner medullla
◦ Here urine has a low pH, and so NH4+ becomes ion trapped and can be eliminated with its proton attached
* This process has a greater capacity than phosphate for H+ excretion, and can be increased 10 fold in response to metabolic acidosis
118
In severe metabolic acidosis what is the most important mechanism for compensation
* It is resorbed in the thick ascending limb as ammonia, moves through the medulla to re-enter the collecting duct “ammonia recycling”- concentrated in the inner medullla
◦ Here urine has a low pH, and so NH4+ becomes ion trapped and can be eliminated with its proton attached
* This process has a greater capacity than phosphate for H+ excretion, and can be increased 10 fold in response to metabolic acidosis
119
How effective is the ammonia excretion process
* It is resorbed in the thick ascending limb as ammonia, moves through the medulla to re-enter the collecting duct “ammonia recycling”- concentrated in the inner medullla
◦ Here urine has a low pH, and so NH4+ becomes ion trapped and can be eliminated with its proton attached
* This process has a greater capacity than phosphate for H+ excretion, and can be increased 10 fold in response to metabolic acidosis
120
What is the renal bicarbonate threshodl
28mmol/L
121
What are the 4 factors that can perpetuate an alkalosis
Decreased GFR
Decreased K
Decreased Cl
ECF volume depletion
122
What can also buffer in the urine other than phsophate and ammonia
Once pH 5
citrate
Creatinnie
123
What is a volatile acid
An acid that can leave solution and enter the atmosphere e.g. CO2
124
What are non volatile acid examples
Lactate
Ketones
Phosphate
Sulfate
Urate
Citrate
Huppurate
125
How much potassium is filtered per day
900mmol
126
How much K is excreted per day
30-100mmol
127
Potassium, regulation is primarily by
Secretion regulation
128
Renal K excretion =
Dietary intake - K eliminated in sweat and faeces
129
Urinary K excretion is a function of
Filtration - reabsorption + secretion
130
How is K reasborbed in the PCT, how much is reabsorbed in this fashion?
55%
reabsorbed passively via the paracellular route due to:
‣ Solvent drag → coupled to flow of Na+ and H2O
‣ Concentration gradient → created by reabsorption of H2O
- electrical gradient in late PCT
131
How is K absorbed in LOH? How much of it is absorbed in this fashion?
* TAL of LoH (30% of filtered K+ is reabsorbed):
◦ Apical Potassium/chloride/sodium symporter in thick ascending limb
◦ K+ is reabsorbed by via paracellular route due to potassium leakage channels causing + charge promoting transcellulr flow of +ions
132
What happens ot K in the DCT and CCD
◦ Principal cells of CCD and LDCT → 2° active secretion K+ → via:
‣ Basolateral Na+ /K+ ATPase → (i) generates an electrochemical gradient that draws Na+ intracellularly from the tubular lumen (via the ENaC channel), and (ii) pumps K+ from peritubular capillaries into tubular cell
‣ The –vely charged lumen generated by influx of Na+ across ENaC channel → favours tubular secretion of K+
◦ Type A intercalated cells of cortical collecting duct and distal convoluted tubule → 2° active reabsorption of K+ (10%):
‣ H+ is produced within tubular cell by hydration of CO2 (using CA) → H+ is then exchanged for tubular K+
133
What happens in the medullary collecting duct to K
5% rebasorption
no secretion capacity
134
Renal K regulation occurs mainly by? What triggers this to ocur?
Secretion
Distal nephron
- Self regulation --> increased K stimulates
1) Na/K ATPase on principal cells
2) Aldosterone release
135
What effect does pH have on K secretion
◦ Plasma pH
‣ Alkalosis via ↓ plasma [H+ ] causes ↑ K+ secretion by → stimulating basolateral Na+ /K+ ATPase in principal cells
136
What happens with increased tubular fluid flow to K?
‣ ↑ tubular fluid flow causes ↑ K+ secretion by → maintaining ↓ luminal [K+ ] (Ie. continuously washing it away) → permits passive diffusion of K+ ↓ its [ ] gradient into tubular lumen
‣ Conversely reduce tubular fluid due to reduced GFR or other factors reduced secretion
‣ Primary changes in body water do not alter pottasium secretion because ADH stimulates tubular potassium secretion, when total body water is hgher ADH secretion is low and urine production is high, increasing potassium secretion but conversely tempered by low ADH. Urinary potassium excretion therefore is stable, vice versa
137
At baseline how much water is excreted by the kidney per day
1.5L
138
Describe average daily losses of fluid
* At baseline kidney excretes 1.5L/day despite 180L of glomerular filtrate and 20% of cardiac output per minute.
* This balances 2.5L per day intake, 900ml of insensible skin and respiratory losses, 100ml faeces losses and 50ml of sweat.
139
Describe how water is regulated through filtration
* Freely filtered at the glomerulus, rate of filtration directly proportional to glomerular blood flow
* Water excretion can be reduced by reducing cortical glomerular blood flow; therefore slowing renal post glomerular blood flow enhancing reabsorption of solutes and water via primarily juxtamedullary nephron flow; this is mediated via
◦ Sympathetic nervous system
◦ Vasoactive substances - endothelin, AT2, circulating adrenaline
◦ In addition to reduced amounts of ANP and BNP --> reduced GFR and increased sodium retention
140
How is water reabsorbed in the PCT? What %
* Passive water movement following Na either trans/paracellular movement through highly permeable tubule wall
* Gradient for nearly all reabsorption in PCT driven by Na/K ATPase and resulting water reabsorption results in stable osmolality to plasma
* Absorption fraction remains stable despite changes in GFR and filtration volumes
* Re-absorption can be enhanced by increasing Na reabsorption via AT2/sympathetic stimulation leading to increased passive reabsorption of water
◦ This can be triggered from central SNS directly, RAAS activation (low tubular flow, low afferent arteriole pressure, low baroreceptor tone)
141
Descending LOH water reabsorption how? How much?
* Descending loop of Henle permeable to water and not solutes, due to countercurrent mechanisms medullary hypertonic osmotic gradient favours passage of water out of tubular lumen resulting in hypertonic luminal fluid
* Ascending loop impermeable to water, however increasing solute removal through ascneding loop of Henle and distal convoluted tubule results in hypotonic fluid passage in luminal fluid (concentrated intersitium)
142
Distal convuluted tubule and collecting ducts reabsorption of water - how? How much
24-25%
Aldosterone
ADH
In complete absence of ADH --> 12-20% loss of water
143
What receptor is stimulated by ADH
V2
144
Define the countercurrent mechanism
The coutnercurrent mechanism in the kidney is the combination of the countercurrent multiplier and exchanger that facilitate the creation and maintenance of a concentration gradient that drives water reabsorption and regulation.
145
Outline the countercurrent multiplier
* Loop of Henle hairpin arrangement which facilitates the development of a progressive increase in osmolarity as you progress from the renal cortex through to the medullary intersitum
* This gradient occurs because of the water impermeability of the ascending loop of Henle which in conjuction with solute reasborption via secondary active transport (Na/K/Cl symptorter on apical surface of thick ascending loop of Henle) causes significant solute reabsorption into the medullary interstium against a concentration gradient. The pumps and active transport can only occur across a maximum 200mosocmol/L difference
* The drop in solute content within the tubule caues a drop in osmolality of filtrate as water is not able to reabsorb, thus resulting in a signficant osmolality difference between remaining filtrate (hypotonic) and medullary tonicity which is utilised later in collecting ducts for reabsorption of water regulated by ADH
* Increasing medullary concentration causes osmosis of fluid from the lumen of the proximal convuluted tubule and descending loop of henle which is permeable to water but the descending loop is impermeable to solutes so diffusion of fluid increases tubular fluid osmolality being delivered to the ascending loop
* As both medullary concentration has increased and tubular fluid has increased in osmolality the difference again allows the pumps in the ascending loop to increase the medullary concentration further
* Selective urea permeability in the PCT, loop of Henle and medullary collecting ducts (UT-A1) faciliates high urea concentration in the medullary interstitium contributing 30-40% to the osmolality
* The medullary interstitium reaches 1400msom/L, where tubular fluid begins at 300mosm on filtration
146
Steps in countercurrent multiplier
Baseline characteristics
- Water insoluble ascending loop of Henle
- Solute insoluble descending loop of Henle
- Powerful transmembrane pumps capable of generating osmotic gradient
1. Ascending loop of Henle pump Na/K/Cl generates a intersitial gradient by removing solute from ascending loop in an area of water impermeability
2. Equalisation via osmosis and diffusion with PCT contents --> in descending LOH however only water can move out via osmosis due to the gradient
3. Delivery of increased osmolality fluid to the ascending LOH however the diffusion gradient has reduced slightly with dilution of medullary intersitium by osmosis, but also increased osmoallity of tubular fluid so gradient for pump to work against has reduced --> further acceleration of the osmotic gradient via pumps in impermeable region
4. Repeat
147
How does countercurrent exchange work
* Vasa recta are the parallel blood vessels to nephron tubular flow but as a countercurrent system
* They facilitate reabsorption of ions into blood however their slow flow ensures there is no washout of medullary concentration gradient - as they comprise the blood subject to filtration earlier in the glomerulus they have lower plasma volume and therefore higher visocity (slow flow) and high oncotic pressure favouring reabsorption of water
148
How does countercurrent exchange i the skin occur
* Countercurrent blood flow in the skin is a mechanism of heat preservation and differs to kidneys both in function but also structure as countercurrent structures are vascular exchange between artery and vein, whereas in kidneys this occurs between plasma filtrate lumens as well as between plasma filtrate and capillary flow.
* Arterial blood flow in the skin is closely related to veinous drainage ensuring arterial heat is conducted to blood in returning veins (cooler) to reduce heat lost in peripheries
* With increasing shunt through precapillary vasoconstriction and shunt vessels the fraction of heat lost in peripheral circulation is reduced, and where these shunts are closed due to precapillary vasoconstriction heat loss is increased
149
Define osmosis
◦ This is the movement of solvent molecules freely as opposed to diffusion allowing both solvent and solute molecules to move freely across a semipermeable membrane
◦ Osmosis is molecule movement from higher to lower concentrations (diffusion is the opposite); and therefore explains the movement of water in the thin descending LOH
150
List the processes that allow movement across the renal cell tubules
Osmosis
Passive diffusion
Solvent drag/convection
Facilitated diffusion
Active transport
Secondary active transport
Pinocytosis/endocytosis
151
Describe solvent drag
◦ Solvent drag is where as water moves paracellularly it drags solutes with it down their concentration gradient through the tight junctions that hold cells together
152
What is an example of passive diffusion in the context of renal absorption
CO2
153
What are characteristics of apssive diffusion
No energy expenditure
Travels with electrochemical gradient
Rate fo transfer determined by Ficks laws of diffusion
154
What is an example of facilitated diffusion
Potassium across excitable cell membranes by rectifier cahnnels
◦ Molecule crosses a membrane via a channel without energy expenditure
◦ With electrochemical gradient
155
Describe the changes in the pH along the nephron
Changes in pH along the nephron
* Beginning of proximal tubule: same pH as plasma (eg. 7.4)
* End of proximal tubule: pH 6.8
* Hairpin turn of the loop of Henle: pH ~ 7.4
* End of the thick ascending limb: pH 6.8
* End of the distal convoluted tubule: pH 6.7
* End of the collecting duct: pH 6.0-5.5
156
What are the changes triggered by hypoventilation in the kidney
* The following changes are triggered by the delivery of CO2 to the basolateral membrane of proximal tubule cells:
* Initial changes:
◦ Increased acidification of tubule fluid, even acutely, by unclear mechanisms (potentially due to CO2 entry and subsequent acidification of tubule cells producing increased apical H+ export)
◦ NHE3 Na+/H+ transporter expression increases over the next 1-2 days
◦ Renal ammonia synthesis and ammonium secretion is rapidly increased
◦ ATP-powered H+ pumps are distributed to the apical membrane
◦ Upregulation of carbonic anhydrase activity
* Later:
◦ Bicarbonate reabsorption in the proximal tubule is increased
◦ (by 50% over 3-5 days, at PaCO2 of 80%)
◦ At the end of the process of adaptation, the increased bicarbonate reabsorption maintains a stable status quo and the renal acid excretion decreases back to a more normal level, similar to what it was before the onset of the chronic respiratory acidosis
◦ In this status quo, ammonia excretion remains elevated while the excretion of other titratable acids is reduced
157
What % of Na is excreted per day
<1%
158
Sodium handling in the neprhon
- Filtered
Freely
159
How is the Na handled in the PCT
‣ Na/K ATPase at basolateral membrane drives a constant electrochemical gradient (low intracellular Na/negative intracellular charge) favouring sodium reabsorption from lumen to proximal tubular cells
‣ This is facilitated via secondary active transport
* Counter-transport with hydrogen (NHE3 sodium hydrogen exchnager)
* SGLT transports cotransport with glucose
* Cotransport with amino acids/organic ion transporters
‣ Passive solvent drag transcellularly down electrochemical gradient
‣ Glomerulotubualr balance ensures that regardless of filtered sodium volume 65% is reabsorbed in PCT - this is regulated by
* Filtered glucose increases with filtration volumes --> as Na/glucose are cotransported Na is reabsorbed proportional to filtered glucose which is proportional to filtration amount
160
What % of Na is absorbed in thick ascending limb? How?
◦ Thick ascending loop of Henle - 25-30% of Na reabsorbed
‣ Via Na/K/2Cl (NKCC transporter) luminal pump as a secondary active transport again driven by basolateral Na/K ATPase
‣ Small amounts via secondary active transport as per PCT and paracellular movement due to net positive charge in lumen
161
Is there any Na absorbed in the DCT?
◦ Distal convoluted tubule 5% of sodium reabsorption
‣ Sodium/chloride cotransport (NCC cotransporter) again secondary active transport and is load sensitive (reabsorption increases with increased delivery), again driven by basal Na/K ATPase
162
What % of Na reaches the collecting duct? How is it absorbed?
◦ Collecting duct - variable 5-10%
‣ Aldosterone mediated facilitated diffusion absorption in principal cells through insertion of Na (ENaC) and K channels in apical membrane facilitating Na reabsorption down electrochemical gradient generated by Na/K ATPase in basolateral membrane
163
Regulation of Na is primarily via?
GFR and tubular absorption
164
What factors modulate sodium excretion
1. GFR - reduced ECF, perfusion. increased filtrate flow leads to reduced reabsorption
2. RAAS system - activated by low sodium content in the distal convuluted tubule, low perfusion pressure and low BP --> eventually promotes reduction in GFR (Na conservation), maximised Na reabsorption directly by AT2 action on Na/H exchanger in PCT, and indirectly through aldosterone and ADH
3. Aldosterone
- Activated by ACTH, catecholamines, AT2
- Increases reabsorption of Na
4. ANP - increases both filtration fraction and therefore filtered Na as well as reducing reabsorption
5. ADH - directly triggers Na reabsorption
6. Renal sympathetic triggers
