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pharm phys intro > kidney > Flashcards

kidney Flashcards

1
Q

what proportion of the body is water and how is this split?

A

avg 60% of body eight is water

62% is intracellular

the rest is extracellular:
2% transcellular (CSF)
3% plasma
12% interstitial

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2
Q

what is the ion content of intracellular vs extracellular fluid like?

A

intra = very high K+ (150mM)
low Na+ (10mM)
low Cl - (4mM)

extra = low K+ (5mM)
high Na+ (140mM)
high Cl- (130mM)

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3
Q

what’s the ion concentration of plasma like?

A

same as extracellular fluid, but with proteins and importantly, the Na+ conc. determines the circulating volume which determines pressure

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4
Q

sodium and water input roughly equal output, how?

A

water - mostly urine but also sweat and respiration
Na+ - mostly urine but Also stool and sweat

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5
Q

describe the location of the kidney

A

between the 12th thoracic and 3rd lumbar vertebrae, towards the back

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6
Q

what are three kidney congenital abnormalities?

A

renal agenesis - just doesn’t develop, not compatible with life
ectopic kidney - forms in the pelvis increasing risk of kidney stones
horseshoe kidney = monobrow kidney

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7
Q

describe the internal microanatomy of a kidney

A

outer capsule = support and protection
cortex is underneath the capsule
medulla and medullary rays (blood vessels)
ureter

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8
Q

what are nephrons and how does filtrate move throughout the kidney?

A

nephrons are the functional unit of the kidney, 1.5 mil present in each kidney
afferent arteriole supplies the glomerulus with blood, filtrate drains down into bowman’s capsule, filtered blood exits via efferent arteriole
filtrate moves from capsule to proximal tubule, then loop of Henle now in the medulla and not the cortex, then distal tubule, then collecting duct

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9
Q

compare acute and chronic renal failure

A

chronic = defined as a fall in the glomerular filtrate rate (125ml/min is considered healthy)
acute renal failure is reversible while chronic requires dialysis and transplant
in chronic, haemoglobin levels and kidney size both decrease, not in acute
chronic leads to peripheral neuropathy, damage of peripheral nerves

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10
Q

describe the progression of renal failure

A

thickening of glomerular membrane
scaring of the glomeruli
nephrons die (atrophy)
kidney gets smaller
lastly, water and salt are retained, causing a host of issues - hypotension, hyperkalaemia, mild acidosis (H+ not excreted)

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11
Q

how is chronic renal failure treated?

A

once symptoms show, its irreversible, so you treat the symptoms to minimise impact, planning for dialysis and transplant down the line

possible changes include:
restricted protein, salt, water
phosphate binders to reduce chance of metastatic calcification
Na bicarb to deal with acidosis
diuretics to treat salt and water retention

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12
Q

what are the physiological effects of renal failure and why they happen?

A

poor excretion of urea and creatine = anorexia (not in the mental sense, just weight loss), nausea, vomiting, neuropathy, pericarditis (inflammation of the pericardium)

leak of proteins into urine

no production of the hormone erythropoietin = controls RBC production, lack of RBC = anaemia

failure toe excrete phosphate = metastatic calcification (calcium and phosphate combine to form crystals of calcium phosphate, also causes pruritus - itching)

low calcium in serum can lead to bone disease

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13
Q

what are the stages of renal failure and how are they defined?

A

mild renal - GFR > 75 - bloods = normal - no uraemic syndrome, not progressive

mild - GFR = 50-75 - subtle changes in blood - no uraemic syndrome, early bone disease

moderate - GFR = 25-50 - bloods have mild changes - mild uraemic syndrome, anaemia

severe - GFR = 10-25 - moderate blood changes - moderate uraemic syndrome, salt and water retention

end-stage - GFR = <10 - severe blood changes - severe uraemic syndrome, need dialysis and transplant

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14
Q

what are some causes of renal failure?

A

30% is glomerulonephritis (damage to glomeruli with many causes e.g. infection)
25% diabetes mellitus
20% other
10% hypertension
5% polycystic kidney disease (tubular structure replaced by cysts)
10% unknown

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15
Q

glomerulus -
size?
how much does it filter?
what is the end result?

A

200um in diameter
180L filtered a day, for reference plasma roughly totals 3L
product is the ultrafiltrate = protein free plasma (with exceptions like albumin)

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16
Q

glomerulus -
size?
how much does it filter?
what is the end result?

A

200um in diameter
180L filtered a day, for reference plasma roughly totals 3L
product is the ultrafiltrate = protein free plasma (with exceptions like albumin)

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17
Q

what is reabsorbed in the proximal tubule?

A

70% of filtrate in terms of water and sodium
100% of glucose and amino acids should be absorbed there
90% of bicarbonate and of K+

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18
Q

define apical and basolateral membrane when referring to the kidney?

A

apical - the side the filtrate is in contact with
basolateral - side with the capillaries

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19
Q

explain what moves across the proximal tubule membranes and how (not bicarb)

A

apical - has a NA+/glucose cotransport (SGLT1 and 2)
Na+/phosphate cotransport (NaPiII)
Na+/amino acid cotransport

these three things just diffuse across the basolateral membrane to be reabsorbed

the basolateral membrane has a Na+/K+ ATPase to keep intracellular Na+ low
and a K+ channel allowing potassium out, in order to provide a driving force for the ATPase and create a -70mV membrane potential. so overall Na+ is being reabsorbed, water of course follows

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20
Q

what did a mouse study on NaPiII in the proximal tubule show?

A

had knockout mice and WT mice, knockout mice had a load of calcification deposits, resulting in kidney stones in the 1)tubules (nephrocalcinosis) and in the kidney, like the cortex or medulla (nephrolithiasis)

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21
Q

how is bicarbonate reabsorbed in the proximal tubule?

A

NHE3 on the apical membrane exchanges Na+ into he cell and H+ out
in the filtrate, this H+ combines with bicarbonate to form carbonic acid and carbonic anhydrase breaks this down into CO2 and water to move into the cell
once in the cell carbonic anhydrase does the opposite and turns CO2 and water back into carbonic acid, which dissociates, the H+ moving out across NHE3 again and the bicarbonate being reabsorbed into the blood across a Na+/bicarb cotransporter in the basolateral membrane
this contributes to water reabsorption

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22
Q

what is the renal threshold for glucose?

A

its the concentration glucose has to be at in order fort he kidney to start removing it in urine - this is 300mg/100ml

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23
Q

what is the transport maximum for glucose?

A

the value is 375mg/min - this is the fastest rate at which the kidney can reabsorb glucose, even if concentration of glucose rises it cannot be reabsorbed faster than this

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24
Q

what does the proximal tubule secrete?

A

transport membranes in the basolateral membrane are really good at removing organic ions, including protein-bound substances in the plasma and foreign compounds like penicillin (so a higher dose is often required, due to our ability to remove it so well)

25
Q

what are the transport proteins in the membranes of cells of the thick ascending limb?

A

apical - NKCC2, transports a Na+, a K+ and 2Cl all into cell from filtrate
ROMK (Kir 1.1) a K+ channel allowing K+ out (in order to move back in and drive NKCC2)

basolateral - CLCK assisted by beta subunit called Barttin, they’re involved in chloride reabsorption
(also a Na+/K+ ATPase and a K+ channel)

26
Q

Bartter’s syndrome - what is it/how does it occur?
what are the physiological impacts?

A

its a mutation in any of the transport proteins of the thick ascending limb -

if NKCC2, you wouldn’t reabsorb salt, if CLCK or barttin there’s an accumulation of CL- in the cell so there’s a struggle to c0ontinue to move Cl- in via NKCC2
if ROMK, K+ can’t be recycled, so NKCC2 can’t work (all circles back to NKCC2)

symptoms:
loss of salt via urine as its not reabsorbed
polyuria (wee a lot - less salt absorbed less water follows)
hypotension due to fluid loss
hypokalaemia (K+ isn’t reabsorbed as much)
metabolic alkalosis (pH increases above 7.5)
hypercalciuria (if it effects Na/Cl it must effect Ca, inc. chance of kidney stones)

27
Q

what was the ROMK knockout experiment and its findings?

A

in this experiment they looked at fractional excretion (amount in urine/amount filtered, so if FE is 100% nothing was reabsorbed
results:
salt wastage occurred, like in Bartter’s
polyuria occurred
there was acidosis instead of alkalosis
plasma K+ was not changed compared to WT

28
Q

what are loop diuretics - examples and function?

A

furosemide or bumetanide inhibit NKCC2, causing salt wastage but also polyuria, used to treat high blood pressure

29
Q

what are the membrane proteins in early distal tubule cells?

A

Apical = NCC - a sodium and chloride cotransporter (water follows)
and a Mg2+ channel (we’re not really sure how it gets into the cell)

basolateral = same as thick ascending limb, ATPase, K+ channel and barttin

30
Q

what is the cause of Gitelmman’s syndrome and what happens?

A

loss of function mutation in the NCC gene, leading to:
slat wasting and polyuria
hypotension
hypokalaemia
metabolic alkalosis
hypOcalciuria tho why this happens is still debated

31
Q

what experiment using frogs eggs was done regarding NCC and what were the findings?

A

inject RNA - protein of interest is made, compare WT vs mutation
put a loud of radioactive Na+ around the frogs eggs, see how much gets taken up
fluorescence showed that the mutation must affect the trafficking protein as NCC doesn’t make it to the cell membrane

32
Q

what are thiazide diuretics used for and what do they target?

A

like chlorothiazide, used to treat high blood pressure, target NCC in distal tubule

fun fact - people with single/recessive mutation for ROMK, NCC, NKCC2 are less likely to get high blood pressure/cardiovascular disease

33
Q

describe how principle cells of the late distal tubule and collecting duct work, including all membrane proteins

A

reabsorb sodium and water, secrete K+ and H+
Na+ channel ENaC on apical side allows Na+ in, a Na+/K+ pump on the basolateral side allows this Na+ to then be reabsorbed, while moving K+ into cell from blood, where it is secreted out of K+ channel ROMK on the apical side (K+ channel on basolateral side Kir2.3 removes K+ from cell to drive the pump)
water enters via aquaporin 2 on the apical side and continues moving tis way out of the cell on the basolateral side via AQP3 and 4

34
Q

what are possible issues with principle cells and the drug/s used to treat them?

A

diabetes insipidus - (issues with AQPs so struggle to reabsorb water
Liddle’s syndrome - absorb too much Na and therefore too much water
pseudo-hypoaldosteronism - unresponsive to aldosterone

treatment = amiloride, a diuretic (inc. fluid loss) that targets ENaC, it is K+ sparing because if ENaC is inhibited less K+ is secreted

35
Q

describe what alpha intercalated cells do

A

secrete H+ and reabsorb bicarbonate to help out the body when things are too acidic, which is more often then the opposite so alpha cells tend to dominate

Basolateral - chloride channel pumps Cl- out so that anion exchange 1 can exchange Cl- into the cell and bicarbonate out, to be reabsorbed

Apical - proton pump removes H+ into filtrate

36
Q

describe what beta intercalated cells do

A

Have a chloride/bicarbonate anion exchange on the APICAL to excrete bicarbonate in order to lower pH
The basolateral has a proton pump to reabsorb H+ to lower pH. Also has a Cl- channel to help remove Cl- that enters the cell due to the anion exchanger on the apical

37
Q

describe what beta intercalated cells do

A

Have a chloride/bicarbonate anion exchange on the APICAL to excrete bicarbonate in order to lower pH
The basolateral has a proton pump to reabsorb H+ to lower pH. Also has a Cl- channel to help remove Cl- that enters the cell due to the anion exchanger on the apical

38
Q

what percentage of sodium, water and potassium is reabsorbed in the DT and CD?

A

Na - 9% in presence of aldosterone
water - 24% in presence of vasopressin
K+ - none

39
Q

a women was in a car crash and suffered extreme trauma to the kidney area, explain what could happen

then describe a potential treatment plan

A

blood loss would result in hypotension, lack of perfusion of the kidney would cause a fall in GFR, ripped muscle cells - rhabdomyolysis - releases myoglobin that’s toxic to kidneys, resulting in acute renal failure
there would be high K+ due to lack of secretion by principle cells and the intracellular fluid of ripped muscle cells, causing tachycardia
bicarbonate would be low due to trying to reduce acidosis resulting from losing ability to secrete H+ properly

treatment -
IV saline with low K+, some bicarb, rehydrate in this case due to blood loss (not typical as usually there’s oliguria you don’t wanna overload them)
dialysis if oliguria persists

40
Q

what happens in acute renal failure?

A

fall on GFR rate over hrs/days
many possible causes
accumulation of nitrogenous waste
Lasts 1 week ish and is reversible, treat with dialysis while addressing what caused the initial problem

Hypervolaemia (fluid volume is too high in the body)
Low urine production - oliguria due to fall in GFR
Hyperkalaemia - lack of K+ secretion so there’s a lot in the ECF. effects cardiac excitability - really messes up ECG
Acidosis (effects NS)
High urea/creatinine = nausea

41
Q

vasopressin - where is it made and released (how is it released as well)?

A

made in neurosecretory neurons in the hypothalamus as a pre-hormone that is later modified, in the cell body to be trafficked down the axons to where it is released
the posterior pituitary gland, where it is released like a NT (AP, Ca moves in, vesicles fuse etc…)

42
Q

if body fluid osmolality goes up…

A

the plasma gets more concentrated so more vasopressin is released, more water is reabsorbed and vice versa

43
Q

giving numbers, what’s the typical osmolality range for plasma and the change hypothalamic osmoreceptors can detect (also where are they)?

A

plasma = 285-300 mosmol/kg (at this level vasopressin should be at 4 pg/ml)
change detected = 3 mosmol/kg (1%)
found in the supra-optic and paraventricular nuclei

44
Q

what can trigger a
1) increase and 2) decrease
in vasopressin
also what should you not do if on ecstasy?

A

1) high solute/low water consumption, stress, nicotine
2) excess water consumption or alcohol consumption decrease osmolality of plasma

*ecstasy is an amphetamine - it makes you retain water you shouldn’t be - so do not drink a load of water if you’re on ecstasy as this can lead to brain oedema due to inability to control body fluid levels

45
Q

explain exactly how vasopressin effects the principle cells of the collecting duct

A

binds to receptor V2
protein kinase A signalling cascade
Aquaporin 2 channels in vesicles are inserted into the membrane to increase water reabsorption (AQP 3 and 4 are not regulated by vasopressin, they just do their thing)
Vasopressin drops, V2 no longer activated, so neither is protein kinase A, the AQP2 vesicles go and fetch AQP2 and take them back out of the membrane

Net effect: increase in vasopressin = increase in H2O reabsorption = fall in body osmolality

46
Q

what are the differences between the two kinds of diabetes insipidus?

A

central DI = no release of ADH but treatable via DDAVP nasal spray (replaces ADH)
nephrogenic DI = no response to vasopressin or AQP2 water channels have a defect, there is a range of different treatments

47
Q

what is aldosterone?
what does she respond to and what for?
where does she act?

A

she is a mineralocorticoid
responds to an increase in plasma K+ (only needs a 0.1 mM rise) or a decrease in ECF volume
she results in Na+ and water reabsorption and K+ and H+ secretion
she acts on LDT and CD

48
Q

describe aldosterone’s principle cell genomic action

A

she’s a steroid hormone so is lipid soluble and diffuses straight across the plasma membrane

Binds to cytosolic receptor, this complex moves to nucleus, results in RNA transcription and synthesis of ENaC on apical and Na/K ATPase on basal (to increase Na reabsorption)
ROMK on apical and Na+/H+ antiport (to increase H+ and K+ secretion)

this is a slow system - requires protein production

49
Q

what is NPo?
what are aldosterone’s non genomic effects?

A

NPo = probability of in this case Na+ channels being open
aldosterone increases NPo of Na+ ion channels, this non genomic action is much faster

50
Q

what effect does aldosterone have an alpha IC cells?

A

comes into cell, binds to receptor and goes to nucleus, causes transcription and translation of H+ pump to increase H+ secretion

51
Q

what is the net effect of aldosterone?

A

Increase in Na+ in plasma (not conc, as water follows)
So increase in ECF volume too
Decrease in plasma H+
Decrease in plasma K+ (more ROMK)

52
Q

what happens in Liddle’s disease and what diuretic is used to treat it?

A

there’s low aldosterone but a gain of function mutation in ENaC = high Na+ reabsorption, so more water is reabsorbed, causing hypertension

treat with amiloride

53
Q

pseudohypoaldosteronism?

A

mineralocorticoid receptor mutation means cells no longer respond to aldosterone, leading to unwanted salt loss despite high aldosterone levels

54
Q

what is the renin-angiotensin system?

A

renin = an enzyme that cleaves angiotensinogen to angiotensin I, which is converted to angiotensin II by Angiotensin Converting Enzyme (ACE) in capillary beds (Mostly in the lungs)
it works with aldosterone to increase ECFV and Na+ plasma

55
Q

what causes renin release? how does the release work?

A

macula densa cells in the DT detect reduced sodium
baroreceptors in afferent arterioles of the kidney detect reduced perfusion pressure
sympathetic stimulation of the macula densa cells)

these cells release stuff that cause granular cells to release renin

56
Q

what does angiotensin II then actually do?

A

it acts at the zona glomerulosa
causes release of aldosterone from adrenal glands
vasoconstriction of the arterioles to inc. BP
overall increases plasma Na+ and ECFV due to aldosterone, plus inc. BP

57
Q

how might ACE inhibitors be useful?

A

they prevent production of angiotensin II, reducing Na+ reabsorption and therefore water reabsorption, reducing ECFV and therefore BP

58
Q

fun fact about sars coronavirus II?

A

effects ENaC

59
Q

using the scenario of you ingesting a nice bit of salt, how are ECFV and osmolality integrated?

A

plasma Na+ would go up, promoting water loss in cells causing an increase in ECFV, so you’ve got a high ECFV but also a higher plasma osmolality due to more Na
The rise in plasma osmolality would: increase vasopressin release, so more water Is reabsorbed, osmolality should decrease but then ECFV would rise further

The increase in ECFV would:
Reduce aldosterone levels, which would increase loss of Na+ and water, reducing ECFV

These counteract -
Vasopressin system increases ECFV further, but we prioritise correcting the ECFV so vasopressin sensitivity is decreased (this can go the other way too). This is because blood pressure is affected by ECFV so we need to bring that down

pharm phys intro (9 decks)

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