renology and urology - wk 3 Flashcards
functions of the kidney
o Filtration of blood o Detoxification o Regulating blood pressure o Regulating blood ph o Regulating haematopoiesis o Making vitamin D
what are the 2 things the kidney needs to filter molecules - and brief explanation of each
1- A pump
- Aka the heart
- Uses blood pressure from the heart to drive fluid through the filter
- Regulates the pressure by dictating how much of the output pressure of the heart is directed to this job
2- A filter
- “Design” problems
o Need a very fine filter (cut off c. 4nm = 40A, free flow below 18A)
o We need the filter not to clog
o We need to be able to filter lots of fluid in a small-ish space
whats the very fine filter in the kidneys called
- whats its structure
The slit diaphragm
o Podocytes (in the pic to the right) – meaning foot cells
o Lie over the blood capillary
o Long finger like processes
o At molecular level this is made of nephron proteins
These stick out and stick together to make a large adhesive structure in the middle
o There are pores between nephron molecules
These pores are the spaces through which vv small molecules can go
o Only 3% of the slit diaphragm is actually slit (the hole itself)
o So it’s a major source of resistance to fluid flow
o So need enormous areas of it to get enough flow of proteins through it
o Also need pressure to push fluid through the filter
how does kidney restrict blood supply and drain
Restrict afferent arteriole
- Blood pressure in capillaries drops
- Filtrate rate drops
Restrict efferent arteriole
- Blood pressure in glomerular capillaries rises
- Filtration rate rises
how not to clog the filter
Pinocytosis of trapped proteins
- Proteins can become trapped in the pores of the filter
- This can be fixed via pinocytosis
- Similar to phagocytosis but smaller…
o Vesicles of membrane with receptors for proteins
o Grab the proteins and take them into the cell
o Exporting them or degrading them via lysosomes and reusing the protein products
what are the layers before the slit diaphragm in the kidney
Endothelial cell – Course filter on outside – keeps cells out but let’s proteins in
Cleaned by blood flow and phagocytes
Glomeruli Basement Membrane (GBM) – Finer filter that stops bigger complexes going through and jamming the diaphragm
Renewed by mesangial cells
Then slit diaphragm with pinocytosis to help clean it up
describe a renal corpuscle and its purpose
- Called a renal corpuscle
o Afferent arteriole carrying blood in
o Then lots of capillaries – glomerular capillaries
o Then unite again in efferent arteriole
Whole thing covered in Bowman’s capsule which captures the filtrate and roots it into a tube
- Massive surface area in a small space
- allows filtration of lots of fluid in a small space
how many renal corpuscles are within a kidney and what can alter this amount
- Have lots of renal corpuscles in one kidney
- Humans – 50,000 – 1,000,000
- Same variation if nutrient starved during development in the womb
typical values of blood an plasma flow and glomerular filtration rate, also how much plasma is removed as filtrate
- Blood flow to kidneys – 1,2L / min
- Plasma flow to kidneys – 0.66L/min (assuming normal haematocrit of 0.45)
- Rate of filtration through glomeruli (summed across all) = 0.13L/ min
- > 20% of plasma is removed as filtrate
- Amount of filtration will decline in people with renal problems
how to determine the glomerular filtration rate
- Creatinine is filtered into the urine and not recovered
o Measure creatinine conc. In blood and urine
o Measure flow rate of urine by measuring the urine production of patient within set number of hours then calculating flow rate per minute
actual amount of creatinine in urine = urine conc. Of creatinine x flow rate of urine
amount of creatinine that got into the urinary space = plasma conc. Of creatine x glomerular filtration rate (GFR)
GFR x plasma conc = urine flow rate x urine conc.
THEREFORE…
GFR = (urine conc. X urine flow rate) / plasma conc. Of creatinine
dialysis machine mechanism
- Essentially work in the same way as a real kidney
- Contain
o A membrane which is a fine filter
o Blood on one side of the membrane returning to the patient
o Other side of the membrane have a dialysate
A liquid identical to plasma aka full of small molecules but without the toxins
So overall net flow of toxins from blood to dialysate which is then passed away and fresh dialysate is brought in
how often do patients need dialysis and whats the prognosis
Patients who have renal failure need dialysis every 2-3 days
- Either as above with their blood
- Or with different body fluids and some of the patients own membranes as the filter
Dialysis works but it’s not good long-term usually
- Median life on dialysis <5 years
- This is less than average life expectancy with cancer
what makes up a nephron
- Renal corpuscle
- Proximal tubule
- Henles loop
- Distal tubule
what do the proximal tubules have that the distal tubules don’t and what is unusual about these
microvili
In proximal tubules…
- Tight junctions of the epithelial cells are much leakier than other areas of the body
- Allows ions to get past them
epithelial structure
- Basement membrane around edge
- Single layer of epithelial cells
o Anchored to epithelial membrane
o Polarised - Cell adhesion complexes where lateral and apical domain meet
o Tight and adheren junction - Membrane on the apical side (full of microvilli in the proximal tubules)
what molecules do the nephron epithelia have to recover
Na+ K+ Ca2+ Mg2+ Cl- HCO3- PO4 2- H2O amino acids glucose proteins
what are the general types of transporters/ channels in the proximal tubule to recover things
Primary active transporters
- (Na/K ATPase and H ATPase are the only common ones in the plasma membrane)
Solute Carrier Family (SLC) proteins
- ~300 many are co-transporters powered by established conc gradient (eg Na)
- ‘secondary active transport’
Aquaporins (water channels)
Ion Channels
Protein endocytosis receptors
how do we change the equilibrium between filtrate and plasma
The filtrate and the plasma will be around equilibrium (in context of small molecule/ions we want to recover)
- To move things from filtrate to plasma need to move from equilibrium
- Need to do work (ie move a lot of food towards equilibrium to move solute away from it – 2nd law)
- Need to burn up ATP
o Kidneys are vv highly packed with mitochondria
explain primary active transport
- Located on basal side of the cell
- Main one is Na/K ATPase
- Inports 2 K and exports 3 Na using ATP
- This activity generates a membrane voltage – basis of electrochemistry in membrane
- Since sodium wants to move back into the cell
o There’s a strong gradient
o This can be used to power the recovery of other things using co-transporters
sodium recovery - what transporters are involved
Sodium Proton Exchanger – SLC
- For one Na coming back into the cell one proton/H+ is transported out
(distal tubules)
Sodium chloride co-transporter – SLC
- For one Na coming back in one chloride is brought into the cell
(loop of Henle)
Na-K Cl transporter – SLC
- For one Na coming in, 2Cl and one K are brought in
- Electrically neutral
ROMK (renal outer medullary K channel)
- Allow potassium that’s came into the cell back out
- Regulated to allow leakage
amino acid recovery
- Eg. Na comes in and so does 2Cl and neutral amino acids
- Lots of different variations of these channels to recover all diff. amino acid
glucose recovery
Mostly SLC5A2 - Na:glucose = 1:1 uptake ratio SLC5A1 - 2:1 ratio This is rate limited! - Because if there’s an excessive amount of glucose in the blood there will be excess amount of glucose in primary filtrate - So cells can’t recover all the glucose - Normally there’s no glucose in urine - when high levels of glucose in blood there’s high level of glucose in urine (it tastes sweet) eg in diabetes mellitus
what are the 3 types of organic cation and anion transporters
- organic anion transporters (OATs)
- Organic Cation transporters (OCTs)
- Organic cation/ carnitine transporters (OCNTs)
- Organic Cation transporters (OCTs)
- Usual Na/K ATPase
- For price of sodium coming in a proton goes out = proton gradient
- Antiporter channel uses proton gradient – 1 proton coming in, 1 organic cation goes out
Also active transporter of organic cations
- Such as one that transports chemotherapy out of cell protecting cancer cells = BAD
- Uses ATP
Also passive cation channels
- Organic cations for extracellular fluid equilibrate into the cytoplasm
- Then the active ones kick the cations out of the cytoplasm and into the urine (apical side)
- organic anion transporters (OATs)
- Currency exchange
- Na/k ATPase
- On basal side of cell – 1 sodium comes in, 1 alpha-ketoglutarate also comes into the cell
- Antiporter – 1 alpha-ketoglutarate comes out pulling 1 anion into the cell
- Passive channels allow anions to drift out
Dangerous because… - System pumps anions in but lets them drift out
- So if anion has a low out drift rate then import channels can create a build-up of anion in cell
- Leads to the cell becoming toxic = damage
- Many drugs in clinical use damage kidney cells via this mechanism
example of anions transported
- Methotrexate
o antitumour - Furosemide
o Acts on kidney - Penicillin
o Penicillin is quickly expelled through kidney
o Probenecid treatment stops kidneys from expelling penicillin
o So penicillin lasts longer / you need less
phosphate recovery
- 1 Na comes in and 1 phosphate comes in via a co-transporter
bicarbonate recovery
- Proton exporter – 1 Na in, 1 H/ proton out
- Proton can combine with any bicarbonate in the filtrate to form carbonic acid
- Carbonic anhydrase hydrolyses this to make water and CO2
- CO2 can cross cell membrane without need for transporters
- Once across the membrane carbonic anhydrase turns it back into carbonic acid which naturally dissociates into proton/H and bicarbonate
- So proton is effectively coming round in a cycle and bicarbonate is taken back up into the body fluids from the urine
why bicarbonate recovery doesn’t effect body ph and how it changes during acidosis
- This has no effect on the body Ph
- Because although H+ is being expelled, we are effectively regenerating it in the cell
- There’s no net loss of bicarbonate or protons/ H+
- If there’s remaining protons when all bicarbonates been taken up – ACIDOSIS
If this is the case a diff. reaction is used
o Hydrogen phosphate can pick up H+
o This new compound will leave the compound in urine
o This does effect acid base
o So if you’re in acidosis the H+ will be expelled from the body via this mechanism
o Ammonia can also take up protons and leave via the urine this also helps correct acidosis
intercalated cells
- Later on in the kidney before urine leave
- Alter Ph
TYPE A CELLS - expel protons
Proton ATPase
- Directly hydrolyses ATP to get the energy to expel protons
Proton potassium antiporter
- Expelling protons
TYPE B CELLS- retain protons
- Same ATPase but on the basal side instead of apical side
- Throws bicarbonate out into the urine
- Corrects for alkalosis
recovery of calcium
- Since tight junctions aren’t that tight calcium simply diffuses across
- Once water is being removed from urine the calcium tends to become more concentrated in body so runs down gradient into urine to equiblirate
recovery of water
- Recovered passively through aquaporins
o Not pumps only allow travel down gradients - All above pumps pump ions out of lumen of kidney back into body so fluid in kidney lumen becomes more and more dilute therefore setting up an osmotic gradient that makes water want to move to follow the salt
- So there is passive recovery of water
whats an extra measure the proximal tubules have to recover proteins
- Proximal tubules cells have special vv large proteins like megalin
- Good at binding to other proteins driving receptor mediated endocytosis
- Allows proximal tubule cells to take proteins up and bring cells back from urine
in summary what does the proximal tubule recovered
- Recovery of 65% of sodium, chloride, phosphate, calcium etc
- Recovery of some water
- But hasn’t concentrated the urine
- Hasn’t controlled acid/base
how do we concentrate the urine and draw out maximum amount of water
o Na/K ATPase
o SLCs and ion channels that can parasitize the Na+ gradient to move ions and small molecules about
o Osmosis will make water follow ions (only takes water form a dilute solution to a concentrated one)
In order to make concentrated urine we must get water out of the concentrated urine into the plasma of the body
So we must make a solution that’s even more concentrated than the urine
Kidney makes an area of it’s own tissue extremely concentrated with ions to draw the water out of the urine
explain the pulling of ions from the proximal tubule to the tissues and what this results in
- In proximal tubule water flows with ions into the plasma due to leaky tissues (tight junctions)
- These junctions are only a property of the proximal tubules
- If we don’t have these tight junctions and aqua porins leads to a diff. system…
o Ions get dragged back from the urinary space into a super concentrated area in the basal side
o This area will be super Hypertonic (super salty)
o So water will want to go here
o But won’t be able to travel here because there’s no aquaporins
the loop of henle - properties of each limb
Descending limb
- Permeable to water
- But doesn’t pump ions
- Impermeable to urea
Ascending limb
- Impermeable to water
- Permeable to ions
- Permeable to urea
explain the recovery of ions in the ascending limb of loop of henle
In ascending part there’s recovery of ions via the sodium pump
- This makes the surrounding extracellular fluid vv salty
o in the medulla of the kidney
- This fluid is vv close to the descending limb which allows water to travel into it through the water permeable descending limb
- Leaves urine more concentrated
- Since middle bit is salty makes it easier to get water out of the start of the system as it draws it out
- At the end there’s dilute urine as ions have been pumped out
how much sodium, chloride and water is recovered in the loop of henle
This system recovers ~25% of sodium and chloride and ~10% of filtered water
= running total of 90% NaCl including the proximal tubule
where are the renal corpuscles and henle in the kidney
o Renal corpuscles are in the cortex
o Loops of henle come into the medulla
how are the blood vessels organised in the kidney to facilitate the medulla remaining salty ie not being flushed away
o Organisation of blood vessels
o Blood that leaves the glomerulus leaves in an efferent arteriole
o This arteriole goes down into the loop of henle
o As blood comes down it enters the hypertonic region
o Has water drawn out of it and ions going into it
o So blood getting more and more concentrated as it reaches the bottom as it comes back up it gives the ions back as it’s vv salty and it picks up some water
o SO water drawn out of blood as it descends and added back as it ascends, ion go into blood as it descends and out of blood as it ascends
whats the defect of the blood vessels moving through the loop of henle
- Oxygen difference is affected in same way as water is
- So oxygen descending tends to get short circuited to the ascending part
- Rather than remaining in the blood to go down to the bottom
whats a summary of the activity in the distal tubule
More recovery of ions no water transport
- Polarity in urine less than that in tissue so naturally water wants to go out
- Also, active ion pumping recovering more salt
- Leads to very dilute urine
whats considered the end of the nephron, and what comes after this
Due to developmental reasons the end of the distal tubule regarded as the end of the nephron
But in terms of plumbing, it leads straight onto a branched urine collecting system called the collecting duct
the collecting duct pathway and how much filtered water is removed in this area
- The collecting duct system leads from the cortex back through the hypertonic zone (medulla of kidney) to the pelvis
- Taking dilute urine back through vv salty zone means that water wants to go from vv dilute urine into the hypertonic zone
- So up to further 24% of filtered water removed here
whats the cumulative removal of water from urine in the nephron and collecting duct
~99%
when is the recovery fo water regulated and by what
- This is regulated bc sometime don’t want to recover all your water
- Eg if you are intaking lots of fluid
- Regulated via aquaporins (cells which allow passive transport of water)
o In these cells aquaporins can be in the plasma membrane (have effect) or taken into vesicles inside the cell to be stored (so have no effect)
o Depending on how much water you want to retain there are more or less in the membrane
o Controlled by AVP hormone
