Renal physiology and pharmacology Flashcards
What are the functions of the kidney?
Filtration of blood
Detoxification
Regulation of blood pressure
Regulation of blood pH
Regulation of haematopoiesis (produces erthyropoietin)
Activates Vit D
What is the slit diaphragm?
Gaps between podocytes which wrap around the blood vessels in the kidneys
Smaller molecules could pass through these gaps
What is the biggest hole size in the slit diaphragm?
Size of albumin molecule
Why is high pressure needed to push blood into the filtrate?
Pushing molecules through filter- only about 3% of the total area is slit so there is major resistance
Thermodynamics- need pressure to stop water from flowing back to the area with greater ion concentration
What are efferent and afferent arterioles?
Efferent= drains blood from kidney
Afferent= applies blood to kidney
What happens when afferent and efferent arterioles are restricted?
Afferent= blood pressure in glomerular capillaries drops and thus filtration rate drops
Efferent= blood pressure in capillaries rises and filtration rate rises
How are stuck molecules removed from the filter in the kidney?
Small molecules that get stuck in the filters are brought in pinocytosis (phagocytosis of small molecules)
Mesangial cells are constantly recycling the glomerular basement membrane so that large molecules which are stuck are moved
What was the structure of the glomerulous membrane?
GBM= glomerular basement membrane
How are the parts of the glomerular membrane cleaned?
Endothelial cells= cleaned by blood flow and phagocytes
Podocytes= cleaned by pinocytosis
Basement membrane= renewed by mesangial cells
What was the glomerulus?
The glomerulus, the filtering unit of the kidney, is a specialized bundle of capillaries that are uniquely situated between two resistance vessels
Alot of branching that comes together
What is the space in which the glomerulus sits?
Bowman’s capsule
What is the renal corpsule?
Glomerulus structure and Bowman’s capsule
How many renal corpsules do humans have?
50,000-1,000,000 per kidney
What is Barker hypothesis?
Barker hypothesis- number of nephrons follows mother’s amino acid nutrition
Nutrition restriction (especially lack of protein) during foetal life may lead to having as little as 100,000 nephrons. May be adaptive so the foetus loses less proteins. The consequence is high blood pressure
What do high levels of plasma creatinine indictate?
Indicative of kidney problems
How does the glomerular filtration rate compare with levels of creatinine in the plasma?
What does the amount of creatinine in the urine tell us?
The amount filtered, as it is not reabsorbed
What is the equasion for the clearance rate of a substance that is not reabsorbed in the kidney?
What are the options for those who have severe chornic filtration conditions?
Dialysis or transplant
What is the nephron divided into?
What is the differences in proximal and distal tubules?
Proximal have microvilli, distal tubules do not
Where in the nephron are tight junctions leaky?
The proximal tubule
What is the common plasma membrane transporter in the proximal tubule?
Na+ K+ ATPase
What are the different solute recovery channels in the nephron?
Primary active transporters- require energy ( Na+ K+ ATPase and H+ ATPase)
Solute carrier proteins- co-transporters powered by established concentration gradients
Aquaporins
Ion channels
What does Na+ K+ ATPase do?
How is sodium recovered in the proximal tubule?
Where is potassium recovered?
Occurs in the loop of henle
How is potassium recovered?
Sodium can co transport Cl and K, sodium can enter due to the gradient causes by NaK ATPase
There is also regulated leakage of potassium in the renal outer medullary K channel
Where does amino acid recovery occur?
The proximal tube
How are amino acids recovered?
Brought in with Na+ that can be brought in due to concentration gradient caused by Na+ K+ ATPase
Where does glucose recovery occur?
Mostly in the proximal tubule, a little in the loop of Henle
How is glucose recovered?
What is indicative of diabetes mellitus and why?
Glucose in the urine- glucose recovery from kidneys can become saturated and no more can be taken up
Where does phosphate recovery occur?
Proximal tubule
How is phosphate (PO4 2-) recovered?
Co transported with sodium
How is bicarbonate recovered?
Calcium anhydrase converts it to H2O and CO2
CO2 diffuses through cell and re joins with water
Where does bicarbonate reuptake occur?
Proximal tubule
How does bicarbonate reuptake not affect acid base?
Bicarbonate is re absorbed
H+ is recycled and goes round and round in the pathway
What happens if there is left over protons after bicarbonate has been re absorbed?
Bonds to ammonia (NH3) or hydrogen phosphate (HPO4 2-) and is excreted
Where does the ammonia come from that excess protons can bind to?
Glutamine in the cell can be broken down to NH3 and bicarbonate
Useful as more H+ excreted and more bicarbonate, so pH rises
How can protons be brought back to the body or excreted by themselves?
Type A and type B cells
How is water reuptaken?
Via aquaporins
How are calcium ions recovered?
- Calcium recovery is driven by osmosis once the urine has become more concentrated
- Calcium ions can cross tight junctions directly, down the concentration gradient into the body
- With ions removed water will have moved back into the body, meaning the concentration of calcium ions is greater in the body and they can flow down the concentration gradient
How are proteins re-uptaken in the proximal tubule?
Takes place using receptors such as megalin, which are huge and bring in proteins via endocytosis
How do organic cation and anion transporters work?
Cation= Allows passive movement down gradient
Anions= push into the cell and drift out
What organic transporter is dangerous and why?
Anions= since they push in, concentrations can increase and cause toxicity and renal failure
What drug can block the uptake of organic ions into the cell and why is it useful?
Probenecid- this is useful as it means small dose of a drug e.g. penecillin will be excreted slower and have greater effect
What are examples of organic cations and anions?
Cations= dopamine, antihistamines, morphine
Anions= cyclic peptides, prostaglandins, methotrexate, penicillin
What is the summary of what occurs in the proximal lumen?
Are tight junctions in the loop of henle leaky?
No
What is the structure of the loop of henle and what is absorbed where?
Cells in the thin descending limb have lots of aquaporins but little ion transport.
The other way round in the ascending limb
How is water reabsorbed in the loop of Henle?
There is an uptake of ions in the ascending limb that creates a hypertonic area where water travelling in the descending limb is pulled towards out of the filtrate
Water is drawn towards the hypertonic area due to the anatomic structure of the kidneys
How are ions reabsorbed in the loop of henle?
How much water is reabsorbed in the loop of Henle?
10% of filtered water
Where in the loop of Henle is water diluted and where is not?
How is the hypertonic region stopped from being swept away by blood flow in the tissues?
- Salty parts are kept away from corpsules
- Also the blood vessels emerging from the glomerulus go on to form a secondary capillary system- the vasa recta
- Where counter current exchange takes place
What occurs in the distal tubule?
More recovery of ions, no water transport
What occurs after the distal tubule?
The collecting duct, which also passes through the hypertonic zone
How does body re absorb water in the collecting duct?
Via aquaporins
Collecting duct cells choose where the aquaporins are located
What else is recovered in the collecting duct in small amounts?
The duct can also choose to leak urea back in the body, to add to the hypertonicity. It is not enough to cause toxicity
What is the basic anatomy of the kidney?
There is renal pyramids connected by collective tissue that drain into the kidney pelvis (bowl)
There is seperation between normal and hypertonic zones
Why are the kidneys are particularly sensitive to ischaemia?
The long runs of parallel arteries and vein and arterioles and venules means there is countercurrent exchange of oxygen, so that much gets shunted from artery to vein before the blood enters the kidneys. This means the kidneys are particularly sensitive to ischaemia
What occurs in low renal oxygen levels?
Erythropoietin is released and more RBC made in bone marrow
What detects blood pressure in the nephron?
- There is direct pressure sensing in the afferent arteriole- the myogenic mechanism
- There is also tubuloglomerular feedback which measures the concentration of salt in the nephron to work out how fast urine is flowing through and if it has enough time to be absorbed
How is blood controlled in individual nephrons?
The end of the distal tubule make contact with the arterioles entering the glomerulus- known as the macula densa and feedback can occur that way
How does the macula densa cells detect and stop elevated glomerular blood pressure?q
What are the two reasons why too much NaCl remains in the distal tubule?
There has been a high salt intake OR
Glomerular pressure is too high and so salt is not absorbed
Where is renin released?
Juxtaglomerular cells
What inhibits the release of renin?
Signalling from macula dense (when there is high salt in the distal tubule) and or elevated glomerular blood pressure
How does the renin-angiotensin-aldosterone system work?
How does angiotensin II cause an increase of Na re-absorbsion?
Affects proximal convoluted tubule
Up regulates the Na+/H+ exchanger through a secondary messenger system
How does aldosterone cause an increase of Na re-absorbsion?
Effects the collecting duct
Drives gene expression of Na+/K+ ATPase channels
How does aldosterone cause less K+ uptake
Regulates gene expression so more H+ channels are transcribed and less activity of H+/K+ channels
What kidney cells does aldosterone effect?
Principle cells (Na+ absorbsion)
Intercalated cells (H+ excretion)
What causes AVP to be released from pituitary gland?
Aldosterone
What is the effect of AVP?
AVP drives the transport of aquaporins from storage into the membrane, thus allowing for more uptake of water in the collecting duct
What happens to the kidneys during the fight or flight response?
Renal nerves have a fight or flight sympathetic response; they secrete noradrenalin which constricts both vessels serving glomerulus so reduces flow (so there is more blood to pump around muscles). Also directly promotes renin release
What causes more sodium loss in the kidneys?
Atrial natruietic peptide from the heart blocks the Na+ reuptake channel in the collecting ducts and causes more sodium loss
What happens when there is low blood calcium?
- The parathyroid releases PTH which acts on the kidney
- PTH inhibits phosphate re uptake, as they tend to go in opposite directions of travel
- They also bind to receptors which drive the production of calcium channels and also the exit channel. Need Vit D for these
- Causes increased Calcium recovery and decreased PO4 2- recovery
What happens if there is a fall in intracellular pH?
- If there is a fall in intracellular pH, apicial Na+/H+ exchangers can detect this and can become more actived
- This causes more H+ to be excreted
Where does regulation of potassium occur?
There is little regulation of K in the proximal tubule, the excretion and absorbsion regulation occurs in the collecting duct
Absorption by intercalated cells is occurring constantly, excretion by principle cells is regulated
What happens to the K+ removal system in chronic K+ deprivation and in high K+ diets?
In chronic K+ deprivation the K+ system gets degraded and channels are removed from the membrane
Opposite in high K+ diet
What happens to potassium in alkalosis?
H+ pumping by intercalated cells is reduced, so there is LESS K+ intake
Can lead to hypokalaemia
What happens to potassium in acidosis?
There is increased H+ outpumping via a H+/K+ channel, so more potassium uptaken.
Can lead to hyperkalaemia
What do diruetics do?
Increase the amount of water and salts lost from the body
What is the mechanism of action of loop diruetics?
Blocks a channel (Cl-/K+/Na+) that stops salt being moved into the interstitium and thus the salty area is less salty and there is less osmolarity drive to bring the water back into the body
What is a common loop diruetic in Scotland?
Furosemide
What are the side effects of loop diuretics?
- They result in the loss of Na+, K+ and Cl- because of failure to recover in the LoH. Loss of essential electrolytes
- Can result in the hypercalcuria (in collecting duct some Ca recovery was dependant on the pull of water)
- More Na getting to the collecting duct means more uptatke there and more K+ loss
What are diruetics main effects on blood pressure?
The main effect on blood pressure is not due to fluid loss but due to the urine being unusually salty- the macula densa and juxtaglomerular apparatus will detect this and stop producing renin
How do thiazide diuretics work?
They block the Na+/Cl- co-transporter in the distal tubule
How do potassium sparing diruetics work?
They block the Na channel- weaker than loop diruetics
Do not have the vice of driving patients into hypokalkaemia
What are examples of potassium sparing diuretics?
Amiloride
Spironolactone
What is the action of spironolactone?
Blocks aldosterone, which causes transcription of the Na channel
What is a common side effect of spironolactone?
Drives mammilary growth in men
What is the mechanism of action of carbonic anhydrase inhibitors?
- Also is carbonic anhydrase inhibitors (causes more bicarbonate to not be recovered, so there is less of a drive to pull water back in as urine is more osmolaric.
- Messes with pH
Where do the different diuretics act?
What is Bartter’s syndrome?
Causes impaired action of the SLC12A2 which stops Cl-, K+ and Na+ from entering at the loop of Henle
Makes medulla less salty and less water is drawn in
Causes loss of Na+, K+, H2O and hypercalcuria
What is Gitelman’s syndrome?
Impaired action of the sodium and chloride uptake channels
Causes loss of Na, K, H2O but hypocalcuria
Loss of K+ because thiazide diuretics act on the distal tubule, and so there is more Na+ left in the collecting duct as it has not been uptaken and is swapped for K+
What syndrome mimics a thiazide diuretic?
Gitelman’s syndrome
What is Liddle’s syndrome?
Makes sodium intake channels very active
Causes volume expansion in the body and hypertension
What can Liddle’s syndrome be treated with?
Amiloride
What is pseudohypoaldosteronism?
Causes underactivation of sodium channel
Causes Na+ loss, K+ retention and high aldosteronism
Aldosterone is trying to correct the problem, but cannot due to a non-functioning sodium channel. Symptoms mimic lack of aldosterone
What does inactivating mutations of aquaporins 2 cause?
Nephrogenic diabetes insipidus
What is Addison’s disease?
Destruction of the adrenal glands, causes lowered/no aldosterone production
This causes loss of Na+, hyper K+, hypervolaemia
Same renal result as treatment with spirnololactone
What is psychogenic polydipsia?
Causes whole body hypo-osmolarity
Compulsive water drinking
What is renal angenesis?
Where both (bilateral) or one (unilateral) kidneys are missing
Bilateral is rare and not compatible with life if there is no medical intervention
What is Potter’s facies?
Flat nose, flat chin and ears against head
Caused by bilateral renal angenesis
Why does Potter’s facies occur?
Normally foetus develops in amniotic fluid so pressure from mother is not pushing on foetus- when no fluid face is flatter
What is congenital cystic disease?
Problems in the cells ability to measure pressure of urine- cells may put transporters on wrong side of cell
Cysts fill with fluids and crush healthy kidney cells
What is supernumerary ureter?
- When there is more an one ureter. If they unite before or at the bladder is not too serious.
- If joins below the bladder there will be continous dribbles of urine and make it easier for infections to get into the kidney
What is Pelvic kidney?
When the kidney ends up in the pelvis. If there is two pelvic kidneys they fuse together to form a horseshoe kidney
What is hypospadias?
Incomplete migration of the urethral groove from the base of the penis to the tip
What is the cloaca?
Common exit of rectal, vaginal and urethral opening. It is seperated by folds
What are the congenital abnormalities of cloacal development?
- Rectovaginal fistula
- Rectoprostatic fistula
- Rectoclocal canal (rectum, vagina and urethra unite inside body)
How is the female reproductive and urology area created?
- Indifferent gonad develops into an ovary
- Upper Mullerian ducts become fallopian tubes
- Mullerian ducts converge & fuse to become the uterovaginal canal
- Neprhic ducts and mesoneprhos degenerates
- Uterovaginal canal forms uterus and upper part of vagina. (Lower part from urogenital sinus)
- The urethra ends within the vulva and does not run to end of the clitoris
How is the male reproductive and urology area created?
- Indifferent gonad develops testis cords
- Testis cords connect to some mesonephric tubules (->epidydymis)
- Mullerian duct regresses
- Distal neprhic duct sprouts seminal vesicles – the part of the nephric duct distal to this is the ejaculatory duct
- Urethra sprouts prostate and bulbourethral glands.
- Urethra runs along the penis and opens at its end
How is the renal system created in a foetus?
- Urogenital system forms from the urogenital ridge (parallel to vertebral column) and nephrogenic cord
- The mesonephros is an area in the thoracic area in the nephrogenic cord. Has a mesonephric duct connected to tubules
- The metanephros forms around week 5- connects to ureter and forms lots and lots of branches
What would be the effect on the kidneys and the whole body of having a renal arterial stenosis?
Causes low blood pressure in that kidney; activation of the the RAAS system. Ischaemia will also cause a GFR decrease
Leads to hypetension, increased risk of stroke and MI
Other kidney- will be affected by hypertension, causing glomerular disease and scarring and proteinuria
Why can those who are experiancing kidney failure become anaemic?
Because the kidneys produce erythropoitein
What are the rates of renal blood flow, glomerular filtration rate and urine output per min?
Renal blood flow= 1.25L/ min
Glomerular filtration rate= 100mL/min
Urine output= 1mL/min
Where does vasopressin act?
The collecting duct
Where is the majority of salt reabsorbed back into the body?
65% is in the proximal tubule
Where does PTH act and what does it do?
Acts on the distal tubule to bring back more calcium into the body
Where does aldosterone act and how does it act?
On the distal proximal tubule; upregulates the Na+/ K+ or H+ transporter so more sodium is brought back into the body and more potassium (or protons if there is no potassium0 is lost
What is the local effect of angiotensin II?
Restricts the efferent arterioles in the kidney. Tries to make the most of the poor blood flow to kidney
What is the renin-angiotensin system?
What is ramipril?
ACE inhibitor
What is the action of Lorsartan?
Blocks angiotensin II receptors
What is aliskeren?
A potassium sparing diuretic
What is the action of spirnolactone?
Blocks the action of aldosterone
What are causes of acute renal impairment?
Dehydration
Hypotension
Glomerulonephritis
Drugs- e.g. NSAIDS
What is renal function expressed as and what is normal?
Expressed as the glomerular filtration rate, normally greater than 100mL/ min but declines progressively with age
What do diuretics do?
Decrease sodium absorption and increases urinary volume
What are the different types of diuretics?
Loop, thiazide (and thiazide like), postassium sparing, osmotic and carbonic anhydrase inhibitors
What is the mechanism of action of loop diuretics?
Decreases Na+ K+/ Cl- absorption in the thick ascending limb
Makes the salty area less salty so less water is drawn in
What is an example of a loop diuretic?
Furosemide
What are loop diuretics indicated for?
Heart failure- acute and chronic
Renal failure, liver cirrhosis and acute pulmonary oedema
What are the adverse effects of loop diuretics/
Hyponatraemia, hypokalaemia, metabolic acidosis
Dehydration, hypovolaemia
Ototoxcity= damage to auditory nerve
Why does metabolic alkalosis occur in patients taking loop diuretics?
There is > loss of H+ in the distal convoluted tube as there is more sodium to swap for it
What are examples of thiazide diuretics?
Bendroflumethiazide
Thiazide like= indapamide, chlortalidone
What is the mechanism of action of thiazide diuretics?
Inhibit Na+/Cl- co transport in the distal convoluted tubule
What are thiazide diuretics indicated for and why?
Hypertension- causes water loss AND seems to have a vasodilation effect on the body
What are the adverse effects of thiazide diuretics?
Hypokalaemia, hyponatraemia, hypomagnesaemia, hyperglycaemia and alkalosis
Fluid depletion, erectile dysfunction
What are the two different ways that potassium sparing diuretics work?
Aldosterone receptor antagonists- spironolactone
Sodium channel blockers- amiloride
What are potassium sparing diuretics indicated for?
Chronic heart failure, liver failure, primary hyperaldosteronism and resistant hypertension
What are the adverse effects of potassium sparing diuretics?
Hyperkalaemia
Spironolactone= oestrogenic effects such as hynaecomastia
When are osmotic diuretics used?
Used in situations where fluid needs to be rapidly offloaded
Raised ICP due to cerebral oedema
Raised intra-ocular pressure
What are the adverse effects of osmotic diuretics?
Initial fluid overload, hypernatraemia
What is the mechanism of action of osmotic diuretics?
Glucose that is filtered, does not get absorbed but drags water out of the body
What is an example of osmotic diuretics?
Mannitol
What are examples of carbonic anhydrase inhibitors?
Acetazolamide, brinzolamide
What is the mechanism of action of carbonic anhydrase inhibitors?
Inhibits carbonic anhydrase in proximal tubular cells which decreases the H+ and HCO3- available for exchange withNa+
What are the adverse effects of carbonic anhydrase inhibitors?
Metabolic acidosis
What are carbonic anhydrase inhibitors indicated for?
Glaucoma and altitude sickness
What drugs can cause dehydration?
Diuretics
Drug induced diarrhoae- laxatives, antibiotics and proton pump inhibitors
Drug induced vomiting- chemotherapy
What drugs are directly toxic to the kidney?
Antibiotics
NSAIDs (ibuprofen)
Proton pump inhibitors
Lithium
Aminoglycosides
What are some drugs that replace renal products?
Erythropoiten= stimulates red blood cell formation in bone marrow.
Vit D= requires hydroxylation in the kidney. Patients can be given hydroxylated version
Sodium bicarbonate= corrects the acidosis of renal failure
What drugs should not be paired together for kidney function?
Pairing drugs that impair renal function (diuretics, ACEi and NSAIDs) with drugs that are renally excreted (digoxin, lithium, gentamicin) can lead to problems
What drugs are eliminated by the kidney?
Drugs that are eliminated by the kidney= digoxin, antibiotics, beta blockers, some analgesics, some antidepressant
What are the effects of renal impairement?
Reduced plasma clearance, increased drug half life and drug accumulation after repeated doses
What is sodium glucose transport inhibitors used for?
Indicated for type 2 diabetes, second or third line after metformin. Inhibits at least 90% of glucose absorption in proximal tubule. Seems to help with chronic renal failure and chronic heart failure.
What are uricouric drugs used for?
Inhibit uric acid re absorption in proximal tubule. Indicated for preventing gout. E.g. sulfinpyrazone
