JD Renal & Pharma Flashcards
What are the six key functions of the kidneys?
- Filtration of blood
- Detoxification (incl drugs)
- Regulation of blood pressure
- Regulation of blood pH
- Regulation of haematopoiesis
- Making vitamin D
We will be focusing on filtration and pH regulation
What dilemma are we presented with when we think of they kidney’s primary function of waste removal?
The blood fills up with waste products and toxins that need to be cleared from the body
But also…
The blood is full of goodies about the same size as waste products and toxins (or smaller, in the case of water), that are precious and must not be lost from the body
How does the kidney solve the problem of filtration?
- Take the blood and filter ’all’ into the renal tubules – includes things we want remove and things we want to keep
- Have a selective recovery system for things we need to keep
- Remaining toxins are removed
- Only need a finite number of receptors for things we want to retain
- High Metabolic demand – need ATP
For filtration to work (at the glomerulus), what two things do we need?
We need…
1. A pump - heart
2. A filter
Note - there is a pressure reducing valve upstream from kidney to regulate pressure in the kidneys
When zooming into the glomerulus, what actually makes up the finest filter in the kidney?
We need to make a very fine filter (cut off c. 4nm = 40Å, free flow below 18Å )
Finest filter – slit diaphragm - located in the space between the podocyte feet
Podocytes have feet like processes that extend and wrap around the capillaries – junctions (held together by nephrin molecules) between podocytes legs allows for filtrate to move into the kidney.
Only about 3% of the total area is actually slit (the hole itself) - major source of resistance to fluid flow
How does the kidney overcome the resistance created by the slit diaphragm and the osmotic gradient pulling fluid back into the capillaries?
Problem 1 - Only about 3% of the total area is actually slit (the hole itself) - major source of resistance to fluid flow
Problem 2 - Capillaries have more solutes dissolved relative to filtrate - osmotic pull back into the blood
Solution - we NEED pressure!
How does the kidney regulate pressure at the glomerulus?
By changing the constriction/dilatation of the afferent and efferent arterioles.
For example…
Restrict afferent arteriole - blood pressure in capillaries drops - Filtration rate drops
Dilate afferent arteriole - blood pressure in capillaries rises - filtration rate increase
Efferent arteriole – constrict – reduce blood exiting – increase glomerular pressure
Efferent arteriole - dilate - increase blood exiting - decrease glomerular pressure
How does the kidney ensure that the filter doesn’t get clogged?
- If proteins get stuck in the podocytes – the cells can pinocytose – only works for smaller things not bigger aggregates.
- Thick basement membrane – lamina densa – good sieve for huge proteins - renewed by mesangial cells
- Walls of the capillaries – endothelial cells also act as a filter – fenestrations - cells are cleaned by blood flow and phagocytes
Note - Small amounts of albumin can get through into the filtrate – large amount is problematic
How is the kidney able to filter a lot of fluid in a small-ish space?
Solution - Bundle a large number of capillaries in the renal corpuscle
Afferent arteriole bringing blood in – podocytes wrapped around capillaries - blood taken back out via the efferent arteriole
Capsular space – holding space for filtrate – enters the proximal convoluted tubule
Apart from packing a lot of capillaries into the renal corpuscle, how else does the kidney ensure that it can filter a lot of fluid?
Large numbers of renal corpuscles in one kidney – average 1 million glomeruli
Nephron number decreases in people that received inadequate nutrition when a baby – protein restriction – foetal programming - Barker’s Hypothesis
How much blood flows to the kidneys/min? What is the plasma flow to the kidneys/min? What is the rate of filtration through all the glomeruli in a kidney?
- 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.
What is GFR? How can it be calculated?
GFR - sum of the filtration rate in all the functioning nephrons – gives an indication of the number of functioning nephrons
Use creatinine to calculate GFR – produced at a constant rate, readily filtered and not absorbed by tubules
Urine creatinine concentration x urine flow rate (volume)/ plasma creatinine concentration
What is the principal behind dialysis?
Dialysis is a way to do the filtration without a glomerulus
Dialysate is equivalent to healthy blood (normal sugar/amino acids) but low on toxins – therefore we get movement of unwanted molecules out of the blood
How can you divide the nephron into 4 main zones?
How do proximal and distal tubular cells differ in terms of histology?
Proximal – microvilli – large surface area
Distal – low/no microvilli
Reminder - what does a typical epithelial membrane look like?
What are some examples of things that the kidney tries to recover from the filtrate?
Not an exhaustive list
Na+
K+
Ca2+
Mg2+
Cl-
HCO3
PO42-
H2O
Amino acids
Glucose
Proteins
What are the 5 principal mechanistic ways that the kidney recovers solutes and water?
- Primary Active Transporters (Na+/K+ ATPase and H+ ATPase are the only common ones in the plasma membrane) – use ATP to move against gradient
- Solute Carrier Family (SLC) proteins – about 300 – many are co-transporters powered by established conc gradients (eg in Na+) – ‘secondary active transporters’
- Aquaporins (Water channels)
- Ion Channels
- Protein endocytosis receptors
Note that filtrate and the plasma will be around equilibrium - hence, recovery from filtrate will require work – burn up ATP - Tubular cells packed with mitochondria
What is one primary active transporter that will act as an engine for the movement of other solutes?
Na/K ATPase – important as it helps to establish a Na+ gradient we can be used to power movement of other desired molecules/ions/etc
What does it do?
Pump Na out of the cell on the basal side, resulting in a gradient between the urinary filtrate and the inside of the cell
Basal side – 2K+ in the cell and 3Na+ out for 1 ATP
Creates gradient – high Na+ in the lumen relative to the cells
How do cells in the proximal tubule excrete protons into the filtrate with the help of the Na+/K+ ATPase?
Na+/H+ exchanger – use the Na+ gradient to power movement of H+ into the urine
SLC9A3 – allows Na+ back in down the gradient while exporting the H+ - antiporter – movement of Na+ down gradient supplies energy for H+ upgradient
How is NaCl recovered in the distal tubule with the help of the Na+/K+ ATPase?
Same concept - Na+/K+ ATPase establishes gradient that drives movement of Na+Cl- into the cell
How is K+ recovered in the loop of henle with the help of the Na+/K+ ATPase?
SLC12A2 – drug target
Na, K and Cl - sodium gradient drives Cl- movement and K+ into the cell
K channels (ROMK) help to clear out K+ that has built up inside the cell - regulated leakage
How are neutral amino acids recovered in the proximal tubule with the help of the Na+/K+ ATPase?
Neutral amino acid pump in with 2Cl- - using the Na+ gradient
Different SLCs – transporting different amino acids – ensure recovery and prevents loss from urine
How are glucose recovered in the proximal tubule (and a little in the LOH) with the help of the Na+/K+ ATPase?
Glucose recovery in the proximal tubule and a little in the LoH
SLC5A1/2 – transport glucose utilizing the Na+ gradient
SLC5A1– 1:1 - Na:Glucose
SLC5A2 - 2:1 - Na:Glucose
Why do people with diabetes end up with sweet urine?
Important medically for diabetes (too much urine) mellitus (sweet) – urine is sweet
Too much glucose in the blood – too much in the primary filtrate – uptake systems have a max capacity to uptake
Once the reabsorption level is saturated – we excrete glucose
What are the different categories of organic molecule transporters?
Organic molecules - drugs and metabolites
SLC22 family:
Organic anion transporters (OATs)
Organic cation transporters (OCTs)
Organic Cation/ Carnitine transporters (OCNTs)
Explain what is happening in the following diagram of an OCT transporter.
- Organic cation drifts into the cell down its gradient (bottom right) using the OCT2 channel
- Na+/H+ sets up H+ gradient in filtrate (use Na+ again to set up H+ gradient)
- MATE antiporter (SLC22A1) moves H+ down the gradient into the cell while exporting organic cations into the urine
- There is also a ATP driven transporter – ABCB1 – pump out organic cations directly
Note this setup ‘safe’ for the cell - in the sense that cations drift into the cell and are pumped out. The cytoplasmic concentration should therefore not exceed that of plasma.
Explain what is going on in the following diagram of OATP transport?
Organic anion transporter – Organic anion transporting polypeptides (OATPs) – transport larger and somewhat hydrophobic organic anions
Organic anion moves into the cell on the basal side and exits on the apical side - story is incomplete.
Explain what is going on in the following diagram of OATs?
Organic anion transporter – Na+/K+ ATPase sets up a Na+ gradient on the basal membrane, which is then used to set up an alpha-ketoglutarate gradient, which can then be used to to pump in organic anions, which can then be drift out on the apical side down the conc. gradient.
Takeaway - Ketoglutarate gradient set up using the Na+ gradient at the basolateral side - Ketoglutarate gradient is then used to pump in organic anions (antiporter)
Why is the following set-up (OATs) potentially toxic towards the cell?
Dangerous – we have a pump in and drift out (different from drift in and pump out) - metabolite can accumulate in cell
Depending on the efficiency of drift out – the metabolite can accumulate and be toxic to kidney cells – important when thinking about drug metabolism and pharmacodynamics of the drug
You have blockers to prevent excessive uptake of organic anions to prevent toxicity on kidney cells – examples probenecid
How does phosphate recovery take place in the proximal tubule?
Proximal tubule
Phosphate recovery – once again using our sodium gradient (Na+/K+ ATPase) to drive in phosphate into the cell on the apical side – can be further exported out on the basal side
Explain, with the help of the following diagram, how bicarbonate is recovered?
Recovering bicarbonate – we want to keep to help maintain pH
- In the urine we find our filtered bicarbonate – bonds to H+ forming carbonic acid – carbonic anhydrase catalyzes the formation of H2O and CO2.
- CO2 diffuses into the cell (move through membranes as non-polar) and converted to back into carbonic acid in the cell using carbonic anhydrase
- Bicarbonate reformed, releasing H+, which can can then be pumped out, resulting in no net change in H+ thus making it a pH neutral reaction
- HCO3- can then move out on the basal side either using a Cl- antiporter or Na+ symporter
How can phosphate be used to help maintain acid/base balance in the body when bicarbonate stores are low?
If there is excess protons (acidosis) and bicarbonate is low, protons can be exported using the H+/Na+ antiporter (encountered before).
The H+ can then be mopped up by phosphate anion and excreted in the urine.
Reaction is not pH neutral
How can ammonia be used to help maintain acid/base balance in the body when bicarbonate stores are low?
If there is excess protons (acidosis) and bicarbonate is low, protons can be exported using the H+/Na+ antiporter (encountered before).
The H+ can then be mopped up by ammonia and excreted in the urine as ammonium.
Reaction is not pH neutral
In kidney cells where does ammonia/ammonium come from?
Ammonia produced from glutamine – glutamine pathway creates ammonia, proton and bicarbonate
1. Ammonia can be exported
2. Proton – exported out as is or bound in ammonium
3. Reaction also produced bicarbonate – can be exported from the cell to help reduce acidosis
Example showing you how the kidneys try to maintain acid/base balance in a state of acidosis - excrete protons into filtrate and create bicarbonate that enters circulation to buffer.
How do type A and B intercalated cells help to maintain acid/base balance?
Intercalated cells
A Cells push protons out – directly with H+ ATPase or using a H+/K+ antiporter – proton released from carbonic acid
B Cells pump H+ back into the body and bicarbonate out
How is calcium normally reabsorbed in the tubules?
Calcium moves across junctions driven by osmosis – urine becomes more concentrated, relative to plasma, once water has been removed
Drives Ca2+ down downgradient – into the body through the leaky junctions
How is water reabsorbed in the tubules?
How is proteins reabsorbed in the tubules?
Protein uptake – huge proteins in the proximal tubule cells stick to proteins in the tubule, which then drives movement via endocytosis
In general terms, what happens in the proximal tubule with regards to solute recovery?
All of this movement of ions is trying to reduce the osmolarity of the tubule – removing species form the filtrate – in order to drive water out of the filtrate back into the body – recovery
How does the PCT maximise solute, and thus water, recovery?
Has a large surface area to maximise solute and water recovery!
- Microvilli
- Pack a lot of length into a small space
Out of solute recovery, water recovery, urine concentration and acid/base control, what does the PCT acheive?
Extra notes
* PCT recovers 65% of the water and solutes!
* Urine will still be at the same concentration after proximal convoluted tubule – as reduction is proportionate – both molecule/ion and water quantities drop by the same amount – concentration is similar
* Some acid/base changes taken place but not the sophisticated changes
What is the principle behind urine concentration?
We have no water pumps, so we rely on osmosis and creating differential concentrations of solutes across membranes.
If the environment around the tubules is more concentrated (which we can make), then water will naturally flow out!
What transporter in the ascending limb of the LOH is responsible for creating an hypertonic solution outside the urine in the medulla?
Area of the kidney responsible for concentration - ascending thin limb
SLC12A2 – uses Na+ gradient to pump in Na+, K+ and 2Cl- -> subsequently on the basal end, Cl- is diffuses out with 3Na+
In this region there are no aquaporins and tight junctions are present – prevents movement of water along with ions – help to create a hypertonic solution outside of the urine
How is the loop of henle organised?
Loop Henle – hairpin loop
- Descending thin limb
- Ascending thin limb
- Thick ascending limb
How does the permeability of the loop of henle change in it’s different regions? What impact does this have on concentrating the urine?
- Ascending thin limb – concentrates the the environment around the LoH (kidney medulla) – allowing for ions + urea to leave but is impermeable to water following
- Urine travelling down the descending limb will experience a strong osmotic pull – result in water moving out/recovered (Cells in the thin descending limb have lots of aquaporins but little ion transport)
- But once the urine in the descending limb reaches the ascending thin limb the urine will already be more concentrated – making the action of the ion transporters more efficient at concentrating the limb (Positive loop)
- Thick ascending limb – the solution becomes more dilute as everything would have been pumped out in the ascending thin limb
As a percentage, how much water and solute does the LOH recover? What is the running total after the LOH?
Mechanism recovers 10% of filtered water and 25% of Na+ and Cl-
Running total – 75% water 90% NaCl
How do we ensure that the high osmolarity in the medulla surrouding the LOH isn’t washed away?
Anatomy (1): we have all of the loops in the same area and all of the renal corpuscles somewhere else
Anatomy (2): we are careful with the way we organize the blood system, which would be the main transport system that could mess this up.
Why is vasculature around the LOH a potential source of solute loss?
The blood vessels emerging from the glomerulus go on to form a secondary capillary system – the vasa recta
We want to avoid that the solutes can taken up by the blood and carried away – removing the hypertonicity of the area
How does the kidney ensure that the blood doesn’t wash away the hypertonic environment of the medulla?
Concept - counter current flow exchange
- Blood coming down – water will be drawn out of the blood (into the hypertonic environment) and ions will move into the blood (down the concentration gradient)
- Bottom of the loop – blood is very concentrated and salt
- Blood going up – water drawn in to, ions out drawn out
In agreement with the loop of Henle – no net effect – both sides are cancelling each other out
Are solutes and water recovered in the DCT?
Coming out of the LoH – dilute urine with low volume
At the end of the distal tubule 95% of NaCl recovered and 75% of water – 5% more of NaCl recovered in distal convoluted tubule
What is the collecting duct? What role does it play in water reabsorption? What channel plays an important role and how is it controlled?
Collecting duct follows the DCT and travels back down to the core of the kidney into the ureter
As the collecting duct travels down, water is drawn out water due to the increased salinity of the medulla - transport via aquaporins
Aquaporin two – can be in the cell membrane or locked up in vacuoles/vesicles - this is regulated by vasopressin – AVP drives movement to apical membrane allowing for water efflux from urine
Can the collecting duct also leak/reabsorb urea?
Yes, the collecting duct can also leak urea into the medulla – also regulated by vasopressin
Allowing some of it back – due to the concentration gradient - high concentration in collecting duct relative to surrounding environment
How does the kidney’s anatomical arrangement help with concentrating urine?
Anatomical arangement
1. The normal and hypertonic zones are seperated - cortex and medulla
2. Route taken by urine passes twice through the hypertonic zone - LOH and collecting duct
All nephrons are arranged in a way that makes this happens:
* glomeruli, DCT and PCT clustered in the cortex
* LOH and collecting duct present in the medulla
Anatomy based question - Why is the kidney particularly sensitivie to ischaemia?
Finer vessels come off to supply the nephrons
Given the fact that the arteries/arterioles and the veins/venules run next to each other, we get exchange of O2, which means that quite a bit of oxygen get shunted from arteries to veins before the blood enters capillaries.
The consequence of this is that the kidney cells later down the line (especially in the renal pyramid - LoH and collecting ducts) receive low amounts of oxygen – making these areas more sensitive to ischemia/states of low O2
Adaptation - Explains why the kidney’s are responsible for EPO release to increase RBCs/oxygen delivery
What are five key things that are regulated/controlled in the nephron?
What are three things that control glomerular blood pressure?
Three things that can regulate BP
1. Systemic blood pressure
2. Constriction/relaxation of afferent arterioles
3. Constriction/relaxation of efferent arterioles
Is the glomerulus quite effective at maintaining a constant flow rate/pressure at different arterial/systemic pressures?
Yes, the glomerulus is able to effectively maintain blood pressure levels – stable between 80 and 180mmHG
Outline the mechanism by which tubuloglomerular feedback takes place.
Elevated pressure – filtrate flows quicker - less time for solute recovery – macula densa pumps out more salt because there is more NaCl to begin with – in response to this JG cells release adenosine – acts on afferent arteriole and constricts – reducing glomeruli blood flow
Low pressure – filtrate flows slower through tubules – more time for recovery/less NaCl in distal tubules – macula densa cells pump out less NaCl because there is less to begin with – JG cells respond to this can release less adenosine – afferent arteriole dilates in response to lower adenosine - increase glomerular blood pressure
Outline how renin release is controlled locally in the kidney?
Renin is an important player in blood pressure control - released by juxtaglomerular cells (located next to macula densa cells)
Recap - Renin converts angiotensinogen into AngI, and Angiotensin converting enzyme (ACE) converts AngI into AngII - which is the main active player
At the level of the kidney…
1. Macula densa cells detecting the salinity of the filtrate - high salinity = high pressure - inhibit renin release by JGCs / low salinity = low pressure - promote renin release by JGCs
2. Baroreceptors in JGCs - detect pressure directly - high pressure = inhibition of renin release / low pressure = stimulation of renin release.
Renin increases - Ang II increases - efferent arteriole constricts - increases glomerular pressure
What effect does AngII have on the body?
Renin – Ang – AngI - ACE – AngII – has a whole bunch of effects on the body
Focus on…
1. Vasoconstriction of arterioles – increase blood pressure
2. Stimulates sympathetic activity
3. AngII directly stimulates salt resorption in kidney tubules (independent of aldosterone)
4. Increased salt recovery via aldosterone
5. Water retention - stimulation of ADH
How does AngII directly stimulate the resorption of NaCl?
AngII acts on cells in the PCT (AGTR1) – increases the activity of this exchanger – SLC9A3 – driving increase in sodium uptake
What effect does aldosterone have on the kidney? Consider both collecting duct intercalated cells and principal cells.
Aldosterone effects in the Kidney – it is a steroid and therefore targets gene transcription
Principal – drives expression of two genes – increases Na/K ATPase and increases expression of sodium intake channel (ENac/ASC) resulting in sodium reuptake. Potassium is pumped countercurrent, so aldosterone also has the effect of driving K+ out (aldosterone also responds to levels of K+ in the body)
Intercalated – drives expression of H+ ATPase – absence of aldosterone H+/K+ only present, so K+ pumped in while H+ is pumped out - but when Aldosterone is present the protons exit via the ATPase so less K+ in pumped in – net effect excretion of K+
What effect does ADH/AVP have on collecting duct cells?
AVP/ADH - drives movement of aquaporins from the vesicle to the membrane – allows for increased water uptake from the collecting ducts
What hormone is released by the body when calcium levels are low? Where is it released and where does it act?
Low Ca+ - parathyroid gland – secretes PTH – acts on the kidney
How does PTH act on the kidneys in order to increase calcium uptake?
Differentiate between its action on the PCT and DCT.
PCT - Ca2+ simply follows other ions/water down loose junctions between cells
So to increase the amount of free Ca2+ in the blood, the body decrease phosphate reabsorption (phosphate normally binds to Ca2+)
DCT - calcium uptake system
PTH – Activates TRPV5 and activates the exit channel – increase re-uptake
Ca2+ move through the cell bound to chaperone proteins - Calbindin – prevents second messenger cascades from being triggered that are regulated by Ca2+
Labelled components (calbindin and exit channel) require vitamin D for synthesis – won’t be produced without Vit-D – calcium re-uptake is lost – can lead to Rickets
Takeaway - PTH results in…
1. Decrease phosphate reabsorption
2. Increase calcium reabsorption
How does the kidney respond to acid-base changes (acidosis)?
We have covered automatic system in the PCT – bicarbonate, ammonia, and phosphate systems
But there are also other mechanisms…
Body in acidosis – fall in intracellular pH – apical Na+/H+ becomes more active – H+ excreted into urinary space
H+ will complex with the same buffers in the urine – phosphate and ammonia
How does aldosterone regulated K+ reabsorption in the collecting duct?
Collecting duct
1. Intercalated cells - Aldosterone drives expression of H+ ATPase – drives H+ out – taking away H+ for H+/K+ antiport – resulting in less K+ import - increasing K+ excretion
2. Prinicipal cells - aldosterone drives expression of Enac and Na/K ATPase – drives Na+ import and only way out for K+ is apically – driving potassium export
What are some longer term changes that we see in principal cells which help in potassium regulation?
Note - Aldosterone changes are much quicker than the effects observed below with tyrosine phosphorylation (longer term changes)
Chronic changes:
1. Low K+ diets causes phosphorylation of tyrosine in apical K+ channels – results in channels being removed from membrane – reducing potassium export
2. High K+ - high potassium diet - dephosphorylation of tyrosine on apical K+ channel - channels remain - increasing K+ export
What is the link between body pH and K+ flux?
Alkalosis
Acute acidosis
Chronic Acidosis
Cell/body in alkalosis (acute or chronic) – H+ efflux and K+ influx will be low as the H+/K+ antiporter will be working less – less K+ is taken up because the antiporter is not working at high levels – effect of this that the body goes into a state of hypokalaemia (high levels of K+ loss) when in a state of alkalosis AND apical K+ channel activity increased in principal cells and so is the Na+/K+ ATPase (minor effect but still contributes to increase K+ efflux) – alkalosis results in hypokalaemia
Acute acidosis – reverse happens - increased re-uptake by antiporter as the body is expelling excess H+ and the apical K+ channel becomes less active, both of which result in hyperkalaemia
Chronic acidosis – not a problem in chronic acidosis as the Na pump is less efficient in PCT – urine more dilute and helps flush K+ - preventing hyperkalaemia
What do loop diuretics do? What do they target?
Targets the ascending limb of loop of henle – cells good at moving salts from the urinary space into the medullary region – block these cells we can minimize water re-uptake
Block SLC12A2 – stop export of salts – medulla becomes less salty – less water recovery – less osmotic pull in both the loop of henle and the collecting ducts – 20% more urine output (based on recovery that each region is responsible)
What are the cons of using loop diuretics?
- They result in loss of Na+, K+ and Cl- because of failure to recover in the TAL of LoH
- They inhibit Na uptake in the macula densa (target the same receptor as the LOH) - So loop diuretics are used more to treat oedema than hyptertension itself - mecula densa receive less sodium, increasing renin release (negates impact of reduce fluid)
- They can result in hypercalcuria – less pull for Ca2+ recovery, increasing the risk of kidney stones - resulting in hypocalcaemia which is especially bad in osteoporotic elderly.
- More Na+ getting to the Coll Duct means more uptake there and more K+ loss - system in overdrive - drives hypokalaemia (shown)
Where do thiazide diuretics work?
Thiazides target channels (SLC12A3 – takes up Na+ and Cl-) in the distal DCT – block salt uptake – less salt uptake – result in less water uptake – osmotic difference is less
Macula densa are found before the cells that are targeted by the thiazide drug – will not be affected - hence, renin won’t increase
Also drives Ca+ recovery – mechanism not understood
Better for hypertension control – partly as they don’t mess up the RAAS system + appear to have an effect on systemic vascular tone –still being investigated
Note - you still lose some K+ as there is more Na+ in the collecting duct
How do potassium sparing diuretics work? Where do they act?
Potassium sparing diuretics – Blocking Na+ uptake (reduces gradient between urine and medulla – decreasing water loss
Drug - Amiloride - ASC/ENAC - amiloride sensitive channels
Less Na+ is being pumped into the cells = less K+ being exported
Don’t have the effect of taking the body into hypokalemia
Where does the diuretic spironolactone act on? What does it do?
Spironolactone – acts on the collecting ducts - blocks the action of aldosterone
Block aldosterone – blocks ASC/ENAc expression – more Na+ in urine – less water lost (lower gradient)
Spironolactone – anti-androgenic hormone – competes with DHT – risk of gyno for men
How do carbonic anhydrase inhibitors diuretics work?
Carbonic anhydrase inhibitor – more bicarb in the lumen (not imported – therefore reduces activity of Na+/H+ exchanger)
Results in more Na+ in the lumen – resulting in less of an osmotic pull
How do osmotic agents work as diuretics?
Osmotic agents (eg mannitol): stay in the lumen and resist water egress osmotically - increase pull of water towards the lumen
Summary - what regions of the nephron/collecting duct do the following diuretics target…
1. CA inhibitors
2. Loop diuretics
3. Thiazide diuretics
4. Potassium-sparing diuretics
5. Spironolactone
Are they all good are dealing with oedema and hypertension?
All cause water and salt loss from body.
All useful against excess tissue fluid/ oedema.
Most only weakly effective against hypertension (maybe because, once bp falls, kidney detects it and RAAS fights back).
Thiazides have an antihypertensive effect, probably via mechanisms of action additional to diuresis.
Congenital Disorder - What is Barter’s syndrome? What effect does it have on the kidneys?
Impaired SLC12A2 - Ascending limb of LOH
Same effect as loop diuretic – loss of Na and K and H2O (gradient is less – less water taken up)
Hypercalcuria Ca2+ follows the other ions
Congenital Disorder - What is Gitelman’s syndrome? What effect does it have on the kidneys?
Gitelman’s syndrome – impaired SLC12A3
Just like a thiazide diuretic – loss of Na+, K+ and H20 and hypocalcuria
Remember thiazide diuretic drives Ca2+ recovery - reduces urine Ca2+ and increases plasma Ca2+
Congenital Disorder - What is Liddle’s syndrome? What effect does it have on the kidneys?
Hyperactivating mutation of the ASC channel - increase sodium uptake, increasing fluid uptake - opposite of diuretic
Leads to fluid expansion and hypertension
Treated with amiloride
Congenital Disorder - What is Pseudohypoaldosteronism? What effect does it have on the kidneys?
Inactive ASC channel – doesn’t work
Result - Na+ loss, K+ retention and high aldosterone as the body is trying to correct this (high K+)
What is renal agenesis?
Absence of one or more kidney’s
Bilateral - Rare; fatal after birth - Lack of amniotic fluid causes Potter’s Facies (deformations caused by the lack of amniotic fluid - lack of shock absorption)
Unilateral – One kidney missing - Common (1/500) - often no clinical implications unless some bright surgeon removes the working one
What is congenital cystic disease?
Congenital cystic disease – kidney tissue gets destroyed by growing cysts – detectable in the first few decades of life
What are supernumerary ureters?
Supernumerary ureter – two ureters come from one kidney
Problematic if the two ureters connect away from the bladder – e.g. past the bladder resulting in incontinence
There is also a higher risk of UTIs as infections can spread quicker
What is a pelvic kidney?
Pelvic kidney – kidney stays in developmental area down by the pelvis
More problematic in females as the ovary’s need the space
What is a horseshoe kidney?
Two pelvic kidneys that are connected to eachother - forming a horseshoe shape
What are congenital abnormalities of cloacal development?
Cloacal – common opening for all the exit canals which are separated later in development by folds
If folds don’t meet – tubes not separated - resulting in fistulas, such as…
- Rectovaginal fistula
- Rectoprostatic fistula
- Rectoclocal canal (rectum, vagina and urethra unite inside body).
What is hypospadias?
Most common congenital abnormality
Urethra zipper is not closed properly
Incomplete migraiton of the urethral groove from the base of the penis to the tip.
Start of Pharmacology - List six key functions of the kidneys?
Important thing to note - Kidney controls the overall volume of the body - 99% of fluid is reabsorbed and 1% is released, means that only we have a urine output of 1.5L/day.
Summary - what are the effects of RAAS on the efferent arteriole, NaCl reuptake, aldosterone, ADH? What impact does that have on systemic blood pressure?
RAAS – defense of renal blood flow, water balance and blood pressure
What happens with renal function/GFR as we age?
Even in health we lose a proportion of GFR as we age.
Some chronic conditions leads to a more rapid loss of nephrons – e.g. high blood pressure
What are some causes of acute renal impairment?
Think…
Pre-renal
Renal
Post-renal
What are some causes of chronic renal impairment?
Hypertension and diabetes are the two main ones!
What are the consequences of renal impairment?
Pharma - What are the main diuretics that we’re interested in? What is the basic principle behind them?
Diuretics – decrease NaCl absorption, decrease H2O reabsorption (decreased osmotic pull), and therefore increased urine volume
Loop diuretics – most powerful
What are the main actions, indications and adverse effects of Loop diuretics?
Also what are the common drug names of loop diuretics?
Examples - furosemide (most common), bumetanide and torasemide
Mechanism - blocks Na+K+2Cl- symporter in the thick ascending limbs – inhibits reabsorption of 15-25% of glomerular Na+ filtrate – reduces water retention
When?
* Heart failure - reduce water load on the body (partly due to the activation of the RAAS system – drops in pressure)
* Renal failure - retain extra fluid - nephrotic syndrome
* Liver cirrhosis with ascites (unable to break down aldosterone)
Adverse effects
- hypo-Na+, K+, metabolic alkalosis – increased activity of a H+ ATPases - driving metabolic alkalosis
- Fluid depletion and incontinence (bladder can’t cope with high volume of urine)
- Ototoxicity - ringing of the ear
What are the main actions, indications and adverse effects of thiazide diuretics?
Also what are the common drug names of thiazide diuretics?
Thiazide – Bendroflumethiazide – most common
Thiazide-like – indapamide (act in a similar manner)
Mechanism - Inhibit Na+Cl- co-transport in the proximal DCT – maximum effect on Na+ 5-10% (reduces pull on the water into the body) and has a vasodilatory effect
Indications – hypertension – predominant use
Adverse effects
- Loss of Na+, K+ and alkalosis (excretion of H+ - presenting more sodium to the distal part of the distal convoluted tubule – increasing H+/K+ exchange)
- Hyperuricemia (cause gout – increase uric acid retention) and hyperglycemia (effect on glucose metabolism)
- Fluid depletion, incontinence and erectile dysfunction (vascular effect)
What are the main actions, indications and adverse effects of potassium-sparring diuretics?
Also what are the common drug names of potassium-sparring diuretics?
Less commonly used than loop and thiazide but still prescribed
Two types:
* Aldosterone receptor antagonist – spironolactone - block aldosterone action (transcriptional inhibition)
* Sodium channel blocker – amiloride – prevents the same exchange as spironolactone (ASC/ENAc inhibition)
Mechanism (collecting duct) - Block the effects of aldosterone – block the exchange – prevents Na+ uptake and K+ or H+ excretion (increased retention)
Indications – chronic heart failure, liver failure with ascites, resistant hypertension and Conn’s syndrome (hyperaldosteronism)
Adverse effects
* Hyperkalaemia (more common for patient with renal impairment and are on other drugs)
* Gynecomastia (aldosterone receptor antagonist - spironolactone)
What are the main actions, indications and adverse effects of osmotic diuretics?
Also what are the common drug names of osmotic diuretics?
Examples - mannitol
Main actions
* freely filtered but non-absorbed creating an osmotic ‘drag’ that decreases water and Na+ reabsorption in renal tubule
Indications (not perscribed - ICU)
* raised intracranial pressure due to cerebral oedema
* raised intra-ocular pressure
Adverse effects
* Initial fluid overload
* Hypernatraemia
What are the main actions, indications and adverse effects of carbonic anhydrase inhibitors?
Main action - interfere with CA, reducing H+ and HCO3-, which is then no longer available for exchange with Na – increases urine Na+
Indications – glaucoma (optic nerve gets damaged) and altitude sickness
Adverse effects - metabolic acidosis
What three renal products might we replace if the kidney is failling to make enough?
Drugs that replace renal products
* EPO – stimulates RBC formation
* Vitamin D – requires hydroxylation in the kidneys – patients given hydroxylated derivatives
* Sodium Bicarbonate – corrects acidosis of renal failure
What are some examples of groups of drugs that may cause dehyrdation and thus damage the kidneys?
Drug causing significant fluid loss – putting pressure/strain on the kidneys
What are some examples of drugs that have a direct effect on the renal vasculature and thus damaging the kidneys?
Drugs interfering with the RAAS system – kidney is more vulnerable – block the ability for the efferent arteriole to be constricted resulting in low glomerular pressure – minimizing the kidney’s ability to modulate renal pressure - important to monitor renal function after prescription
NSAIDs – reduce cortical blood flow and glomerular perfusion by reducing the production of vasodilating prostaglandins – avoid prescribing to elderly patients
What are the different mechanisms that our kidney uses to excrete drugs?
Mechanisms of drug renal excretion
* Glomerular filtration – low molecular weight
* Tubular secretion – active, specialized transporters
But tubular reabsorption also possible! – if lipid soluble (can move across membranes) and affected by urine pH
What factors can influence the kidney’s ability to excrete drugs?
Age, dehyrdation, drugs and disease can all influence the kidney’s ability to excrete drugs.
Examples of drugs eliminated by the kidneys?
What would be the effect on the kidney of someone who keeps having panic attacks?
Think potassium
Hyperventilation – drive out CO2 – alkalosis – less proton export to help bring the body out of alkalosis but as a result less potassium will be taken up – prolonged – hypokalaemia
