Renal 3 Flashcards
What is renal clearance. Give an example of a product which is removed from the body by renal clearance
Removal of compounds from blood and their elimination in urine is known as renal clearance.
e.g. urea, a product of protein metabolism, is removed from the body by renal clearance
Give examples of drugs which are excreted from the body via renal clearance
Amiodarone, digoxin, gentamycin, lithium, methotrexate, pitvastatin, salmeterol, tacrolimus
Give a factor which affect renal clearance rates
With age, the number of functional nephrons tends to decrease.
Consequently, the ability of kidneys to filter and clear compounds, including drugs, is decreased.
Pathology can also affect renal clearance. Give examples of conditions which may affect clearance
Tumours
Glomerularnephritis (inflammation)
Glomerularsclerosis (blood vessel scarring or hardening)
What happens to the drug dosage when renal clearance is affected
When renal clearance is affected
drug dose may be reduced
What parameter do we use to measure kidney function
Glomerular filtration rate (GFR) can be used to measure kidney function (i.e. filtration).
INULIN can be used to measure GFR directly
What is inulin
Inulin is a fructose polymer with a MW 5 kDa (relatively low)
Its administered IV and freely filtered at the glomerulus due to its low mw
Its not reabsorbed nor secreted by the nephron and its also not metabolised by the kidney
This means the amount of inulin filtered = amount excreted in urine
How do we derive the eGFR
GFR can also be estimated (eGFR) using serum creatinine in combination with other factors e.g. age, race and gender, and by using equations
Why would we use the eGFR over the GFR in practice
Estimating the GFR is more convenient than using inulin as creatinine is produced by the muscles (no IV)
Define renal clearance (mathematically)
Renal Clearance is the volume of plasma from which a substance is completely removed per unit time
How is renal clearance important in drug formulation
Important in drug development and in understanding how the body handles drugs
E.g. if a drug is cleared by the kidneys, dose adjustment may be needed (age, pathology)
What are the three measurements needed to calculate renal clearance
Three measurements are needed
V = rate of urine production (vol/time)
[UA] = urine conc. of A
[PA] = plasma conc. of A
What is the formula to work out renal clearance
Clearance(A) = ([UA] x V)/[PA]
Where are the two places drugs are filtered out of the plasma
Drugs can be cleared from the plasma by being filtered at the glomerulus
Drugs may also be cleared from the plasma by secretion from the vasa recta into the tubule
Describe the pathway drugs take through the kidney when being filtered out of the plasma
During renal clearance drugs may be initially transported out of the vasa recta capillary into kidney tubule epithelial cells
Drugs are then transported out of tubule cells into the tubular fluid and may be excreted in the urine
Which are the transporters expressed on the basolateral membrane which pump drugs out of the vasa recta capilliary and into the kidney tubule epithelial cells
OAT1 & 3: organic anion transporter
OATP1: organic anion transporting polypeptide
OCT1: organic cation transporter
Which are the transporters expressed on the apical membrane which pump drugs out of the the kidney tubule epithelial cells and into the tubular fluid
MRP2 & 4: multidrug resistance-associated protein
ABCG2 (BCRP): breast cancer resistance protein
ABCB1 (P-gp): P-glycoprotein
Which transporters move methotrexate into and out of the kidney tubule cells
Methotrexate in - OCT1 & OAT1
Methotrexate out - MRP2, MRP4 & ABCG2
Which transporters move pitvastatin into and out of the kidney tubule cells
Pitvastatin in - OAT3
Pitvastatin out - ABCG2
Which transporters move Rosuvastatin into and out of the kidney tubule cells
Rosuvastatin in - OAT3
Rosuvastatin out - ABCG2
Which transporters move Fexofenidine into and out of the kidney tubule cells
Fexofenidine in - OAT3
Fexofenidine out - ABCB1
Which transporters move digoxin into and out of the kidney tubule cells
Digoxin in - OATP1
Digoxin out - ABCB1
In healthy individuals hat happens to the glucose filtered at the glomerelus
In healthy individuals, all the glucose filtered at the glomerelus into the tubular fluid is reabsorbed into the blood
Which transporters moveglucose from the tubular fluid and into the kidney cells
SGLT2 transporter
sodium glucose transporter 2
How does sodium play a part in the transport of glucose into kidney cells
sodium ions move down their electrochemical gradient and energise the transport of glucose into the cell
How do we exploit the SGLT2 receptors in diabetes treatment
In diabetes treatment the aim is to reduce blood glucose
By blocking the SGLT2 glucose transporter we reduce reabsorption into the blood
Give an example of a SGLT2 inhibitor
Dapagliflozin (Forxiga) – licensed for Type 2 diabetes
It inhibits SGLT2 and aids glucose elimination and reduces blood glucose reabsorption
Part of the molecule mimics a glucose molecule and so binds well to the transporter but blocks its action.
How does sodium aid homeostasis
Na+ is involved many processes in the body, e.g. generation of electrical impulses, muscle contraction and nutrient transport.
It also influences blood volume and pressure.
This is why it is important to regulate Na+ levels within the body
WHat can high sodium levels lead to
High Na+ levels can cause:
Hypertension
Heart disease
Stroke
(Worldwide strokes are the second leading cause of death and the third leading cause of disability)
How does the kidney regulate sodium levels (and what are the key transporters which facilitate this)
Na+ levels are regulated by the kidney.
Na+ is freely filtered at the glomerulus.
70% of filtered Na+ is reabsorbed in the proximal tubule.
Key transporters are:
SGLT2 transporter
Na+, H+ (proton) antiporter
Na+, K+ ATPase
Each of the following transporters carry sodium into or out of the kidney cells. Explain where each is found:
SGLT2 transporter
Na+, H+ (proton) antiporter
Na+, K+ ATPase (x2)
SGLT2 transporter - found on the apical membrane and pumps sodium and glucose into the kidney cells
Na+, H+ (proton) antiporter - found on the apical membrane and pumps sodium into the kidney cells and pumps protons out of the cells and into the tubular fluid
Na+, K+ ATPase - both are found on the basolateral membrane and pump sodium out on the kidney cells and into the vasa recta capilliary. They also pum potassium from the blood into the kidney cells
Where else is sodium reabsorbed and what processes control it
Na+ is also reabsorbed in the collecting duct – and this is under hormonal control
How do high sodium levels result in increased blood pressure
When Na+ is reabsorbed, water follows by passive diffusion.
High Na+ reabsorption can lead to increased blood pressure
How do we regulate sodium levels in the body
So, if Na+ levels drop, we need to increase the amount in the body.
To do this, we increase Na+ reabsorption in the kidney and this is controlled by the steroid hormone aldosterone.
Where is aldosterone produced
Aldosterone is produced in the cortex of the adrenal gland in the top of the kidney
WHat happens when aldoseterone is released
Release of aldosterone causes:
An increase in the number of Na+ channels in the apical membrane of the cell.
An increase in the number of Na+, K+-ATPase pumps in the basolateral membrane – which hydrolyse ATP to energise Na+ transport.
This allows more Na+ to be reabsorbed
How is aldosterone secretion stimulated (7 steps)
Via the renin angiotensin system:
Drop in plasma Na+ and blood pressure are sensed by the kidney juxtaglomerular cells.
These cells then release the enzyme renin
The liver produces angiotensinogen
Renin converts angiotensinogen to angiotensin I
Kidney and lung capillary cells produce angiotensin converting enzyme (ACE)
ACE converts angiotensin I to angiotensin II
Angiotensin II triggers synthesis of aldosterone within the adrenal cortex
What does aldosterone do
Aldosterone triggers synthesis of Na+ channels and Na+, K+-ATPase pumps which allows increased Na+ reabsorption.
Give examples of drugs which act on the renin angiotensin system
ACE inhibitors (e.g. captopril, fosinopril) block ACE activity, prevent formation of active angiotensin II and prevent production of aldosterone.
These are used to treat heart disease (+ diuretic) and high blood pressure
When are diuretics used
In the treatment of oedema, hypertension and congestive heart disease
Briefly describe the action of spironalactone
Spironolactone
(an aldosterone analogue)
Indication: Oedema
It blocks aldosterone receptor which prevents aldosterone from binding to it
Blocks aldosterone function – so additional Na+ channels and Na+, K+-ATPase pumps are not synthesised by the cell.
Briefly describe the action of amiloride
Amiloride: Na+ channel blocker
Indication: Oedema
Reduces Na+ reabsorption
If less Na+ is reabsorbed, less water is reabsorbed
What can cause a build up of acid in the body and how can the kidneys counter this
Poor gaseous exchange and release of carbon dioxide due to diseased lungs (e.g. emphysema) may lead to Respiratory Acidosis (a build up of CO2 in blood which causes it to become acidic)
Kidneys correct this disorder by increasing H+ secretion
Give the chemical equation for the acid base balance in the body and note where the acid and base are usually delt with
(excreted by the lungs) CO2 + H2O <=> H2CO3 <=> HCO3- + H+ (kidneys)
What happens in ineffecient lungs to the chemical acid-base equilibrium
With inefficient lungs there is a build up of CO2 in plasma, the equilibrium shifts to the right and H+ are secreted renally.
How is proton secretion connected to sodium reuptake in the kidney
H+ secretion is coupled to Na+ uptake by the H+ and Na+ antiporter
What is a byproduct of proton secrection by the kidney and why is it important
HCO3- (bicarbonate) is produced during H+ secretion
HCO3- is an important biological buffer
