Lecture 9 - Effects Of Drugs And Chemcials On The Nephron Flashcards
What are some factors that control glomerular filtration rate?
Blood flow, surface area of nephrons, colloid osmotic pressure in bowman’s space and difference in hydrostatic pressure
How can you measure eGFR?
Use plugging, putting a wax plus in the blood capillary. Inject inulin and see how it fast it flows through the nephron
Is inulin totally filtered?
It is neither reabsorbed or filtered. The amount of inulin filtered is the amount of inulin collected
How can colloid osmotic pressure in the bowman’s space be modified?
By changing the amount of protein in bone space.
Increasing colloid osmotic pressure =
Decreasing single nephron GFR
what is Kf?
It is related to permeability coefficient which is related to the surface area of nephrons
What are the 4 variables that control GFR?
Permeability coefficient (Kf), hydrostatic pressure, colloid osmotic pressure difference and rate of blood flow
What is Pcap?
Capillary osmotic pressure - which is used to drive materials out, fluids out of the capillary
What is the bowman’s space usually?
An open space
What is oncotic pressure? - the same as colloid osmotic pressure
Driving fluid in at the distal end
What do changes in Kf lead to?
Changes in surface area or permeability of barrier - which leads to a decrease in GFR
What are some results due to changes in Kf - that cause a decrease in GFR?
Renal failure (fewer nephrons, diabetic nephropathy, nephrotic syndrome and nephritic syndrome
What are 2 pathophysiolgical changes for diabetic nephropathy?
Hyperfilatration and glycation proteins
What is diabetic nephropathy?
Pumps glucose back into the proximal tubule - need to remove Na+ as well as glucose as it uses the same transporter. Prolonged glucose and na+ reabsorbtion means you get vasoconstriction and vasodilation of blood vessels leading to hyper filtration.
What happens with prolonged filtration?
Get an increase in pressure at the glomerulus and this leads to damage to the glomerulus capillary cells
What else happens with high blood glucose concentration?
You get high glycelation proteins which eventually drives reactive oxygen species formation in the PCT cells
What happens in nephritic syndrome?
Get large holes appearing in the glomerular filtration barrier - start to see breakdown of collagen and red blood cells appear in the urine.
What can you see in nephrotic syndrome?
You can see an increase in proteins but not cells
How do changes in Kf lead to decrease in GFR?
Nephrons are destroyed and this reduces the surface area so less plasma will be filtered so there is a decrease in glomerular filtration rate
What does flow rate through the glomerulus influence?
It influences filtration
What happens in single nephrons experiments when you give them atrial naturetic peptides?
It will decrease both Afferent and efferent resistances. Which means you can control the flow through the nephrons
What happens with normal flow?
There is a response between Afferent and efferent. A classic reduction difference in pressure and hydrostatic pressure. Increase in oncotic pressure and fluid is removed. Pressure difference is 0
What happens when you increase the flow?
Get a greater degrees of filtration, oncotic pressure decreases and hydrostatic pressure stays the same
What happens in normal flow in regards what is filtered?
Small molecules are filtered out and the protein concentration in the capillary increases - as volume decreases in each Bolbus
What happens in fast flow in regards to what is filtered?
Protein in capillary increases less as less water is removed from each bolbus due to shorter time in the glomerulus
What do changes in hydrostatic pressure in the capillary lead to?
Increase in volume status and hypertension. Which increases capillary hydrostatic pressure and increase GFR
What do changes in the hydrostatic pressure in bowman’s space lead to?
Renal stones and kinks in the ureter. No longer have an open chamber. Increase hydrostatic pressure and decreases GFR
What happens if there are changes in oncotic pressure in the capillary?
Increase in volume status, decrease in protein status. Results in decrease in oncotic pressure and increase in GFR
What do changes in the oncotic pressure in bowman’s space lead to?
Changes in proteinuria which increases oncotic pressure and increases GFR
What is the equation for net oncotic pressure?
Oncotic pressure in capillary - oncotic pressure in the bowman’s space
What is a type of acute kidney disease?
Drug induced nephrotoxicity
What are examples issues contributing to the rise in renal damage?
Diabetes mellitus, poly pharmacy and more medical procedures that may stress the kidney
What are some multi factorial changes in drug induced nephrotoxicity?
Changes in haemodynamics, damage to glomerulus, tubular cell damage and inflammation
Why are the nephrons so susceptible to toxic insults?
Because the kidneys are highly diffused tissues.
What organ is right at the top of the perfusion table?
The kidney - this means anything that you absorb, snort, inject it is a very high likelihood of reaching the kidneys
What is the kidney exposed to?
Highly circulating toxins
What happens in the pars convoluta (curved bit) in the PCT?
Absorption of water, solutes and xenobiotics
What happens in the pars recta (straight bit)?
The kidneys has its own enzymes that metabolise drugs and they are located here. Bioformation of xenobiotics
What is the primary target for nephrotoxicity?
The PCT, damage to the PCT leads to an increase loss of solutes in the urine
What does diabetes mellitus do?
Glucose that is remained in the tubule dissipates the osmolarity gradient and results in water loss
What do aquaporins allow?
Allow water to move directly through the cells rather than through the intercellular spaces.
Describe water movement (it is paracellular)
The solutes are actively transported into the PCT cells and then effluxed into the lateral interspace and this increase the osmotic gradient. Which drives water reabsorption
What happens in the tubular fluid the more concentrated the compound is?
The more toxic it becomes.
How can non toxic chemicals in the plasma suddenly become toxic?
Can become toxic when you remove 70% of the water. Suddenly the PCT cells are exposed to the high concentration
What are the transporters like that move chemicals from the urine and tubular lumen back to the PCT cells?
The are non specific - they transport chemicals back into the systemic circulation
Why is bad about the transporters being non specific?
They often misidentify drug molecules and metabolites. Metabolites that are intended for excretion may be reabsorbed into the PCT and drugs that are secreted from the blood may become trapped in the PCT cells
What is cisplatin?
One of the key anti cancer drugs
What is the transporter for cisplatin?
OCT2 - it has a high affinity for cisplatin
What is the uptake of cisplatin into the PCT bad?
End up poisoning the kidneys and lead to proximal tubular cell death
How do you solve the uptake of cisplatin?
Administer an uptake blockers which competes with cisplatin and is secreted into the PCT cell and then effluxed into the urine
What happens if the PCT isn’t working due to cisplatin hurting the mitochondria without the blocker?
Na+ and water will not be absorbed
What are secretions of anions and drugs like?
Anions and cations are transported in both directions into the PCT from the tubular capillaries and excreted into the urine. Transporters are very specific to misidentify drugs
What can lead to toxicity from effluxs?
Differential reflux of Cephaloridin can lead to toxicity
How do cephaloridin lead to toxicity?
They are absorbed from systemic circulation by cation/anion transporter but they are not a substrate for efflux transports so they remain in the pCT - can lead to mitochondrial injury
What are cephalosporins?
They are generally not nephrotoxic - most of them are good for MDR1 and MDR4 efflux pumps
What are bad types of cephalosporins?
1 and 2 referred to as cephaloridine - accumulates inside the PCT and damages leading to apoptosis
What is Fanconi syndrome?
Organic solutes lost to urine, increase Na+ loss, increased water loss (from cephaloridine toxicity)
What happens if you administer drug-drug interactions?
Drug 2 is a better substrates than drug1 therefore both are pumped into the PCT, however only drug 2 is excluded so drug1 will accumulate to toxic concentrations
What is an example of a mitochondrial toxin?
Tenofovir
What substrates are key for endocytosis?
Megalin and Cubulin
