Lecture 10 - Effects Of Drugs And Chemcials On The Nephron Part 2 Flashcards
How else apart from toxins can inflammation occur?
As a result of chronic conditions like diabetes
What does inflammation of the kidneys tubules do?
Leads to damage to the glomerular filtration barrier. Either due to edema or by infiltration of the inflammatory cells
What is edema?
It is swelling due to too much fluid
What happens when the filtration barrier loses its integrity due to inflammation?
Start to see large molecules like proteins appearing in the tubular fluid and into the urine
What happens to long term damage of the glomerular due to inflammation?
Get thickening of the Barrier as a result of fibrotic tissue (kidney fibrosis) which reduces the GFR rate
What could kidney fibrosis also cause?
Could become too thick and block the glomerular all together - meaning there is less space for the plasma to flow through capillaries - resulting in glomerulus death
What is an example for a toxin that gets taken by the podocytes?
Bucillamine - cells that wrap around the basal laminar - kill podocytes
What is the collecting duct surrounded by?
Tight junctions - water can not move in and out normally it has additional processes that help
What can amphotericin B do in the loop of henle?
It can form smaller pores in the apical membrane of the loop of henle.
What happens to amphotericin B as filtrate volume drops?
It increases rapidly
What happens when you start to see amphotericin B pores in the membrane? - Amphotericin treatment
causes leakages of K+ and Mhg2+ in the PCT, loss of the ability to excrete protons in the collecting cut
What is lithium usually given to people for?
Treatment for bipolar disorder. It interferes with the vasosupressin system
What does ADH (vasosupressin do)?
Inserts water pores in the collecting duct cells membrane to enable reabsorption of solute free water from the collecting duct
Where is ADH released from?
Pituitary
What happens when ADH binds to the collecting duct cells?
It triggers a second mechanism system which triggers the release of water pores from storage vesicles, aquaporin 2 can then exocytose the vesicle (now have a gate way for water to move)
What does lithium do that is bad for the collecting duct?
When it enters the collecting duct cell it directly interferes with the second messenger signal.
What are the 3 fates of tubular handling?
Filtered,
filtered then reabsorbed,
filtered and secreted
What is the filtered fate?
It is left untouched by the nephron - amount excreted = amount filtered e.g. inulin creatinine
What is the filtered and reabsorbed fate?
Amount excreted less then amount filtered e.g. glucose amino acids Na+
What is the filtered and secreted fate?
Amount excreted is more than amount filtered e.g. PAH drug molecular and metabolic end products
What converts chemicals from small to high MW?
Small lipid chemicals
How this process done? - small lipid molecules converting chemicals from small to high MW
2 step process:
1 - cytochromosomes p450, ADH and esterases introduce a functional group into the chemical
2 - transferases attach covalently a large water soluble molecule eg sulphate - creating conjugation
What is the down side of the process? - small lipid molecules converting small to high MW?
The activated chemical can turn a non toxic chemical into a toxic one. Introducing a functional group can make the compound more reactive and bind to proteins. Alterations the function
What is an example for heavy metal?
Mercury
What organ is the principle site of action for toxicity of mercury and other heavy metals?
The kidneys
What happens once mercury is inside you?
Easily oxidised to the inorganic form which can be absorbed through various routes and is very damaging
What happens if mercury is methylated?
If it becomes methyl mercury it is very toxic and can pass through cell membranes more easily
What is glutathione?
Is one of the water soluble high molecular compounds that is used for metabolism but also as an antioxidant (designed to protect against reactive oxygen species)
What type of peptide is glutathione?
It is tripeptide - reacting with anti oxygen species or electrical chemicals - heavy metals as well
What does mercury target once in the body?
It takes the par recta which contains the metabolic activity
How does mercury in the target the pars recta?
It binds to glutathione by the sub hydrol groups in the liver, it is then taken up into the PCT from reabsorption as it looks like a small protein
What occurs when mercury is in the pCT?
Acute toxicity - cellular necrosis in the pars recta
What is cadmium?
It is used in the electronic industry - present as an environmental contamination
What is cadmium excreted as?
As metallothionein complex
Where is cadmium synthesised?
In the liver and this is where it makes the metallomethionein complex
Where does the complex go?
It gets taken up by the kidneys and cadmium is broken down from the complex
What happens when cadmium is free from the complex?
It can cause damage leading to toxicity
What are many haloalkenes?
They are nephrotoxins producing proximal renal tubular damage
What is an example of haloalkenes?
1,1 dichloroethene
What are haloalkenes associated with?
The bio activation via the cysteine conjugate Beta lyase pathway
What is hexachlorobutadiene?
It is an electrophilic Chemical so glutathione binds to it — synthesis in the liver ( a water soluble chemical ) pumped into the bile
Where does the bile end up?
In the GI tract as bile is an emulsifier it is released in the GI tract upstream of the absorption site
What happens once the bile is in the GI tract?
It ends up in the kidney in the PCT cells - an enzyme called beta lyase converts it into DNA reactive metabolite which causes damage to the PCT cells
What is aristolochic acid (AA) characterised by?
Interstitial nephritis - associated with upper urinary tract cancers at later stages of
What is AA believed to be?
A causative agent and is secreted by PCT cells
What is the mechanism for AA?
Caused by local metabolism in the kidney and in the liver - leading to formation of a number of active metabolites
What is a key active metabolite?
Artisolactam I or II
What is vasodilation mediated by in the control of GFR?
Mediated by prostaglandin release
What is vasoconstriction mediated by in the control of GFR rate?
Renin-angiotensin system
What do calcineurin inhibitors do?
Increase renin synthesis and decrease PGE2 and COX2
What do NSAIDS do?
Decrease PEG2 release
What do ACE inhibitors do?
Decrease all synthesis
What is related to ischaemic cells death?
NSAIDS
What gives a measure of renal function?
Creatinine clearance
Where is the basal Lamar?
The mesh of the filtration barrier which sites between the endothelial cells and the podocytes
What is the basal Lamar made of?
It is made of collagen
What does it mean if you detect collagen in the urine?
The glomerular is damaged
Where is the alpha sub family found?
In the pars recta
Where is the gamma sub family found?
In the distal tubule
What is the kidney injury molecule -1 (KMI-1)?
A transmembrane glycoprotein
What is a novel biomarkers for the glomerulus?
The basal Lamar
