Studied by 0 peoplewhere does cisplatin cause damage
proximal and distal tubule
3 main functions of kidney
maintain fluid/electrolyte and acid/base balance 2.Excrete metabolites, xenobiotics
Regulate BP, secrete hormones
BUN
Blood urea nitrogen evaluates kidney function
Creatinine
Filtered by kidneys but not reabsorbed - rapid evaluation of kidney function
2 reasons kidneys are vulnerable
High blood flow - anything in circulation will get to it 2.Excretory function - it concentrate toxins while eliminating them
Kidney recieves what % of cardiac output
21% - over 1L/min
% body weight of kidneys
0.04%
Autoregulation of kidneys
Kidneys autoregulate their blood flow even if BP is abnormal, kidneys will still function as long as its between 80-170
The total circulating volume of blood passes every ___ minutes
6
2 capillary beds of kidney
glomerular
Peritubular
What in the kidney can lead to precipitation of various substances
intratubular pH
How many nephrons does each kidney have
1 million
T or F Nephrons can regenerate
F - only repair themselves
What happens when nephrons are starved of blood for too long
die
Collecting ducts
As urine is formed, goes into ducts that will get larger and larger until it leads to bladder
Main reason kidneys are resistant to damage
Have large functional reserve - can survive with 1 kidney
What does kidney do to take over function of lost nephrons
Hypertrophy- grow in size Occurs when you lose a kidney
3 parts of nephron
glomerulus tubules collecting duct
What is glomerular filtration
Blood will flow through bowmans capsule into proximal tubule
What happens after glomerular filtration
tubular reabsorption and secretion
How much is filtered and reabsorbed per day
180L filtered 178.5 reabsorbed
Capillary pressure in glomerulus
high
What kind of filter is glomerulus
macromolecular
3 forces acting on glomerulus
Hydrostatic pressure Osmotic pressure Pressure inside bowmans capsule
Hydrostatic pressure of glomerulus
forces fluid out
Osmotic pressure
opposing pressure Due to plasma proteins - will retain fluid inside
Pressure inside bowmans capsule
opposing pressure
Net pressure in glomerulus
Net outward pressure of 10mmhg - fluid leaves vessels
Pressure of blood flowing through glomerulus is altered due to what
amount of salt detected in the distal convoluted tubule
What controls blood flow through glomerulus
smooth muscle of arterioles contracting or relaxing sympathetic nerve endings macula densa cells in contact with distal tubule and the arteriole
What are glomerular capillaries surrounded by
Podocytes
Role of basement membrane in glomerular capillaries
Acts as filter since capillaries are full of holes
Role of podocytes
hold filter (basement membrane) in place make molecules that coat basement membrane
Action of podocytes
Make and determine the filtration properties of the basement membrane
3 layers of glomerular capillary
Endothelium (fenestrated) Basement membrane ( - charge, filter) Epithelium - podocytes
% of fluid that gets filtered into capsule
20%
Where is does most reabsorption occur
Proximal tubule
Most vulnerable area of nephrone
proximal tubule
Kind of transport in proximal tubule
active transport for glucose, Na, amino acids water will follow
Where does active transport occur in proximal tubule
At basolateral membrane
Where are co transport mechanisms for sodium in proximal tubule
at luminal membrane
Proximal tubule absorbs what % of filtered solutes and water
60-80%
Proximal tubule requirement
high ATP this makes it more vulnerable
Where are renal p450s
proximal tubule this makes it more vulnerable
Action of toxins at proximal tubule
Block ATP production Block enzymes/transporters Impair blood flow
Main actions at loop of henle
reabsorption of electrolytes where urine is concentrated
How is urine concentrated at loop of henle
Active transport of sodium Passive absorption of water (osmotic forces)
Cause of Acute renal failure - Intrarenal failure
direct damage to kidneys by inflammation, toxins, drugs, infection, or reduced blood supply
Cause of Acute renal failure - Prerenal failure
Sudden and severe drop BP
Cause of Acute renal failure - Postrenal failure
Sudden obstruction of urine flow
90% of blood flow goes to
renal cortex (where nephrons are)
What parts of renal system will have higher luminal concentration of toxicants
Medulla and papillae
What happens to toxin that is secreted unchanged
Will become more concentrated as it gets through the nephron
What are the problems caused by incr concentration of toxins if they are secreted unchanged
Damage in distal region These regions have slower blood flow - prolong exposure
Acute tubular necrosis
Death of cells at different regions along the nephron
Evidence of acute tubular necrosis
Casts - dead epithelial cells that clump up and clog tubules
Main problems in bowmans capsule and glomerulus
Immune complex deposition
Immune complex deposition
deposition of a complex of antibodies that bind antigens located along the basement membrane
Where does immune complex deposition often occur
bowmans capsule and glomerulus
What does complex of antibodies do (immune complex deposition)
attract immune mediators - inflammatory response
What do circulating immune complexes do
stick to basement membrane when they are filtered cause immune response
What toxicant causes immune complex deposition
Chronic mercury exposure
What anti body is present during chronic mercury exposure
IgG throughout the basement membrane of glomerulus
Why do immune complexes get deposited in renal system if they can occur in any capillary
high blood flow and high capillary pressure in glomerulus
3 parts of immune response intiated by immune complex deposition
inflammation
Complement activation
Recruitment of neutrophils
What can antigen-antibody complexes damage
Podocytes - effacement
Most common place for toxins to damage kidney
proximal tubule
Main toxins that can effect proximal tubule
Antibiotics Anticancer drugs Mycotoxins Heavy metals
Mycotoxin orellanine
fungus mushroom nephrotoxin
What does mycotoxin orellanine produce
free radical production
What does mycotoxin orellanine do to body
cause renal tubular necrosis Delayed onset of symptoms results in kidney failure
Kidney failure due to mycotoxin orellanine can go 2 ways
acute and recover
Progress to chronic failure
Kidneys infected with mycotoxin orellanine will show
tubular degeneration Distortion and necrosis
Proximal tubule will concentrate which substances
Mercury cadmium antibiotics : neomycin gentamycin streptomycin
Type of antibiotics that effect proximal tubule
Aminoglycosides
Example of aminoglycoside
Gentamycin
Where do antibiotics go once reach proximal tubule
reabsorbed binds to anionic lipids
What happens to antibiotics after binding to anionic lipids
taken up into lysosomes via endocytosis
What happens once antibiotics are inside lysosome
willl cause rupture of lysosome to release enzymes and free radicals (which normally help them kill bacteria)
How do antibiotics cause tubular necrosis
Ruptured lysosomes release free radicals that cause damage to cell
Common name for ethylene glycol
Antifreeze
Where is ethylene glycol toxic
proximal tubules
What happens to proximal tubule when ethylene glycol is ingested
immediate toxicity to tubular epithelial cells (renal tubular necrosis)
Metabolism of ethylene glycol
Metabolized into oxalic acid React to form calcium oxalate and cause kidney stones
Why would ethylene glycol be ingested
Sweet smelling and tasting Possible alcoholics drink it children stumble upon it
Ethylene glycol metabolized by what (how is this toxic)
alcohol dehydrogenase - becomes Glycoaldehyde ALDH becomes glyoxylic acid damaging to kidneys
Where is oxalic acid found naturally
Variety of plants - leaves of rhubarb
Where is nephrotoxicty caused by melamine and cisplatin
distal tubule
crystal deposition due to melamine causes
tubular necrosis hemorrhage inflamamtion
Toxicity of cisplatin necrosis
Taken up by tubular cells Cause vascular injury - alter GFR trigger inflammation distal and proximal tubular necrosis
Cisplatin mechanism of apoptosis
alters function of mitochondria Will now release enzymes for apoptosis
What causes damage in loop of henle
high levels of fluoride compounds with low solubility can precipitate (acyclovir, sulfonamides)
How does fluoride cause damage to loop of henle
Decr NaCl reabsorption in distal portion of nephron
How do compounds with low solubility damage loop of henle
Precipitate causing crystals in collecting ducts precipitation will trigger inflammation, dilation and tubular epithelial hyperplasia
What toxicant effects medulla
NSAIDS (acute) and mixtures of analgesics (chronic)
Action of NSAIDS
block COX 1 and COX2
How to NSAIDS effect medulla
blocks cox2 cox2 has housekeeping roles in kidney block prostaglandins --> too much vasoconstrition--> reduced GFR
Cox2 housekeeping roles
Make vasodilator prostaglandins
Action of vasodilator prostaglandins
maintain flow through afferent arteriole to maintain normal GFR
What happens when vasodilator prostanglandins blocked
Too much vasoconstriction --> reduced GFR --> incr concentration of compounds in distal nephron NSAIDS do this
Note
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