nephrotox - READY TO REVIEW Flashcards
what are the three main regions of the kidney
(from out to in) renal cortex, renal medulla, renal pelvis
whats the functional unit of the kidney
nephron
what are the key functions of the kidney
regulate bone mineral metabolism
regulate RBC formation
excrete metabolic waste + water
influence blood pH
regulate blood pressure
why is the kidney so susceptible to toxicity (4 reasons)
high blood flow –> high amounts of drug / chemical in systemic circulation being delivered to the organ
forms concentrated urine ; so could lead to toxicants concentrated
non toxic conc in plasma –> toxic in kidney
kidney has drug metabolising enzymes –> could lead to bioactivation
what is AKI and what is it based on
acute kidney injury; a sudden loss of kidney function
based on serum creatinine increases or changes in urine output.
what can cause the decline in GFR in AKI?
55-60% –> prerenal –> things occuring upstream of the kidney –> renal vaso, intravascular volume depletion, insufficient cardiac output
5% post renal –> an obstruction in the urethra or bladder
35-40% intrarenal –> glomerunephritis, tubular cell injury, death, back leak, renal vascular damage, infammation in interstitial space.
t/f: AKI related mortality is one of the lowest mortality rates
FALSE! highest
whats the difference between the aquisition of AKI in low income vs high income countries
low income: community aquired, due to dehydration, toxins, seen in younger patients
high income: hospital aquired, related to sepsis, drugs, invasiv procedures, occurs in elderly patients.
what is the glomerular filtration rate normally dependent on
blood flow to glomerulus
glomerular capillary pressure
glomerular permeability
low intratubular pressure.
what can decrease the GFR in acute renal failure
constriction of the afferent arteriole, obstructuon, back leak
whats the difference between acute kidney injury and chronic kidney disease
CKD: deterioration of renal fucntion due to prolonged chemical exposure
AKI can develop into CKD
t/f: if you have AKI you’re less likely to develop CKD
FALSE! you’re 10 - 30 times more likely to develop CKD.
why are patients with AKI more likely to develop CKD (2 reasons)
- persistant low level injury after AKI leads to CKD// makes the kidney more susceptible to further damage
- initial kidney injury triggers secondary processes that lead to CKD development
GFR is a marker for kidney damage. what does it tell you?
low GFR –> CKD or AKI
what does serum creatinine tell you about kidney damage
elevated serum cret - impaired kidney fucntion
what does proteinuria tell you about kidney damage
indicates kidney damage
what does blood urea nitrogen tell you about kidney damage
elevated –> kidney damage
what does cystatin C tell you about kidney damage
elevated –> kidney damage
what does it mean that nephrotox is a dose limiting adverse effect of cisplatin
that to combat the nephrotoxicity you need to wthold it or reduce the dose or stop it all together.
what does cisplatin do (to DNA)
its a platinum based drug. it induces DNA corss links and DNA adducts.
what class of genotoxic agents does cisplatin belong to
its an alkylating agent
how does the cell handle cisplatin
with each metabolizing step, replaces a Cl with an OH. this lets it bond with the DNA/
what is cisplatin used for clinically. how many of these patients experience kidney damage?
chemotherapy
more than 30%
t/f: combination regimens reduce risk of renal toxicity
false: they increase it
how do you manage cisplatin induced AKI
discontinue the chemo
delay the chemo
switch to a less nephrotoxic chemo
why is cisplatin so toxic to the kidney
reaches 5x more cons in renal cells than in plasma.
upatken by the SLC
leads to ROS, ER stress, activation of inflamm / apop pathways
what is the pathway from cisplatin exposure to AKI or CKD
uptake through SLC, biactivation, DNA damage, ox stress, mito damage, ER stress, autophagy, cell cycle regulation, cell death, inflammation, senenscence
AKI can develop into CKD.
whats the relationship between copper, the copper transporter 1, and cisplatin
if you silence Ctr1, or incurease Cu, you decrease cisplatin uptake.
silencing Ctr1leads to less apoptotic cells and necrosis after cisplatin exposure.
examples of aminoglycosides include:
tobramycin, kanamysin, GENTAMICIN!!!!!
what are aminoglycosides used for? how are they excreted?
used to treat bacterial infections
filtered by glomerulus, excreted unchanged.
what family does gentamicin fall into?
aminoglycoside; nephrotoxin.
how does gentamicin accumulate in tubular cells?
megalin and cubulin form a endocytic receptor complex.
gentamicin endocytosis through this receptor.
endosomes traffic the gentamicin to different intracellular components like the golgi and ER, and the lysosomes.
how does gentamicin trigger ER stress and the UPR?
it goes and inhibits protein synthesis + folding , this leads to ER stress and unfolded protein response. calcium is releases
how does gentamicin lead to apoptosis?
calcium release and ER stress trigger apop proteins (bid –> MOMP –> caspase repsonse)
how does gentamicin get redistributed in the cytosol? how does this contribute to its renal tox?
when the conc exceeds a certain threshold in the organelles, it destabalizes lysosome, golgi, er membranes –> gentamicin is released into cytosol
once in cytosol, acts on mitochondria, triggers cytochrome c release, other apop proteins–> leads to apoptosis.
what are the consequences of tubular epithelial damage? what effect does it have on pressure?
- you get loss of tight junction integrity, the brush border gets messed up
- then you start to get cell death, apop, necrosis,
- then they lift off start to obstruct the lumen,
- the obstruction leads to increased pressure.
t/f: gentamicin has only one mechanism of toxicity
FALSE! it has multiple.
what are the different mechs of gentamicin toxicity
- mitochondrial tox (impaired cell energy, increased ROS)
- inhibiting membrane transporters
- tubule cell death, activation of caspase response
- ox stress
- inflammation + ischemia
whats the difference between direct cellular injury and immune mediated injury
direct cell is damage to the epithelial cells, endothelial cells, mesangial cells.
immune is immmue diseases leading to glom damage - membranous nephropathy is an example disease that can cause imm mediated injury.
what drug can lead to membranous nephropathy
D penicillamine.
if you immediately get rid of the thing causing the membranous nephropathy, does your albumin and proteinurea go back to normal right away?
NO! it takes some time for it to go back to norma
what are the three different models of d penicillamine induced membranous nephropathy
in model 1: preformed immune complexes get trapped in the sub epi space
in model 2: circulating pathogenic antigens are planted in the sub epi spaces. they react with antibodies to form in situ immune complexes.
in model 3: autoantibodies react with the antigens on the podocyte membranes. they form immune complexes.
how does a membranous neuropathy capillary compare to a normal one
it has much thicker capillary walls, cant filter as well.
what kind of toxicity does aristolochic acid cause?
leads to tubular dysfucntion, proteinureia, interstitial fibrosis.
what is the aristoclochic acid mech of toxicity?
its a mix of compoinds. forms DNA adducts –> genotoxic and carcinogenic. GRP 1 CARCINOGENIC!
OAT mediated transport
nitrogen reduced to form a nitrenium
forms protein + DNA adducts.
* nitrenium ion !!*
whats the difference in toxicity between AA-1 and AA-2. so what?
both produce DNA adducts, but AA1 produces renal proximal tubule necrosis and interstitial fibrosis but AA2 doesnt. so the AA1 nephrotox may not be due to the DNA adducts.
how does sulfamethoxazole induce nephropathy
gets metabolized to NASM.
forms sulfonamide crystals
leads to lesions in the tubules
leads to AKI –> resolved after durg discontinuation
