nephrotoxicity Flashcards
why are the kidneys susceptible to injury
because the process that concentrates urine can also concentrate xenobiotics in the tubular fluids
what can drive toxicants into cells in the tubules
the high concentrations of xenobiotics that can accumulate in the tubules
can you have toxic conc in the kidneys but not in the blood and why
yes because it can concentrate in the kidneys
what can cause the toxicant to precipitate out of the tubules + what can this lead to
if enough water is reabsorbed, which can lead to physical damage in the tubule (from crystals precipitating out)
what can happen if enough water is reabsorbed of the tubules
the toxicant can precipitate out and can lead to physical damage in the tubule (from crystals precipitating out)
besides renal concentrating the xeno and precipiration, what else can cause damage
active renal transport and metabolism
what is nonoliguric renal failure
inability to concentrate urine (becomes too dilute)
what is oliguria
reduced urine flow
what is anuria
no urine flow (rare)
what is polyuria
excessive urine flow
what are 7 clinical urine signs
oliguria, polyuria, anuria, nonoliguric renal failure, proteinuria, hematuria, glucosuria
what does increased urine volume with decreased osmolarity indicate
inability to concentrate urine
what does inability to concentrate urine indicate possible damage in
loop of henle, distal tubule, collecting duct
what is proteinuria
excess protein in urine
what is hematuria
blood in urine
what is glucosuria
glucose in urine
what is an example of a high MW protein
albumin
what does it mean if there is albumin in the urine
glomerular damage
what MW is albumin
high
what MW is B2-microglobulin
low
what does it mean if there is B2-microglobulin in the urine
proximal tubule reabsorption problem via endocytosis
is it bad if there are LW proteins in the tubule
no, because they can usually get reabsorbed
what does it mean if there is alkaline phosphatase in the urine
that there is tubule brush border damage
what does it mean if there is gamma-glutamyl transferase in the urine
that there is tubule brush border damage
what does it mean if there is lactate dehydrogenase in the urine
that there is general cell damage
what does it mean if there is blood in the urine
a sign of glomerular damage or toxicity to renal tubules
where does glucose reabsorption take place
proximal tubule
if it isnt diabetes, why would there be glucose in the urine
maybe there is damage in the proximal tubule
what is acute kidney injury a common symptom of + what mortality
a common symptom of nephrotoxic damage - 50% mortality
what happens in acute kidney injury (2 things)
there is an abrupt decline in glomerular filtration rate (GFR) and a resultant increase in nitrogenous waste in blood
what is azotemia
high blood urea nitrogen (BUN)
what else can be comprimised after a xenobiotic insult
tubular integrity can also be compromis
what happens once tubular integrity is comprimised
damaged cells loosen from the basement membrane which leads to gaps in the cell lining, tubular obstruction and blockage
if less stuff is being filtered into the urine, how can you make up for total urine output
by secreting more straight into the tubule
what are the 3 categories of acute kidney injury
prerenal, renal, postrenal
what is acute kidney injury
abrupt decline in function that impairs ability to maintain metabolic balance
what is prerenal acute kidney injury
impaired arterial perfusion (preglomerular, blood flow to the glomerulus)
what is renal acute kidney injury
anything that affects the functional components - vascular, glomerular and tubulointerstitial (areas between tubules)
what is postrenal acute kidney injury
obstruction of urine flow from renal pelvis to urethra (like collecting ducts can be blocked or obstructive)
what is the major cause of renal acute kidney injury
acute tubular necrosis
what is acute tubular necrosis
when patches of tubular epithelium go necrotic, they leave the basement membranes and block the lumen
what does acute tubular necrosis lead to (2)
abrupt fall in GFR and generally glomerular dysfunction
how would someone know if they have acute tubular necrosis
muddy brown urine, oliguria
which form of acute tubular necrosis does not present with oliguria
ones caused by aminoglycosides
how much does direct toxicity acount for all acute tubular necrosis cases
35%
what are 2 ways to measure GFR
clearance of creatinine or inulin
why can use use creatinine or inulin as a way to measure for GFR
because neither are secreted or reabsorbed - all that is filtered by glomerulus ends up in urine by passing through glomeruli
what is normal inulin clearance
125mL/min
what are indirect markers of GFR (2)
blood urea nitrogen (BUN) and serum creatinine concentration
when will blood urea nitrogen (BUN) and serum creatinine concentration be altered (like at what % decrease in GFR will you notice the changes)
at 50-70% decrease
what is creatinine made from
muscle
what happens once creatinine is in the nephron
it does not get reabsorbed, it is straight up excreted
what is the best way to measure for GFR
by measuring blood and urine at the same time, not good to just measure blood
what are 4 things that GFR depends on
- adequate blood flow to glomerulus
- adequate glomerular capillary pressure
- glomerular permeability
- low intratubular pressure
what happens to GFR with afferent arteriolar constriction (before the bowman capsule)
decrease GFR
what happens with an obstructing cast in the tubular lumen
increases tubular pressure, less filtration
what happens with a back leak
glomerular filtrate leaks into the extracellular space and bloodstream
what can cause a back leak
cells sloughing off, esp in prox tub, so they exit through gaps. this can also happen if the tubule pressure is too high
how can the system compensate for damage
remaining functional portions can increase CFR
what is a way that the nephron will adapt to decreased GFR
proportionate increase in proximal tubule water and solute reabsorption
why can clinical testing not notice any abnormalities
because the nephron will compensate for damage and it will mask the damage (until they are overwhelmed)
when does renal failure finally occur
when compensatory mechanisms are overwhelmed
how are endothelial cells anchored to the basement membrane
with integrins and RGD peptides
what happens to the tubular epithelium with toxic injury (first)
loss of tight junction integrity and cell substrate adhesion
what happens to the tubular epithelium with cell death and necrosis
cytoskeleton gets messed up, all the proteins are reoriented, no anchor, they fall off - sloughing
what happens once cells slough off in the tubular endothelium
cast formation and tubular obstruction
what are casts
proteinaceous mix of cell debris and protein excreted by tubular epithelial cells
what is rhabdomyolysis + causes
break down of muscle from drugs of abuse, statins, lighting, extreme exercise where hyperthermia occurs (also can be animal venoms or reactions to various drugs)
what happens specifically in rhabdomyolysis
myoglobin is released from muscles
what happens with myoglobin in the tubules
it reaches high concentration, and can be filtered through the glomerulus and reabsorbed by the cells lining the tubule
what happens to myoglobin in acidic intracellular environments
the globin chain dissociates from the iron containing ferrihemate protion - fenton reactions!!!
what can happen if iron is released
it can participate in the fenton reaction
what happens with the fenton reaction in the tubules
oxidative stress and tubular cell death
how can rhabdomyolysis cause cast formation
excess myoglobin starts to precipitate our the tubules, resulting in cast formation + epithelial cells dying adding to the cast
how does excess myoglobin cause cast formation
water is being absorbed, so then myoglobin is being concentrated
is it easy to distinguish acute tubular necrosis and prerenal acute kidney injury
no its difficult
can some drugs cause both prerenal acute kidney injury and acute tubular necrosis
yes
how can NSAIDS cause both prerenal acute kidney injury and acute tubular necrosis
NSAIDS constrict blood vessels leading to kidneys (prerenal acute kidney injury) while also causing acute tubular necrosis
what does acute tubular necrosis do to urine + why
muddy brown because of presence of casts
what does prerenal acute kidney injury do to urine
usually normal appearance actually
what is the most common injury site in the nephron
the proximal tubule
why is the proximal tubule very sensitive to chemicals (2)
because membrane transporters tend to concentrate chemicals in this region
Cyt P450 and B-lyase are almost entirely here
are proximal or distal tubule cells more sensitive to ischemic damage
proximal
which enzymes are found almost entirely in the proximal tubule
cytochrome P450 and B-lyase
where are cytochrome P450 and B-lyase found
almost entirely in the proximal tubule
why is it that since cytochrome P450 and B-lyase is almost entirely in the proximal tubule, it is more toxic
They metabolize things but also can activate compounds and make them a lot more toxic
what are a few things that can cause direct injury to the proximal tubules
halogenated hydrocarbons (chloroform), aminoglycosides antibiotics, mercury
how can radioconstrast agents hurt the proximal tubules
they can vasoconstrict, leading injury secondary to ischemia
how do xenobiotics often end up in the urine
via active secretion
how are xenobiotics taken up from blood + where do they go
by transporters, enter cells of the renal proximal tubule
can xenobiotics be reabsorbed once in the urine
yes
what is an example of a bad xenobiotic being reabsorbed from the urine
OAT 1 can transport methylmercury
is driving solutes into glomerular filtrate usually active or passive
active, needs ATP (already high conc there)
what happens if you have a OAT knockout then are given mercury + why
there will be no tubule damage because OAT is responsible for mercury entering the tubule cells
what is chloroform (why do we have it nowadays)
an industrial solvent
what is chloroform a contaminant of
water
how is chloroform absorbed + how fast
rapidly by inhalation, ingestion
what are 3 acute toxicities of chloroform
CNS, hepato, nephro
what does chloroform do to liver
steatosis (fatty liver) and centrilobular necrosis (zone 3)
what does chloroform do to kidneys
necrosis of proximal tubular epithelial cells, proteinuria, glucosuria, increased BUN
how is chloroform toxic
when it is converted by P450 enzymes to phosgene
what is the intermediate between chloroform and phosgene
trichloromethanol
what turns chloroform into trichloromethanol
CYP2E1
what is the deal with phosgene
it is a highly reactive electrophile, it can covalently modify proteins and lead to cytotoxicity and necrosis
how does the body adapt to phosgene
it uses GSH to turn it into OTZ
do guys or gals have more CYP2E1 usually
guys
why do some people react differently to chloroform
people have high variability between CYP2E1 levels, even guys and girls
what does the actions of phosgene lead to
mitochondrial dysregulation and mitochondrial permeability transition effects
what dose of chloroform can hurt you and why
needs relatively high doses cause GSH is abundant
what are aminoglycosides
antibiotics
what can aminoglycosides do to kidneys
non-oliguric kidney failure (no decreased urine production)
what do aminoglycosides do to GFR
reduce
what do aminoglycosides do to serum creatinine
increase
what do aminoglycosides do to blood urea nitrogen
increase
how does aminoglycoside toxicity present itself with pee
first polyuria (early event) then protein urea and glucosuria
what is the mechanism of aminoglycosides
inhibit sphingomyelinase and phospholipase in lysosomes
what happens to lysosomes with aminoglycosides
increase size and number, causing renal phospholipidosis, may rupture and release lysosomal enzymes and toxicants which damage the tubules
what is the charge of aminoglycosides
positive
why can aminoglycosides interacts with negative phospholipids in brush border
because aminoglycosides are positive and phospholipids are negative
why do lysosomes burst with aminoglycosides + what does it lead to
the concentrations of toxins get so high, it bursts, leading to enzymes and toxins being released to the whole cell
how do you fix acetaminophen overdose
n-acetylcysteine
what happens to trichloromethanol
it turns into phosgene
