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PMCOL 303 > nephrotoxicity > Flashcards

nephrotoxicity Flashcards

1
Q

why are the kidneys susceptible to injury

A

because the process that concentrates urine can also concentrate xenobiotics in the tubular fluids

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2
Q

what can drive toxicants into cells in the tubules

A

the high concentrations of xenobiotics that can accumulate in the tubules

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3
Q

can you have toxic conc in the kidneys but not in the blood and why

A

yes because it can concentrate in the kidneys

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4
Q

what can cause the toxicant to precipitate out of the tubules + what can this lead to

A

if enough water is reabsorbed, which can lead to physical damage in the tubule (from crystals precipitating out)

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5
Q

what can happen if enough water is reabsorbed of the tubules

A

the toxicant can precipitate out and can lead to physical damage in the tubule (from crystals precipitating out)

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6
Q

besides renal concentrating the xeno and precipiration, what else can cause damage

A

active renal transport and metabolism

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7
Q

what is nonoliguric renal failure

A

inability to concentrate urine (becomes too dilute)

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8
Q

what is oliguria

A

reduced urine flow

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9
Q

what is anuria

A

no urine flow (rare)

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10
Q

what is polyuria

A

excessive urine flow

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11
Q

what are 7 clinical urine signs

A

oliguria, polyuria, anuria, nonoliguric renal failure, proteinuria, hematuria, glucosuria

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12
Q

what does increased urine volume with decreased osmolarity indicate

A

inability to concentrate urine

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13
Q

what does inability to concentrate urine indicate possible damage in

A

loop of henle, distal tubule, collecting duct

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14
Q

what is proteinuria

A

excess protein in urine

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15
Q

what is hematuria

A

blood in urine

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16
Q

what is glucosuria

A

glucose in urine

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17
Q

what is an example of a high MW protein

A

albumin

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18
Q

what does it mean if there is albumin in the urine

A

glomerular damage

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19
Q

what MW is albumin

A

high

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20
Q

what MW is B2-microglobulin

A

low

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21
Q

what does it mean if there is B2-microglobulin in the urine

A

proximal tubule reabsorption problem via endocytosis

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22
Q

is it bad if there are LW proteins in the tubule

A

no, because they can usually get reabsorbed

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23
Q

what does it mean if there is alkaline phosphatase in the urine

A

that there is tubule brush border damage

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24
Q

what does it mean if there is gamma-glutamyl transferase in the urine

A

that there is tubule brush border damage

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25
Q

what does it mean if there is lactate dehydrogenase in the urine

A

that there is general cell damage

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26
Q

what does it mean if there is blood in the urine

A

a sign of glomerular damage or toxicity to renal tubules

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27
Q

where does glucose reabsorption take place

A

proximal tubule

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28
Q

if it isnt diabetes, why would there be glucose in the urine

A

maybe there is damage in the proximal tubule

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29
Q

what is acute kidney injury a common symptom of + what mortality

A

a common symptom of nephrotoxic damage - 50% mortality

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30
Q

what happens in acute kidney injury (2 things)

A

there is an abrupt decline in glomerular filtration rate (GFR) and a resultant increase in nitrogenous waste in blood

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31
Q

what is azotemia

A

high blood urea nitrogen (BUN)

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32
Q

what else can be comprimised after a xenobiotic insult

A

tubular integrity can also be compromis

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33
Q

what happens once tubular integrity is comprimised

A

damaged cells loosen from the basement membrane which leads to gaps in the cell lining, tubular obstruction and blockage

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34
Q

if less stuff is being filtered into the urine, how can you make up for total urine output

A

by secreting more straight into the tubule

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35
Q

what are the 3 categories of acute kidney injury

A

prerenal, renal, postrenal

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36
Q

what is acute kidney injury

A

abrupt decline in function that impairs ability to maintain metabolic balance

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37
Q

what is prerenal acute kidney injury

A

impaired arterial perfusion (preglomerular, blood flow to the glomerulus)

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38
Q

what is renal acute kidney injury

A

anything that affects the functional components - vascular, glomerular and tubulointerstitial (areas between tubules)

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39
Q

what is postrenal acute kidney injury

A

obstruction of urine flow from renal pelvis to urethra (like collecting ducts can be blocked or obstructive)

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40
Q

what is the major cause of renal acute kidney injury

A

acute tubular necrosis

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41
Q

what is acute tubular necrosis

A

when patches of tubular epithelium go necrotic, they leave the basement membranes and block the lumen

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42
Q

what does acute tubular necrosis lead to (2)

A

abrupt fall in GFR and generally glomerular dysfunction

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43
Q

how would someone know if they have acute tubular necrosis

A

muddy brown urine, oliguria

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44
Q

which form of acute tubular necrosis does not present with oliguria

A

ones caused by aminoglycosides

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45
Q

how much does direct toxicity acount for all acute tubular necrosis cases

A

35%

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46
Q

what are 2 ways to measure GFR

A

clearance of creatinine or inulin

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47
Q

why can use use creatinine or inulin as a way to measure for GFR

A

because neither are secreted or reabsorbed - all that is filtered by glomerulus ends up in urine by passing through glomeruli

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48
Q

what is normal inulin clearance

A

125mL/min

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49
Q

what are indirect markers of GFR (2)

A

blood urea nitrogen (BUN) and serum creatinine concentration

50
Q

when will blood urea nitrogen (BUN) and serum creatinine concentration be altered (like at what % decrease in GFR will you notice the changes)

A

at 50-70% decrease

51
Q

what is creatinine made from

A

muscle

52
Q

what happens once creatinine is in the nephron

A

it does not get reabsorbed, it is straight up excreted

53
Q

what is the best way to measure for GFR

A

by measuring blood and urine at the same time, not good to just measure blood

54
Q

what are 4 things that GFR depends on

A
  • adequate blood flow to glomerulus
  • adequate glomerular capillary pressure
  • glomerular permeability
  • low intratubular pressure
55
Q

what happens to GFR with afferent arteriolar constriction (before the bowman capsule)

A

decrease GFR

56
Q

what happens with an obstructing cast in the tubular lumen

A

increases tubular pressure, less filtration

57
Q

what happens with a back leak

A

glomerular filtrate leaks into the extracellular space and bloodstream

58
Q

what can cause a back leak

A

cells sloughing off, esp in prox tub, so they exit through gaps. this can also happen if the tubule pressure is too high

59
Q

how can the system compensate for damage

A

remaining functional portions can increase CFR

60
Q

what is a way that the nephron will adapt to decreased GFR

A

proportionate increase in proximal tubule water and solute reabsorption

61
Q

why can clinical testing not notice any abnormalities

A

because the nephron will compensate for damage and it will mask the damage (until they are overwhelmed)

62
Q

when does renal failure finally occur

A

when compensatory mechanisms are overwhelmed

63
Q

how are endothelial cells anchored to the basement membrane

A

with integrins and RGD peptides

64
Q

what happens to the tubular epithelium with toxic injury (first)

A

loss of tight junction integrity and cell substrate adhesion

65
Q

what happens to the tubular epithelium with cell death and necrosis

A

cytoskeleton gets messed up, all the proteins are reoriented, no anchor, they fall off - sloughing

66
Q

what happens once cells slough off in the tubular endothelium

A

cast formation and tubular obstruction

67
Q

what are casts

A

proteinaceous mix of cell debris and protein excreted by tubular epithelial cells

68
Q

what is rhabdomyolysis + causes

A

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)

69
Q

what happens specifically in rhabdomyolysis

A

myoglobin is released from muscles

70
Q

what happens with myoglobin in the tubules

A

it reaches high concentration, and can be filtered through the glomerulus and reabsorbed by the cells lining the tubule

71
Q

what happens to myoglobin in acidic intracellular environments

A

the globin chain dissociates from the iron containing ferrihemate protion - fenton reactions!!!

72
Q

what can happen if iron is released

A

it can participate in the fenton reaction

73
Q

what happens with the fenton reaction in the tubules

A

oxidative stress and tubular cell death

74
Q

how can rhabdomyolysis cause cast formation

A

excess myoglobin starts to precipitate our the tubules, resulting in cast formation + epithelial cells dying adding to the cast

75
Q

how does excess myoglobin cause cast formation

A

water is being absorbed, so then myoglobin is being concentrated

76
Q

is it easy to distinguish acute tubular necrosis and prerenal acute kidney injury

A

no its difficult

77
Q

can some drugs cause both prerenal acute kidney injury and acute tubular necrosis

A

yes

78
Q

how can NSAIDS cause both prerenal acute kidney injury and acute tubular necrosis

A

NSAIDS constrict blood vessels leading to kidneys (prerenal acute kidney injury) while also causing acute tubular necrosis

79
Q

what does acute tubular necrosis do to urine + why

A

muddy brown because of presence of casts

80
Q

what does prerenal acute kidney injury do to urine

A

usually normal appearance actually

81
Q

what is the most common injury site in the nephron

A

the proximal tubule

82
Q

why is the proximal tubule very sensitive to chemicals (2)

A

because membrane transporters tend to concentrate chemicals in this region
Cyt P450 and B-lyase are almost entirely here

83
Q

are proximal or distal tubule cells more sensitive to ischemic damage

A

proximal

84
Q

which enzymes are found almost entirely in the proximal tubule

A

cytochrome P450 and B-lyase

85
Q

where are cytochrome P450 and B-lyase found

A

almost entirely in the proximal tubule

86
Q

why is it that since cytochrome P450 and B-lyase is almost entirely in the proximal tubule, it is more toxic

A

They metabolize things but also can activate compounds and make them a lot more toxic

87
Q

what are a few things that can cause direct injury to the proximal tubules

A

halogenated hydrocarbons (chloroform), aminoglycosides antibiotics, mercury

88
Q

how can radioconstrast agents hurt the proximal tubules

A

they can vasoconstrict, leading injury secondary to ischemia

89
Q

how do xenobiotics often end up in the urine

A

via active secretion

90
Q

how are xenobiotics taken up from blood + where do they go

A

by transporters, enter cells of the renal proximal tubule

91
Q

can xenobiotics be reabsorbed once in the urine

A

yes

92
Q

what is an example of a bad xenobiotic being reabsorbed from the urine

A

OAT 1 can transport methylmercury

93
Q

is driving solutes into glomerular filtrate usually active or passive

A

active, needs ATP (already high conc there)

94
Q

what happens if you have a OAT knockout then are given mercury + why

A

there will be no tubule damage because OAT is responsible for mercury entering the tubule cells

95
Q

what is chloroform (why do we have it nowadays)

A

an industrial solvent

96
Q

what is chloroform a contaminant of

A

water

97
Q

how is chloroform absorbed + how fast

A

rapidly by inhalation, ingestion

98
Q

what are 3 acute toxicities of chloroform

A

CNS, hepato, nephro

99
Q

what does chloroform do to liver

A

steatosis (fatty liver) and centrilobular necrosis (zone 3)

100
Q

what does chloroform do to kidneys

A

necrosis of proximal tubular epithelial cells, proteinuria, glucosuria, increased BUN

101
Q

how is chloroform toxic

A

when it is converted by P450 enzymes to phosgene

102
Q

what is the intermediate between chloroform and phosgene

A

trichloromethanol

103
Q

what turns chloroform into trichloromethanol

A

CYP2E1

104
Q

what is the deal with phosgene

A

it is a highly reactive electrophile, it can covalently modify proteins and lead to cytotoxicity and necrosis

105
Q

how does the body adapt to phosgene

A

it uses GSH to turn it into OTZ

106
Q

do guys or gals have more CYP2E1 usually

A

guys

107
Q

why do some people react differently to chloroform

A

people have high variability between CYP2E1 levels, even guys and girls

108
Q

what does the actions of phosgene lead to

A

mitochondrial dysregulation and mitochondrial permeability transition effects

109
Q

what dose of chloroform can hurt you and why

A

needs relatively high doses cause GSH is abundant

110
Q

what are aminoglycosides

A

antibiotics

111
Q

what can aminoglycosides do to kidneys

A

non-oliguric kidney failure (no decreased urine production)

112
Q

what do aminoglycosides do to GFR

A

reduce

113
Q

what do aminoglycosides do to serum creatinine

A

increase

114
Q

what do aminoglycosides do to blood urea nitrogen

A

increase

115
Q

how does aminoglycoside toxicity present itself with pee

A

first polyuria (early event) then protein urea and glucosuria

116
Q

what is the mechanism of aminoglycosides

A

inhibit sphingomyelinase and phospholipase in lysosomes

117
Q

what happens to lysosomes with aminoglycosides

A

increase size and number, causing renal phospholipidosis, may rupture and release lysosomal enzymes and toxicants which damage the tubules

118
Q

what is the charge of aminoglycosides

A

positive

119
Q

why can aminoglycosides interacts with negative phospholipids in brush border

A

because aminoglycosides are positive and phospholipids are negative

120
Q

why do lysosomes burst with aminoglycosides + what does it lead to

A

the concentrations of toxins get so high, it bursts, leading to enzymes and toxins being released to the whole cell

121
Q

how do you fix acetaminophen overdose

A

n-acetylcysteine

122
Q

what happens to trichloromethanol

A

it turns into phosgene

PMCOL 303 (25 decks)

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