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psc2019 > lecture 10 (renal) > Flashcards

lecture 10 (renal) Flashcards

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1
Q

what are the inflammatory responses to toxins?

A
  • deposition of toxin = severe inflammatory response
  • damages integrity of glomerular barrier
  • barrier leaky to large proteins (proteinuria)
  • barrier becomes thicker = decrease in GFR
  • glomerulus becomes blocked = ischemia, glomerular death
  • tokens taken up by podocytes
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2
Q

what are the chemicals that target the glomerulus?

A
  • gold
  • mercury
  • cyclosporine complexes
  • penicillamine
  • bucillamine
  • antibody complexes
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3
Q

what is amphotericin B?

A
  • anti fungal
  • pore former
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4
Q

how does amphotericin B work?

A
  • forms small pores in apical membrane of loop of henle and CD cells
  • filtrate volume drops
  • not much volume reaches collecting duct
  • concentration of chemicals filtered is increased
  • allow leakage of salts and bacteria
  • increases permeability
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5
Q

what does this increased permeability cause?

A
  • loss of function
  • cell death
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6
Q

what is the impact of amphotericin B toxicity?

A
  • loss of K+
  • lossof Mg2+
  • loss of ability to produce concentrated urine
  • acidosis via loss of ability to excrete proteins in collecting duct
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7
Q

what is lithium toxicity targeted to?

A
  • collecting duct
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8
Q

what is lithium given as a treatment for?

A
  • bipolar disorder
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9
Q

what occurs in lithium toxicity?

A
  • interferes with vasopressin system
  • ability to move water back through collecting duct cells into plasma
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10
Q

what occurs with ADH?

A
  • released from pituitary gland
  • binds to receptor on collecting duct
  • triggers 2nd messenger
  • triggers water pores from storage
  • causes exocytosis of vesicles
  • forms gateway for water to move into plasma
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11
Q

how is lithium thought to work?

A
  • lithium enters collecting duct cell to directly interfere with secondary messenger system
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12
Q

what are the 3 different tubular handlings?

A
  • filtered
  • filtered then reabsorbed
  • filtered and secreted
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13
Q

what occurs in filtered?

A
  • left untouched by nephron
  • amount excreted = amount filtered
  • eg. insulin, creatine
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14
Q

what occurs in filtered then reabsorbed?

A
  • amount excreted < amount filtered
  • eg. glucose, amino acids, Na+
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15
Q

what occurs in filtered and secreted?

A
  • amount excreted > amount filtered
  • eg. PAH drug molecules, metabolic end products
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16
Q

how are the lipophilic chemicals converted to water soluble chemicals?

A
  • phase 1 = functionalisation (by cytochrome P450, esterase’s)
  • forms activated chemical
  • phase 2 conjugation (detoxification)
  • easily eliminated from cell
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17
Q

what is the downside of this process?

A
  • activated chemical can turn non toxic chemical into toxic chemical
  • functional group makes chemical more reactive so can bind to macromolecules leading to toxicity
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18
Q

what is mercury?

A
  • heavy metal
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19
Q

what 3 forms does mercury exist in?

A
  • elemental
  • inorganic
  • organic
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20
Q

what is elemental mercury?

A
  • environmental pollutant
  • high vapour pressure
  • can be inhaled
  • low cytotoxicity (cell activation leading to death)
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21
Q

what does elemental mercury oxidise to form?

A
  • inorganic mercury (Hg2+)
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22
Q

what is inorganic mercury?

A
  • occupational
  • highly cytotoxic
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23
Q

what is organic mercury?

A
  • methylated mercury
  • cytotoxic
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24
Q

what does mercury do to the kidney?

A
  • damages it
  • causes degeneration
  • necrosis of tubular epithelial cells
  • vacuolation
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25
what is mercury used to treat?
- diuresis - reduces sodium rebasoprtipn
26
what is the role of glutathione?
- protection against reactive oxygen species - reacts with electrophiles directly - tripeptide
27
what is the function of glutathione conjugates?
- hydrolysed to S-substituted cysteines followed by acetylation to give mercapturic acids that are excreted
28
what occurs with mercury and glutathione?
- mercury binds to 2 molecules of glutathione - keeps mercury neutral - easier to excrete to cell - conjugated in liver usually
29
what is the movement of glutathione?
- exported through urine to kidney - taken up in PCT cells once in kidney by reabsorption - released from GS complex - combines with SH groups to deplete the local GSH leading to mitochondrial stress - inhibitor of membrane bound enzymes - acute toxicity and cellular necrosis
30
what does cadmium target?
- proximal tubule cells
31
what is cadmium (cd) excreted as?
- metallothionein complex
32
what is metallothionien?
- low MW protein - large number of SH groups - synthesised in liver - protects tissues from CD
33
what is metallothionein taken up by to cause toxicity?
- kidney - cd in renal cells leading to toxicity - cd pumped out of cell - cell complex boron down by lysosomal enzymes - causes free cadmium leading to toxicity
34
what does cycling between CdMT and free cd cause?
- accumulation in kidney - long half life
35
what are haloalkanes?
- nephrotoxins - produce proximal renal tubular damage
35
what are haloalkenes associated with?
- bio activation via cysteine conjugate beta lyase pathway
35
what is hexachlorobutadiene?
- haloalkene - starts in liver - glutathione binds and loss of chlorine so water soluble - pumped into bile ending in GI tract - directly loses glycine residue resulting in cysteine product - reabsorbed in GI tract ending up in kidney
36
what is the beta lyase pathway?
- starts in liver - xenobiotic combines with glutathione forming GSH-complex - loss of spare amino acid forming cysteine conjugate - enters systemic circulation via organic anion transporter - metabolism by B-lyase converts to hyperactive metabolite
37
what is aristolochic acid associated with?
- endemic nephropathy
38
what is endemic nephropathy?
- highly focal progressive renal disease
39
what is endemic nephropathy characterised by?
- interstitial nephritis - upper urinary tract cancers
40
what is aristolochic acid secreted by?
- proximal tubule cells - effluxes by OAT4
41
what is aristolochic acid metabolised to?
- highly reactive intermediate leading to formation of persistent DNA adducts in renal tissue - traps metabolites inside cell
42
what is the process of metabolism of aristolochic acid?
- formed after reductive metabolic activation mediated by hepatic and renal cytosolic NADPH and cytochrome P450
43
what does increasing afferent resistance of arterioles cause?
- decreased renal blood flow - decreased filtration pressure
44
what does decreasing afferent resistance of arterioles cause?
- increased renal blood flow - increased filtration pressure
45
what does increasing efferent resistance of arterioles cause?
- decreased renal blood flow - increased filtration pressure
46
what does decreasing efferent resistance of arterioles cause?
- increased renal blood flow - decreased filtration pressure
47
what is filtration pressure maintained by?
- control of blood flow to and from glomerulus
48
what is vasoconstriction mediated by?
- renin angiotensin system
49
what is the method of vasoconstriction?
- renin secretion increased - converts angiotensinogen to angiotensin II by ACE
50
what does the vasoconstriction cause?
- constriction of the efferent and afferent arterioles - causes net increase to intraglomerular pressure - decrease in overall blood flow
51
what is vasodilation mediated by?
- prostaglandin release
52
what is the method of vasodilation?
- PGE2 secretion leads to net dilation of afferent arterioles - increases overall blood flow
53
what do calcineurin inhibitors do?
- increase renin synthesis leading to increase in angiotensin II release - decrease PGE2 and COX2 causing reduced renal blood flow and reduced GFR
54
what are examples of calcineurin inhibitors?
- cyclosporine - tacrolimus
55
what do NSAIDs do?
- decrease PGE2 release - decreased angiotensin II release so less vasoconstriction
56
what does amphotericin B do?
- forms pores in membrane - influx of Ca2+ vasoconstriction
57
what do ACE inhibitors and angiotensin receptor blocking agents do?
- all synthesis decreases - efferent arteriole is dilated - decreased intraglomerular pressure
58
what are ACE inhibitors important in?
- renovascular diseases like renal artery stenosis
59
what does drug induced ischemia impact?
- renal medulla
60
what are the causative agents of ischemia?
- drugs which change/reduce blood flow
61
what is NSAID associated with?
- medullary ischemia in patients with low blood pressure
62
what is the mechanism of iscaemic cell death?
- local prostaglandin synthesis switched on by ischemia to produce local vasodilation - increases blood flow - NSAIDs block local prostaglandin synthesis
63
what is the impact of ischaemic cell death?
- loss of K - loss of Mg - loss of ability to produce concentrated urine - acidosis via loss of ability to excrete protons in collecting duct
64
what is under the umbrella term of chronic kidney disease?
- chronic renal sufficiency - chronic renal failure - end stage renal failure
65
what measures renal function?
- creatinine - decreases as renal function deteriorates
66
what is creatinine production dependent on?
- loss of gain of muscle
67
what is plasma concentration affected by?
- hydration state
68
why are novel biomarkers needed?
- dont measure functional disturbance - only affected near end stage - detect damage to tissue
69
what does collagen presence in the urine highlight?
- damage to the glomerular basement membrane in bowman capsule
70
what is a human kidney marker of injury?
- KIM-1
71
what is KIM-1?
- transmembrane glycoprotein - low expression in normally functioning kidney
72
when does KIM-1 expression increase?
- after ischemic re-perfusion injury
73
what is KIM-1 a marker of?
- proliferating, de-differentiated proximal tubule cells shed from membrane after cleavage by MMP
74
what is KIM-1 measured in?
- serum - urine
75
what is creatinine used to treat?
- BALBc mice

psc2019 (19 decks)

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