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Toxicology > Kidney toxicity > Flashcards

Kidney toxicity Flashcards

1
Q

what are the 3 pats of the kidneys anatomys

A
  • Cortex = 90% of blood flow
  • Medulla = exposed to high lumenal conc of toxicants for longer periods
  • Papilla
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2
Q

why is the kidney susceptible to toxicity

A
  • High renal blood flow = kidney is only 0.5% of total body mass but receives 25% cardiac output
  • Glomerular filtration and water reabsorption results in conc of xenobiotic and metabolites in tubular fluid. Non toxic conc in plasma can become toxic in kidney and possibly precipitates in lumen
  • Renal transportation of chemicals into tubular cells = active transport can cause tubular accumulation of heavy metal ect
  • Biotransformation of parent compounds to toxic metabolites especially in pars recta of proximal tubules
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3
Q

List the location of toxic effects

A

Glomerulus
Proximal tubules
Renal haemodynamics
Loop of Henle
Distal tubule
Collecting ducts

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4
Q

What toxic effects are found in the glomerulus

A

Inflammatory response - leads to membrane damage, leakage
Immune complexes (haptens and/or complete antigen), blockage

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5
Q

What toxic effects are found in the proximal tubule

A

antineoplastics
halogenated hydrocarbons
heavy metals
antibiotics

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6
Q

What toxic effects are found in the renal haemodynamics

A

Calcineurin inhibitors, NSAIDs, ACE inhibitors and ARBs
- control glomerular filtration rate

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7
Q

What toxic effects are found in the loop of Henle and distal tubule

A

amphotericin which forms pores in the apical membranes of cells, resulting in loss of solutes

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8
Q

What toxic effects are found in the collecting duct

A

lithium linked

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9
Q

describe the types of mercury

A
  • Elemental environmental pollutant, high vapour pressure, inhalation; low cytotoxicity, but easily oxidised to…
  • Inorganic (Hg2+) occupational, skin/oral
  • Organic eg methyl mercury lipophilic skin/oral
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10
Q

GS-Hg-SG formed in the liver from gonjugation with what and where does it go ?

A

mercury and glutathione
translocation to the kidney in systemic ciruclation then uptaken into proximal tubule cell from tubular fluid

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11
Q

what possibly happens to GS-HG-SG when its uptaken from the tubular fluid to proximal tubule cells

A

removal of ‘spare’ AA from glutathione to yeild cysteine conjugates

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12
Q

what happens when Hg++ is released

A

combines with SH groups on proteins,
depletes GSH, leading to mitochondrial stress
inhibits membrane bound enzymes

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13
Q

what shows acute toxicity and therefore cellualr necrosis in pars recta

A

Enzymes normally found in “brush border” (g-glutamyl transpeptidase, alkaline phosphatase) detected in urine
At higher doses, tubular necrosis occurs

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14
Q

how is cadmium excreted

A

metallothionenin complex

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15
Q

what is metallothionein

A

low MW protein with large number of SH groups synthesied in the liver to protect tissues form cadmium

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16
Q

What happens when cadmium is in the kidyes

A

in renal cells = toxicity
cadmium is pumped out the cell and forms a complex with metallothionenin
- if in the cell complex then this is broken down by lysosomal enzymes to free cadmium again = toxicity

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17
Q

True or False - there is cycling between CdMT and free Cd in cell

A

True
leads to long half life and results in accumulation in kidneys

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18
Q

When CdMt leaves the hepatocytes it enters the renal proximal tubule cells where it ….

A

-undergo lysosomal hydrolysis to release cadmium bind reversible binds to SH groups
- when this occurs Mt is degenerated and resynthesied
-cycling oxidative stress

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19
Q

what are halogenated hydrocarbons (Haloalkanes)

A

carbon tetrachloride (CCL4) Chloroform (CHCl3)

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20
Q

what does proximal tubule damage due to haloalkanes cause

A

glucosuria, proteinuria, polyuria
anuria and renal failure at high dose

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21
Q

what are the mechanisms of toxicity of haloalkanes

A
  • Activation by mixed function oxidases to toxic metabolites followed by covalent binding
    (eg chloroform (CHCl3) metabolised to COCl2 (phosgene) by P450 in liver)
  • Then parent or metabolite carried in blood from liver to kidney
  • Local activation to COCl2 in kidney (prostacyclin synthase) detoxified by reaction with glutathione or cysteine
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22
Q

Most haloalkanes are _ producing _

A

nephrotoxins
proximal renal tubular damage

23
Q

haloalkanes are associated with bioactivation via the _

A

cysteine conjugates B lyase pathways

24
Q

Hexachlorobutadiene is conjugated with glutathione to produce

A

PCBG

25
Q

What happens to PCBG before it enters the bile
- then the GI tract

A
  • under goes y-glutamyl transferase to produce S-(1,1,2,3,4-pentachlorobutadienyl)cysteinylglycine
  • Then its converted to PCBC by dipeptidase when reabsorbed in the GI tract
26
Q

what is PCBC and what happens to it once it leaves the GI tract

A
  • can be reversibly turned into N-Ac-PCBC (via N-acetyl transferase) and back to PCBC (acylase)
  • via B lyase its converted to 1,1,2,3,4-pentachlorobutadienythiol and then a thioketene
  • PCBC is actively transported into kidney tubule by organic anion transporter, but the cysteinyl glycyl conjugate can also be absorbed via the gamma glutamyl transferase in the tubule cell
27
Q

what is thioketene

A

proposed DNA reactive metabolite

28
Q

What is the cysteine S conjugate B lyases

A

Located in the Kidney + other tissues. Requires pyridoxal-5-phosphate and a-keto acid
Has aminotransferase + transaminase action
Divert cysteine conjugates from mercapturate formation, localised to proximal tubule
= causes mitochondrial toxicity

29
Q

describe the beta lyase pathway

A

In the Liver/Bile = GSH conjuagtes xenobiotics which then is converted to the cysteine conjugate (via gamma glutamyl transferase)
- travels via systemic circulation -
Proximal tubule = turns to thiokentene via Cys conjugate B-lyase

30
Q

How is the glomerular filtration rate controled

A

Filtration pressure maintained by control of blood flow
- vasoconstriction
- vasodilation

31
Q

how is vasoconstriction mediated

A

Renin-Angiotensin system
- renin secretion increased, converts angiotensinogen ultimately to angiotensin II (AII) – this constricts both afferent and efferent arterioles leading to net increase in intraglomerular pressure

32
Q

how is vasodilation mediated

A

prostaglandin release
- PGE2 secretion leads to net dilation of afferent arteriole (increasing overall blood flow)

33
Q

what are the therapeutic agents that target renal haemodynamics

A

Calcineurin inhibitors (Cyclosporine & tacrolimus)
NSAIDs
Amphotericin B
Angiotensin converting enzyme (ACE) inhibitors & angiotensin receptor blocking (ARB) agents

34
Q

what does calceurin inhibitors do

A

Increase renin synthesis leading to increase in AII release
Decrease PGE2 and COX2 – net result is reduced renal blood flow and GFR

35
Q

what does NSAIDs do

A

Decrease PGE2 release – a problem if blood flow to glomerulus is reduced:
PGE2 is important to avoid Angiotensin II resulting in unchecked vasoconstriction

36
Q

what does amphotericin B do

A

Forms pores in membrane - influx of Ca2+ vasoconstriction

37
Q

Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blocking (ARB) agents

A

Angiotensin II synthesis decreases – efferent arteriole is preferentially dilated, leading to decrease in intraglomerular pressure.
Important in renovascular disease such as renal artery stenosis

38
Q

how does antibiotics effect the kidneys

A
  • Reabsorbed into proximal tubular cells by endocytotic processes via the megalin-cubulin complex
  • Accumulates in lysosomes, golgi bodies and ER
  • In lysosomes, inhibits lysosomal phospholipases and other membrane phospholipid-processing enzymes
  • Lysosomal membrane disruption and mitochondrial dysfunction
39
Q

How does aminogycoside toxicity effect the proximal tubule

A

binds to membrane -> taken up by endocytosis -> accumulates in lysosomes -> toxicity
- luminal aminoglycoside conc increases as fluid is absorbed along length of PCT

40
Q

what occur in the early stages of aminoglycoside treatment

A

competes with proteins for endocytosis = protein appears in urine

41
Q

what is the effects of cephalosporins in the kidneys

A

selective toxicity to proximal tubule cells
- Absorbed from systemic circulation by cation/anion transporter (on basolateral membrane)
- Not a substrate for efflux transporters, so highly retained within proximal tubule cells
- Only antibiotics which are transported cause toxicity
- Mechanisms include mitochondrial injury and lipid peroxidation

42
Q

how is cephaloridine taken up

A

OAT1 transporters at basolateral membrane as its not a substrate for efflux pumps

43
Q

what is fanconi syndrome

A

organic solutes lost to urine increased NA loss increased H20 loss

44
Q

how do we administer cisplatin without killing patients

A

co-administer with an uptake blocker

45
Q

How does the renal system handle cisplatin

A

cisplatin = nephrotoxic
- Because it is efficiently taken up into proximal tubule but rate of secretion is lower
- Higher exposure results in destruction of mitochondria → proximal tubular cell death
Organic solutes lost to urine increased Na loss increased H2O loss – Fanconi syndrome

46
Q

what is the function of ADH (vasopressin)

A

Inserts Water Pores into Collecting Duct Cells Membrane to enable re-absorption of solute-free water from the collecting duct

47
Q

how is lithium nephrotoxic

A

competes for ADH receptor - reuslting in polyuria

48
Q

what are the methods for detecting and evaluating chemical induced renal injury

A
  • Polyuria
  • Decreased reabsorption =(Glucosuria/ aminoaciduria, pH/electrolytes)
  • Proteinuria
  • Anuria (Tubular obstruction)
49
Q

How does proteinuria show renal injury

A
  • Low MW proteins, esp. b2 microglobulin, in urine (normally taken into tubular cells by endocytosis)
  • Albumin: damage to glomerulus (reabsorbed by endocytosis in mild injury, becomes saturated in severe injury)
  • proximal tubule enzymes
50
Q

how does creatinine clearance give a measure of renal function

A
  • In early stages plasma creatinine may remain within normal limits for population
  • Production dependent upon muscle bulk - loss or gain of muscle affects value
  • Plasma concentration affected by hydration state
51
Q

why is there a need for novel biomarkers

A

Only a MARKED loss of renal mass results in a lack of function
- traditional clinical parameters only detect loss of function
- Novel biomarkers detect damage to tissue

52
Q

list some novel biomarkers

A

Collagen IV - glomerular basement membrane
a-GST - proximal tubules
RPA-2 - loop of henle
y-GST = distal tubule/collecting tubules
RPA-1 = collecting duct (RPA-1 renal papillary antigen – a marker of renal papillary necrosis)

53
Q

what is kidney injury molecule -1 (KIM-1)

A

a transmembrane glycoprotein with very low expression levels in normal kidney
- expression increases markedly after ischemic re-perfusion injurgy
- A marker of proliferating, de-differentiated proximal tubule cells; shed from membrane after cleavage by MMP.
- Measured in both serum and urine and expressed in both humans and rodents.

54
Q
A

Toxicology (11 decks)

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