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PED3011 Toxicology > Kidney Toxicity > Flashcards

Kidney Toxicity Flashcards

1
Q

What is the role of the kidney

A

Excretion of wastes
Regulation of body homeostasis

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2
Q

Describe the kidney anatomy

A

Cortex, medulla, papilla

7 lobes structure

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3
Q

Why is the kidney susceptible to toxicity

A

1- High renal blood flow
2- Concentration of xenobiotics in tubular fluid due to glomerular filtration and water reabsorption
3- Bio transformation of parent compound to toxic metabolite

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4
Q

What are the toxic effects experienced in the glomerulus

A

Inflammatory response
Immune complexes
Blockages

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5
Q

What xenobiotics damage the proximal tubule

A

Antineoplastics
Halogenated hydrocarbons
Heavy metals
Antibiotics

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6
Q

What areas does amphotericin affect

A

Loop on Henle and distal tubule

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7
Q

What xenobiotics affect renal haemodynamics

A

Calcineurin inhibitors
NSAIDs
ACE inhibitors
ARBS

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8
Q

Describe the heavy metal mercury

A

Elemental environmental pollutant
Reduce Na+ reabsorption in Loop of Henle

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9
Q

Where does Hg+ act on the kidney

A

Selective to pars recta proximal tubular epithelial cells

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10
Q

How does Hg reach the kidney

A

Conjugated with GSH -> GS-HG-SG
Translocation to kidney in systemic circulation
Uptake into proximal tubule cell from tubular fluid

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11
Q

What happens when GS-HG-SG reaches the proximal tubule cell

A

Hg2+ is released and combines with SH on proteins
Depletes GSH = to mitochondrial stress
Inhibits membrane bound enzymes

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12
Q

Describe acute and severe Hg toxicity in the kidney

A

Acute: cellular necrosis in pars recta
Severe: tubular necrosis

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13
Q

How is cadmium excreted

A

Metallothionein complex

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14
Q

What is the role of metallothionein in the body

A

Synthesised in liver to protect tissues from Cd
Large number of SH groups

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15
Q

How does Cd toxicity happen

A

Cd-MT complex taken up by renal proximal tubule cell
Complex broken down by lysosomal enzymes
= free Cd that bind to Sh groups

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16
Q

What is the mechanism of toxicity of haloalkanes

A

Activated to toxic metabolites by mixed function oxidases
Carried in blood from liver to kidney

17
Q

What pathway are haloalkenes bioactivated by

A

Cysteine conjugate B lyase pathway

18
Q

Describe cysteine S conjugate B lyases

A

Found in kidney and other tissues
Require pyridoxal-5-phosphate and a-keto acid
Divert cysteine conjugates from mercapturate formation

19
Q

Describe the B lyase pathway

A

Xenobitoic (+GSH) -> GSH- Conjugate (+yGT+AP) -> Cysteine conjugate (Cys conjugate B-lyase)-> Thioketene

20
Q

How is the glomerular filtration rate controlled

A

Pressure maintained by control of blood flow to and from glomerulus
Via vasoconstriction and vasodilation

21
Q

Describe vasoconstriction in the kidneys

A

Mediated by Renin-Angiotensin system
Constricts afferent band efferent arterioles leading to net increase in intraglomerular pressure

22
Q

Describe vasodilation in the kidneys

A

Mediated by prostaglandin release
Net dilation of afferent arteriole

23
Q

Describe the action valcineurin inhibitors

A

Increase renin synthesis
Decrease PGE2 and COX2
= reduced blood flow and GFR

24
Q

Describe the action of NSAIDs

A

Decrease PGE2 release

25
Q

Describe the action of Amphotericin B

A

Forms pores in membrane
= influx of Ca2+ vasoconstriction

26
Q

Describe the action of ARBs and ACE inhibitors

A

Angiotensin II synthesis decreases
Decreased intraglomerular pressure

27
Q

Describe how antibiotics affect renal cells

A

Reabsorbed into proximal tubular cells by endocytosis processes
Accumulates in lysosomes, golgi bodies and ER

28
Q

Describe how cephalosporins enter renal cells

A

Selective toxicity to proximal tubule cells
Absorbed from systemic circulation by cation/anion transporter

29
Q

Why are cephalosporins highly retained within proximal tubule cells

A

Not a substrate for effluent transporters

30
Q

What are the mechanisms of toxicity for cephalosporins on renal cells

A

Mitochondrial injury and lipid peroxidation

31
Q

What transporter takes up cephaloridine into renal cells

A

OAT1

32
Q

What is Fanconi syndrome

A

Organic solutes lost to urine
Increased Na loss
Increase H2O loss

33
Q

What happens if cisplatin is taken up by renal cells

A

Renal tubular cell death
-> renal tissue damage
-> decrease in GFR
= acute renal failure

34
Q

Why is cisplatin very nephrotoxic

A

Efficiently taken up into proximal tubule
Rate of secretion is lower

35
Q

How is cisplatin a administered in order to prevent renal failure

A

Co-administer with an uptake blocker

36
Q

Where is lithium toxicity targeted to

A

Collecting duct

37
Q

How does lithium toxicity result in porphyria

A

Competes for ADH receptor

38
Q

What can be used as a measure of renal function

A

Creatinine clearance

PED3011 Toxicology (11 decks)

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