Kidney Toxicity

Question 1

What is the role of the kidney

Answer 1

Excretion of wastes
Regulation of body homeostasis

Question 2

Describe the kidney anatomy

Answer 2

Cortex, medulla, papilla

7 lobes structure

Question 3

Why is the kidney susceptible to toxicity

Answer 3

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

Question 4

What are the toxic effects experienced in the glomerulus

Answer 4

Inflammatory response
Immune complexes
Blockages

Question 5

What xenobiotics damage the proximal tubule

Answer 5

Antineoplastics
Halogenated hydrocarbons
Heavy metals
Antibiotics

Question 6

What areas does amphotericin affect

Answer 6

Loop on Henle and distal tubule

Question 7

What xenobiotics affect renal haemodynamics

Answer 7

Calcineurin inhibitors
NSAIDs
ACE inhibitors
ARBS

Question 8

Describe the heavy metal mercury

Answer 8

Elemental environmental pollutant
Reduce Na+ reabsorption in Loop of Henle

Question 9

Where does Hg+ act on the kidney

Answer 9

Selective to pars recta proximal tubular epithelial cells

Question 10

How does Hg reach the kidney

Answer 10

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

Question 11

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

Answer 11

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

Question 12

Describe acute and severe Hg toxicity in the kidney

Answer 12

Acute: cellular necrosis in pars recta
Severe: tubular necrosis

Question 13

How is cadmium excreted

Answer 13

Metallothionein complex

Question 14

What is the role of metallothionein in the body

Answer 14

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

Question 15

How does Cd toxicity happen

Answer 15

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

Question 16

What is the mechanism of toxicity of haloalkanes

Answer 16

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

Question 17

What pathway are haloalkenes bioactivated by

Answer 17

Cysteine conjugate B lyase pathway

Question 18

Describe cysteine S conjugate B lyases

Answer 18

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

Question 19

Describe the B lyase pathway

Answer 19

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

Question 20

How is the glomerular filtration rate controlled

Answer 20

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

Question 21

Describe vasoconstriction in the kidneys

Answer 21

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

Question 22

Describe vasodilation in the kidneys

Answer 22

Mediated by prostaglandin release
Net dilation of afferent arteriole

Question 23

Describe the action valcineurin inhibitors

Answer 23

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

Question 24

Describe the action of NSAIDs

Answer 24

Decrease PGE2 release

Question 25

Describe the action of Amphotericin B

Answer 25

Forms pores in membrane = influx of Ca2+ vasoconstriction

Question 26

Describe the action of ARBs and ACE inhibitors

Answer 26

Angiotensin II synthesis decreases Decreased intraglomerular pressure

Question 27

Describe how antibiotics affect renal cells

Answer 27

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

Question 28

Describe how cephalosporins enter renal cells

Answer 28

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

Question 29

Why are cephalosporins highly retained within proximal tubule cells

Answer 29

Not a substrate for effluent transporters

Question 30

What are the mechanisms of toxicity for cephalosporins on renal cells

Answer 30

Mitochondrial injury and lipid peroxidation

Question 31

What transporter takes up cephaloridine into renal cells

Answer 31

OAT1

Question 32

What is Fanconi syndrome

Answer 32

Organic solutes lost to urine Increased Na loss Increase H2O loss

Question 33

What happens if cisplatin is taken up by renal cells

Answer 33

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

Question 34

Why is cisplatin very nephrotoxic

Answer 34

Efficiently taken up into proximal tubule Rate of secretion is lower

Question 35

How is cisplatin a administered in order to prevent renal failure

Answer 35

Co-administer with an uptake blocker

Question 36

Where is lithium toxicity targeted to

Answer 36

Collecting duct

Question 37

How does lithium toxicity result in porphyria

Answer 37

Competes for ADH receptor

Question 38

What can be used as a measure of renal function

Answer 38

Creatinine clearance