Renal Toxicology

Xenobiotics excreted in urine via kidney, but can be reabsorbed and concentrated

different areas of the kidney may be effected by different chemicals and mechanisms

ultrafiltrate filtered out of blood in nephron, reabsorbed in proximal tubule and this is where toxicity occurs

Screening for damage

Has vol of urine changed from normal

Has pH of blood or urine changed

creatinine levels in urine (normally constant due to muscle breakdown)

Glucose presence in urine - could be diabetes or proximal tubule not reabsorbing

electrolyte levels

enzymes in urine

Histology

specific proteins

blood creatinine (due to lack of excretion) - creatinine clearance rate, if differed indicates problem with glomerulus.

blood urea nitrogen. if increased levels may harm kidneys

several factors needed to be determining

Reabsorption

Proximal convoluted tubule reabsorbs 60-80% of water and other materials such as glucose

PCT is most common site of toxin induced renal injury due to leaky epithelium

Can mistakenly reabsorb metals and GSH conjugates

P450 activity in kidney may bioactivate chemicals

Glomerular filtration toxins concentrated here

Major target organ for toxicity

Gentamycin causes toxicity in PCT - acute pct necrosis in 10% people

Reabsorbed at PCT, then binds to negatively charged phospholipids on luminal side of cell

endocytosis of the drug produces endosomes - lysosomes. reoccurs so high conc in lysosomes

[Gentamycin] in these cells can be 10-100x more conc than blood. 5-6 days half life in cell in kidney

Binding to phospholipids alters membrane composition and leads to influx of calcium into the cell which can cause 1,2 or 3 toxicity.

Can be absorbed into cell and directly interact with mitochondria.

accumulation in lysosomes which ruptures it with dangerous enzymes

Cephloradine

Taken into PCT cell by organic anion transporter 1

inhibiting the pumps allows detection of problem

organic cation transporter allows excretion

intake pump inhibited by probenecid

OCT inhibited by mepiphenidol which increases toxicity

OAT1 inhibitor decreases toxicity therfore OAT1 causes toxicity as it is faster acting

Secondary

Tertiary

Primary

Cell can survive lipid peroxidation
NAPQI covalently binding to proteins

Thiol - Glutathione (GSH) contains thiol group
Thiol group allows binding of toxin instead of to proteins. Removes hydrogen

When GSH runs out, N-aetylcysteine is used as a replacement via antidote

Also contains thiol group and can help make GSH (antioxidant)

Reduces levels of primary toxification

Steatosis - fatty acid droplets in liver

Changes in cytoskeleton results in Ca2+ entering the cell

mitochondrial damage electron transport chain takes place but no atp is produced and Ca2+ is realeased

10K fold difference in [Ca2+] inside and outside the cell

Increase in Ca2+ in cell:
degrades cytoskeleton
activates phospholipases which breakdown mitochondrial membranes, proteases degrading proteins
endonucleases degrading DNA.

Decreases ATP production. Activates apoptosis pathways. increases ROS generation

Blebbing - blisters on plasma membrane

Necrosis - uncontrolled chaotic cell death