Kidney Toxicity Flashcards
What is the role of the kidney
Excretion of wastes
Regulation of body homeostasis
Describe the kidney anatomy
Cortex, medulla, papilla
7 lobes structure
Why is the kidney susceptible to toxicity
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
What are the toxic effects experienced in the glomerulus
Inflammatory response
Immune complexes
Blockages
What xenobiotics damage the proximal tubule
Antineoplastics
Halogenated hydrocarbons
Heavy metals
Antibiotics
What areas does amphotericin affect
Loop on Henle and distal tubule
What xenobiotics affect renal haemodynamics
Calcineurin inhibitors
NSAIDs
ACE inhibitors
ARBS
Describe the heavy metal mercury
Elemental environmental pollutant
Reduce Na+ reabsorption in Loop of Henle
Where does Hg+ act on the kidney
Selective to pars recta proximal tubular epithelial cells
How does Hg reach the kidney
Conjugated with GSH -> GS-HG-SG
Translocation to kidney in systemic circulation
Uptake into proximal tubule cell from tubular fluid
What happens when GS-HG-SG reaches the proximal tubule cell
Hg2+ is released and combines with SH on proteins
Depletes GSH = to mitochondrial stress
Inhibits membrane bound enzymes
Describe acute and severe Hg toxicity in the kidney
Acute: cellular necrosis in pars recta
Severe: tubular necrosis
How is cadmium excreted
Metallothionein complex
What is the role of metallothionein in the body
Synthesised in liver to protect tissues from Cd
Large number of SH groups
How does Cd toxicity happen
Cd-MT complex taken up by renal proximal tubule cell
Complex broken down by lysosomal enzymes
= free Cd that bind to Sh groups
What is the mechanism of toxicity of haloalkanes
Activated to toxic metabolites by mixed function oxidases
Carried in blood from liver to kidney
What pathway are haloalkenes bioactivated by
Cysteine conjugate B lyase pathway
Describe cysteine S conjugate B lyases
Found in kidney and other tissues
Require pyridoxal-5-phosphate and a-keto acid
Divert cysteine conjugates from mercapturate formation
Describe the B lyase pathway
Xenobitoic (+GSH) -> GSH- Conjugate (+yGT+AP) -> Cysteine conjugate (Cys conjugate B-lyase)-> Thioketene
How is the glomerular filtration rate controlled
Pressure maintained by control of blood flow to and from glomerulus
Via vasoconstriction and vasodilation
Describe vasoconstriction in the kidneys
Mediated by Renin-Angiotensin system
Constricts afferent band efferent arterioles leading to net increase in intraglomerular pressure
Describe vasodilation in the kidneys
Mediated by prostaglandin release
Net dilation of afferent arteriole
Describe the action valcineurin inhibitors
Increase renin synthesis
Decrease PGE2 and COX2
= reduced blood flow and GFR
Describe the action of NSAIDs
Decrease PGE2 release
Describe the action of Amphotericin B
Forms pores in membrane
= influx of Ca2+ vasoconstriction
Describe the action of ARBs and ACE inhibitors
Angiotensin II synthesis decreases
Decreased intraglomerular pressure
Describe how antibiotics affect renal cells
Reabsorbed into proximal tubular cells by endocytosis processes
Accumulates in lysosomes, golgi bodies and ER
Describe how cephalosporins enter renal cells
Selective toxicity to proximal tubule cells
Absorbed from systemic circulation by cation/anion transporter
Why are cephalosporins highly retained within proximal tubule cells
Not a substrate for effluent transporters
What are the mechanisms of toxicity for cephalosporins on renal cells
Mitochondrial injury and lipid peroxidation
What transporter takes up cephaloridine into renal cells
OAT1
What is Fanconi syndrome
Organic solutes lost to urine
Increased Na loss
Increase H2O loss
What happens if cisplatin is taken up by renal cells
Renal tubular cell death
-> renal tissue damage
-> decrease in GFR
= acute renal failure
Why is cisplatin very nephrotoxic
Efficiently taken up into proximal tubule
Rate of secretion is lower
How is cisplatin a administered in order to prevent renal failure
Co-administer with an uptake blocker
Where is lithium toxicity targeted to
Collecting duct
How does lithium toxicity result in porphyria
Competes for ADH receptor
What can be used as a measure of renal function
Creatinine clearance
