Target organ toxicity - Nephrotoxicity Flashcards
What is the kidneys function?
To filter waste products and toxins out of the blood while conserving essential substances such as glucose, amino acids, and ions such as sodium
Why is the kidney a target organ?
- Renal Blood Flow
- The concentrating ability of the kidney
- Active transport of compounds by the tubular cells
- Metabolic activation
Which biomarkers are there for for detecting kidney injury?
1) serum creatinine:
May result in a very delayed signal even after considerable renal injury
2) blood urea nitrogen (BUN)
Old school
3) Proteinuria
Presence of:
- Small proteins (Mw < 500000 in the urine indicates insufficient reuptake in proximal tubules.
- Large proteins indicate damage to the glomerular membrane
What is the mechanism behind nephrotoxicity?
1) as the filtrate moves along the nephron –> components can be concentrated to 3 fold in proximal tubuli even > 100 fold in distal tubuli and collecting duct
2) presence of both luminal and basolateral uptake mechanism enhance intracellular concentration
3) biotransformation of drugs to toxic metabolites also potentiates toxicity to tubular epithelial cells
(i.e. N-acetyltransferases, sulfotransferases, and gluthathione transferases, cytochrome P-450 (CYP) and UDP-glucoronosyltransferases UGT)
4) the counter current exchange function of the medullary vasculature can cause accumulation of nephrotoxins in the medulla and kidney papils
5) hypoxia of the medulla increases the susceptibility of tubular cells to toxicants by toxin-induced oxygen consumption
What systemic factors can be affected by kidney injury?
- Acid-base balance (regulation of pH)
- Fluid balance (ECV and BP)
- Electrolyte balance (K+, Na+, Mg++, Ca++, PO4—)
- Elimination of waste products (Creatinin, urea, urea acid, Urobilinogen, xenobiotics)
- Synthesis of components (Cardiovascular, Haematologic and skeletal, and muscle homeostasis as well as i.e. Renin, erythropoietin (EPO), vitamin D)
How are sulphonamides nephrotoxic?
Toxic effect due to 2) the concentrating ability of the kidney
Mechanism:
1) Sulphonamide is accumulated in the tubular fluid, where it is non-charged (not excreted.
2) Sulphonamide is then acetylated to its metabolite in the tubular lumen, where it has a low solubility.
3) Formation of crystals due to low solubility
Toxic effect: necrosis of tubular cells (irritant effect) –> kidney failure
How is ethylene glycol nephrotoxic?
Toxic effect due to 2) the concentrating ability
Mechanism:
Ingestion of high dose ethylene glycol –> formation of oxalate crystals in renal tubules (irritant effect) –> Kidney failure
How is asperin nephrotoxic?
Toxic effect due to 4) metabolic activation
Effect: Aspirin-induced medullary lesions
Mechanism:
Aspirin –> inhibit PG (prostaglandin) synthesis –> vasoconstriction of vasa recta –> reduction of blood flow –> hypoxia –> ischemia
How is gentamycin nephrotoxic?
Toxic effect due to 3) active transport by the tubular cells
Toxic mechanism of Gentamycin:
1) As a cationic aminoglycoside with 5 amino groups it binds to anionic phospholipids on the brush border of the proximal tubular cell
2) The bound aminoglycoside is engulfed by endocytosis in to proximal tubules cell as vesicles –> secondary lysosomes –> cell suffer –> necrosis
3) Accumulation of gentamycin in lysosomes brings tubular intracellular concentration to 10-100 times that in plasma
4) Aminoglycoside inhibits phospholipase action
How is gentamycin ototoxic?
Accumulation of gentamycin in peri and endolymph of the inner ear –> irreversible ototoxic effect –> deaf
How is cephaloridine nephrotoxic
Toxicity due to 3) active transport of compounds by the tubular cells
Mechanism:
1) Active uptake from the blood by OAT1 into the proximal tubulus cells
2) Secreted by OCT into the tubular lumen
OAT1 is more active than the secretion system (OCT) –> active accumulation!
Accumulates in the kidney, especially cortex, and acutely causes:
o Dose-related proximal tubular necrosis
o Selective damage to the S2 segment of the tubule
How are haloalkanes nephrotoxic?
Toxicity due to 4) metabolic activation
Target: brush border of the proximal tubule
Mechanism: Dependent on enterohepatic circulation
It can be metabolized to a reactive thiol, which in the end can lead to ATP depletion
How is cadmium nephrotoxic?
Absorption through inhalation.
Chronic exposure –> accumulation due to T1/2 being 7-30 years
After glomerular filtration the complex is:
1) Reabsorbed in the tubules cells
2) Degraded in lysosomes
3) Free cadmium ion interferes with the mitochondria transport chain generating semiubiquinone –> superoxide –> degeneration and kidney fibrosis
How is lead (Pb2+) nephrotoxic?
It can lead to the formation of superoxide which can lead to kidney fibrosis
