Nephrotoxicity Flashcards
NSAIDs
Toxicity results from high dose or long-term NSAID usage and can be seen with aspirin, ibuprofen, naproxen and indomethacin.
NSAIDs inhibit prostaglandin synthase, so production of the vasodilators PGE2 and PGI2 is impaired and vasoconstrictor influences of catecholamines and Ang II predominate.
NSAID toxicity causes decreased renal blood flow and reduced GFR with oliguria (low urine output).
Kidney damage is characterised by papillary necrosis and interstitial nephritis, both secondary to renal vasoconstriction and reduced glomerular filtration rate
Raised creatinine and blood urea nitrogen (BUN) are seen.
Oxalic acid
Ethylene glycol may be metabolised to oxalic acid. This is also naturally found in rhubarb.
Ethylene glycol is the main component of antifreeze and found in some non-EU wines. It is metabolised by alcohol dehydrogenase to glycolaldehyde.
This is then converted by aldehyde dehydrogenase to glycolate and on to oxalic acid.
Calcium oxalate forms of oxalic acid crystalise in renal tubules, which leads on to nephritis, fibrosis and tubular atrophy.
Symptoms of toxicity include metabolic acidosis, elevated BUN, and increased creatinine.
4-methyl pyrazole, an inhibitor of alcohol dehydrogenase, can prevent the toxicity of ethylene glycol, if administered in time. Sodium thiosulphate, which reduces formation of kidney stones, may be a beneficial treatment.
Cadmium (Cd2+)
Cd2+ and other heavy metals have a high affinity for sulfhydryl (SH) groups including glutathione and the inducible SH-rich protein metallothionein (MT).
Once internalised, cadmium is taken up by liver hepatocytes, where the MT protein is increased.
The Cd-MT complex is filtered and taken up by proximal epithelial cells in the kidney.
Cadmium accumulates in epithelial cells of the proximal tubule, leading to polyuria and appearance of the protein albumin in urine.
Cd-MT can also dissociate, releasing cadmium and delivering it back to the liver to start the process again.
Chloroform (CHCl3)
Chloroform is a heavy, colourless, volatile liquid with a strong odour and sweet, burning taste.
Halogenated hydrocarbons are used extensively as chemical intermediates, solvents, and pesticides.
The primary cellular target of chloroform is the proximal tubule of the nephron, but it is also hepatotoxic.
Proteinuria, glucose in urine and increased BUN levels are seen.
CYP450s lead to formation of a reactive intermediate, phosgene. This binds covalently to nucleophilic groups on cellular macromolecules, causing toxicity. CYPs are found in both the liver and the kidney.
Other halogenated solvents are also nephrotoxic.
Trichloroethylene causes nephrotoxicity via toxic cysteine conjugates. It initially conjugated with glutathione, which normally detoxifies compounds, but this is then chopped up to a cysteine residue.
1,2-dichloroethane produces a sulphur half mustard in a similar reaction.
Aminoglycosides (gentamicin)
Aminoglycosides include antibiotics, such as gentamicin, used against gram-negative bacteria.
Cause acute proximal tubule necrosis and renal failure - non-oliguric renal failure (urine output of less than 1ml/kg/hr) with reduced GFR and an increase in serum creatinine and BUN.
Gentamicin is filtered in the glomerulus and enters the tubular lumen.
It is taken up by proximal tubular cells and it then fuses with lysosomes, destabilising them and causing them to rupture and release their hydrolytic enzymes, which cause damage within the cell.
Gentamicin can also directly damage mitochondria.
There is a complete failure of urine production
When prescribing aminoglycoside antibiotics, clinicians carefully monitor renal function.
Polyaspartic acid helps reduce toxicity by preventing the binding of aminoglycosides to negatively charged phospholipids and so cell entry.
Cidofovir
Antiviral drug that causes renal injury through proximal tubular apoptosis.
Probenecid can be used to reduce renal toxicity. It inhibits the OAT-1 transporter and therefore uptake into the kidney.
