Nephrotoxicology Flashcards
key functions of the kidneys
to filter plasma, removing small MW ions and proteins (30-50 kDa)
Reabsorption of solutes and glucose occurs in the proximal tubules
Loop of hence reabsorbs slat and water
in the distal tubules and collecting duct there is reabsorption of water and active secretion of creatinine.
Measures of kidney function and biomarkers
Electrolyte imbalances and urine volume as well as raised [blood urea nitrogen]
Presence of high [albumin] indicates leaky glomerulus and general kidney injury.
myoglobin presence indicating renal damage due to rhabdomyolysis
ALP and GGT are enzymes that are biomarkers for renal damage.
Kim-1 is a selective biomarker for proximal tubule injury
GFR as a measure of kidney function
a reduced GFR is also an indicator of renal damage, calculated from blood and urine [creatinine]
Inulin is another clearance measure for GFR as creatinine is also secreted during normal function
Cystatin C is a small protein that can also be used to measure GFR.
mechanisms of kidney injury and treatment of renal failure
pre renal: vasoconstriction or reduced blood flow (reduced CO), or hypovolemic shock
intrarenal: nephritis or leakage
Post-renal: obstruction
dialysis or transplant needed for failure.
examples of region specific kidney injury
renal injury is normally region specific
glomerular: oligonucleotide therapy causing nephritis inflammation while cyclosporine and amino glycoside cause injury
proximal tubular injury from penicillin, cadmium, ochratoxin, cephaloridine
loop of hence and collecting ducts injury from cisplatin, fluoride, amphotericin b
papilla (opening of collecting duct to ureter) injury from NSAIDs
mechanisms of NSAID renal injury
can be acute or chronic.
inhibition of PGE2 and PGI2 production leads to renal vasoconstriction, decreasing renal blood flow and GFR
Injury characterised by necrosis and interstitial nephritis
marked by raised creatinine and blood urea nitrogen
mechanism of ethylene glycol and oxalic acid
ethylene glycol (antifreeze) is metabolised (by ADH) into oxalic acid (also found in rhubarb)
oxalic acid leads to crystallisation in the kidney causing nephritis, fibrosis and tubular atrophy
marked by metabolic acidosis and elevated [blood urea nitrogen] and [creatinine]
ADH inhibitor 4-methyl pyrazole can prevent toxicity if administered early
renal injury from cadmium
has relatively high affinity for glutathione and metallothionein
cadmium moves from the liver where it complexes with metallothionein to the kidney where it then dissociates
ends up accumulating in the proximal tubule causing polyuria and albumin presence in urine
this explains the 6-38 years half-life
chloroform renal toxicity mechanism and other halogenated solvent examples
hepatotoxic and toxic to proximal tubule
possibly through the formation of a reactive metabolite by CYP enzymes which binds covalently to cellular macromolecules. also carcinogenic
causes proteinuria, glucose in urine and increase blood urea nitrogen levels
trichloroethylene and 1,20dichloroethane are nephrotoxic through the production of toxic cysteine conjugates
Gentamycin toxicity mechanism
an antibiotic that causes proximal tubular necrosis and renal failure
marked by reduced GFR and increased creatinine and blood urea nitrogen levels
mechanism through fusing with lysosomes, causing them to rupture releasing hydrolytic enzymes that damage the cells.
can also cause mitochondrial damage directly
other examples of renal toxins
ACE inhibitors
glyphosate (herbicide)
cephaloridine
cisplatin
lithium and gold salts
penicilamine (anti-heavy metal drug)
