Lecture 14: Renal Toxicity

Ischemia/reperfusion and _________ are considered to account for over 90% of acute renal failure cases.

nephrotoxicosis

What are the 5 ways nephrotoxicants can damage the kidneys?

1. direct injury to renal tubular epithelium

2. detachment of lethally injured cells from basement membrane → leakage, lumen obstruction

3. renal vasoconstriction → hypoxia and ischemia

4. damage to glomerular filtration barrier

5. impairment of renal healing and repair

What type of mycotoxin is produced by various species of fungi Aspergillus and Penicillium and are produced on a variety of cereal grains, cottonseed, nuts, dried beans, and coffee beans?

ochratoxin

What is the most common ochratoxin?

ochratoxin A (OTA)

What species is though to be resistant to ochratoxin due to GI degradation?

cattle

What species is the most sensitive to ochratoxin?

pigs

What is the MOA of ochratoxin?

• inhibition of protein synthesis and energy production

• induction of oxidative stress

• DNA adduct formation

• apoptosis/necrosis and cell cycle arrest

What enzyme does OTA inhibit?

phenylalanine t-RNA synthase → inhibits protein synthesis

How do aminoglycoside antibiotics exert their nephrotoxic effects?

through apoptosis and necrosis within the renal tubular epithelial cells of the proximal convoluted tubule, distal tubules, and collecting ducts

What aminoglycoside antibiotic has the most nephrotoxic effects?

neomycin

What is the MOA of aminoglycoside antibiotics?

concentration increases beyond threshold → endosomal membranse become disrupted → drug leaks into cytosol → activates intrinsic apoptotic pathway → increases production of reactive oxygen intermediates and interacts with mitochondria to interrupt the respiratory chain

How do NSAIDs have nephrotoxic effects?

prostaglandin synthesis inhibition → renal afferent arteriole vasoconstriction → reduction of renal blood flow → ischemia

What is the underlying mechanism of cholcalciferol?

dystrophic mineralization

What are the tx options for cholecalciferol toxicity?

hormonal therapies to block Ca release from bone, block Ca uptake at GI and a low Ca diet

What toxicity typically presents with peri-renal edema and widespread degeneration of proximal and distal tubules in pigs, cattle, and sheep?

redroot pigweed (amaranthus spp.)

What nephrotoxic effect is seen after ingesting pyrrolizidine alkaloids?

tubular degeneration and necrosis, megalocytosis of tubular globerular cells

Rhubarb, lambs quarter, and dock are examples of what type of nephrotoxicity?

oxalic acid, soluble oxalates

What is the MOA of oxalic acid toxicity?

• tubular degeneration and necrosis

• intra-tubular calcium oxalate crystals

• precipitation of soluble oxalates with serum calcium

• hypocalcemic tetany possible

What nephrotoxic plant causes acute tubular degeneration and necrosis and hemoglobin casts in tubules in horses?

acer rubrum (red maple)

What are the two toxic principles of bracken fern and what symptoms do they cause respectively?

thiaminase: hypovitaminosis B1 (horses)

ptaquiloside: epistaxis, melena, hemorrhage (cattle), enzootic hematuria

What species is affects by lilium spp.?

cats

What is the MOA of lily toxicity?

severe damage to renal tubular epithelium and sloughing of tubular cells, polyuric renal failure, dehydration

What is the toxic principle of vitis spp. (grapes)?

tartaric acid

What is the MOA of grape toxicity?

necrosis of renal tubules, elevated serum calcium and phosphorus → accumulation of gold pigment in tubular lumen

What are the toxic principles of Quercus spp. (oak)?

tannic acid, gallic acid, pyrogallol

What is the MOA of oak toxicity?

compounds react with cell proteins to denature them → cell death

What are the steps of ethylene glycol toxicosis (antifreeze)?

1. CNS phase: early stage, 20 min to 12 hr

2. Acidosis phase: from 8 hrs on - vomiting, depression, anorexia, weakness, coma

3. Renal failure phase: 24 hr on (sooner in cats) - vomiting, anorexia, abdominal pain, azotemia, anuria, crystalluria

What can be found in dogs after about 6 hours post ethylene glycol ingestion and even sooner in cats?

crystals