14. Toxicity: Renal System

functional unit of the kidney

nephron

What are considered to account for over 90% of acute renal failure cases?

ischemia/reperfusion and nephrotoxicosis

What are the different ways that nephrotoxicants damage the kidneys?

1. D

2. D

3. R

4. D

5. I

1. direct injury to renal tubular epithelium, leading to epithelial cell necrosis, sloughing and obstruction of tubules by cellular debris (tubular casts)

2. detachment of lethally injured cells from the basement membrane, resulting in back leakage of filtrate across the exposed basement membrane and adherence of detached cells to sub-lethally injured cells still attached to the basement membrane causing lumen obstruction

3. renal vasoconstriction, resulting in hypoxia and ischemic necrosis of renal structures

4. damage to the glomerular filtration barrier

5. impairment of renal healing and repair

What are some clinical signs of acute renal injury and or failure?

P
N
V
L
A
W
D
P

• polydipsia

• nausea

• vomiting

• lethargy

• anorexia

• weakness

• dehydration

• polyuria/oliguria/anuria

What toxin is produced by various species of the fungi aspergillus and penicillium and are produced on a variety of cereal grain, cottonseed, nuts, dried beans, and coffee beans?

ochratoxins

What is the most common and most toxic of the ochratoxins that have been identified to date?

ochratoxin A

Ochratoxin toxicosis has been reported in what animal species?

swine, ducklings, horses, chickens, rabbits, turkeys, dogs, and fish

What species are thought to be resistant to ochratoxins? Why?

cattle; degradation of ochratoxins within the rumen, although pre-ruminant calves are susceptible

What species are considered to be the most sensitive to ochratoxin?

pigs

What are the possible MOA’s associated with ochratoxins?

I
I
D
A

• inhibitions of protein synthesis and energy production

• induction of oxidative stress

• DNA adduct formation

• apoptosis/necrosis and cell cycle arrest

Ochratoxin A is an inhibitor of what in both in vivo and in vitro models? It is verified that it can also inhibit the activity of what?

protein synthesis; phenylalanine t-RNA synthase

How do aminoglycoside antibiotics exert their nephrotoxic effects?

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

Which aminoglycoside antibiotics is the most toxic? Which is least toxic?

neomycin; kanamycin

In cats, what damage is primarily done by aminoglycoside antibiotics? What damage is secondary?

vestibular damage; renal damage

In dogs, what damage is primarily done by aminoglycoside antibiotics? What damage is secondary?

renal damage; vestibular damage

True or false: In aminoglycoside antibiotics, as the aminoglycoside concentration increases beyond the threshold level, the endosomal membranes become disrupted and the drug leaks into the cytosol where it activates the intrinsic apoptotic pathway, increases production of reactive oxygen intermediates, and interacts with mitochondria to interrupt the respiratory chain.

true

What do adverse effects of NSAIDs on the kidney result from?

the inhibition of COX which results in decreased synthesis of prostaglandins (PGs)

What is the most abundant isoform expressed in the kidneys, and is located in the renal vasculature, collecting ducts, and papillary interstitial cells?

COX-1

What is the primary impact of COX-induced inhibition of PG synthesis in the kidney?

reduction of renal blood flow, resulting in ischemia

What is the underlying mechanism of cholecalciferol?

dystrophic mineralization

When is cholecalciferol intoxication treatment possible?

if initiated prior to mineralization changes

What is the treatment for cholecalciferol toxicity?

H
L

• hormonal therapies to block Ca release from the bone and to block Ca uptake at the GI

• low Ca diet

Renal injury from pigweed has been reported in what species? How does it typically present?

pigs, cattle, and sheep; peri-renal edema and widespread degeneration of proximal and distal tubules

What is the toxic principle of pigweed?

not known

True or false: Although pigweeds do contain some oxalates and accumulate nitrates, the levels are low and the clinical syndrome and lesions caused by pigweed toxicosis are not consistent with those seen in oxalate nephrosis.

true

What is the toxic principle in amsinckia, crotolaria, cynoglossum, echium, heliotropium, senecio spp?

pyrrolizidine alkaloids

What species are predominantly affected by pyrrolizidine alkaloids?

horses, cattle, and pigs

What is the toxic principle in halogetonglomeratus, sarcobatusverniculatus, rheum rhaponicum, rumex spp, and chenopodium spp?

oxalic acid, soluble oxalates

What species are most commonly affected by oxalic acids?

ruminants and pigs

What species is most commonly affected by red maple?

horses

What does the thiaminase in bracken fern cause in horses?

hypovitaminosis B1

What does the ptaquiloside in bracken fern cause in cattle? What else can it cause?

epistaxis, melena, hemorrhage; enzootic hematuria

What is the toxic principle in lilium spp and hemerocallis spp?

consumption of any part of the plant can produce toxicity and the toxic principle has not been identified

What species are affected by lilium spp and hemerocallis spp? What has not been substantiated?

cats; renal toxicity in other species

What is the toxic dose of lilium spp and hemerocallis spp?

uncertain, but consumption of 1 or 2 leaves can induce vomiting and other early signs

What is the mechanism of toxicity of lilium spp and hemerocallis spp?

the exact mechanism is unknown but severe damage to the renal tubular epithelium and sloughing of tubular cells occurs

What has the ingestion of members of the vitis spp, including grapes, raisins, and zante currants, been associated with?

acute renal failure in dogs, cats, and ferrets

What is the toxic principle associated with the vitis spp?

tartaric acid

Affected dogs with tartaric acid generally demonstrate signs of vomiting and or diarrhea within how long?

12 hours

What common injury is associated with raisin intoxication?

necrosis of the renal tubules

What is the toxic principle in quercus spp (oak)?

tannic acid, gallic acid, and pyrogallol

True or false: All parts of the oak at all stages of growth contain these compounds.

true

What species are most commonly affected by oak? In which is it more rare in?

cattle; horses, goats, and sheep

True or false: The toxic compounds assocaited with oak are readily absorbed from the GI. The flora in the rumen can remove small amounts of tannic acid and the goat apparently has tannin binding proteins in its saliva to further detoxify tannic acids. Salts are quickly absorbed from the GI.

true

What is the mechanism of toxicity of oak?

react with cell proteins to denature them, with resulting cell death

Where do the most severe lesions occur with oak intoxication?

kidneys, liver, and digestive tract

What is the most common cause of ethylene glycol toxicosis in domestic animals? Which species are most commonly affected?

consumption of automotive antifreeze; dogs and cats, although all mammals are susceptible

What are the steps in which ethylene glycol causes damage?

1. I

2. P

3. A

1. initial CNS depression and derangement due to an alcohol-like effect on the brain

2. profound metabolic acidosis with significant cardiorespiratory effects due to formation of acidic metabolites of ethylene glycol

3. acute renal failure due to renal tubular injury

When can crystals due to ethylene glycol be found in dogs? What about cats?

6 hours post ingestion; sooner in cats

What is the first stage of ethylene glycol toxicosis? When does it occur?

CNS stage; 30 minutes to 12 hours

What symptoms are seen in the CNS stage?

C
V
P

• CNS signs

• vomiting

• PU/PD

What is the second stage of ethylene glycol toxicosis? When does it occur?

acidosis phase; 8 hours on

What are the clinical signs seen in the acidosis phase?

V
D
A
W
C

• vomiting

• depression

• anorexia

• weakness

• coma

What is the third stage of ethylene glycol toxicosis? When does it ocur?

renal failure stage; 24 hours or sooner in cats

What are the clinical signs seen in the renal failure stage?

V
A
A
A
A
C

• vomiting

• anorexia

• abdominal pain

• azotemia

• anuria

• crystalluria