Renal and Hepatic Toxicity Flashcards
Why is the kidney a common site of toxicity?
- Very high blood flow (22-25% cardiac output)
- Concentration of compounds
- Most important organ for the excretion of xenobiotics
- mainly dependent on the water solubility of the toxicant
- highly lipid soluble are reabsorbed across the tubular cells into the bloodstream again
proximal convoluted tubules
Most common site of toxin induced injury
Why are the proximal convoluted tubules the most common site of toxin induces injury?
- Cytochrome P450 and cysteine conjugate B-lyase localize here
- Bioactivation result in damage
- Loose epithelium allow compounds to enter cells
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Increased transport of anions, cations and heavy metals
- accumulation and ischemic injury to epithelial cells
acute renal failure
- Characterized by decreased GFR and renal azotemia
- Caused by transient damage to tubule, glomerulus or vasculature.
- Signs are vomiting, GI bleeding, PU/PD progressing to anuria, diarrhea, and tremors
chronic renal failure
- Mostly related to pathological changes triggered by initial injury
- Secondary changes are compensatory mechanisms
- Signs are primarily edema, hypocalcemia and parathyroid activity, reduced RBC counts
action of parathyroid gland
mobilizes Ca
action of calcitonin
puts calcium back into bone
ethylene glycol
- major ingredient in antifreeze
- 2nd most common cause of fatal poisoning in animals
- Most frequently used for malicious poisoning
- Mostly exposed in Spring and Fall
- Very high rate of lethality (80% +) due to delay in clinical signs
ethylene glycol toxicity
- taste sweet to animals, so they like
- Lethal dose in cats: 1.5ml/kg of undiluted antifreeze or about 1 tbsp of 50:50 antifreeze:water
- Lethal dose in dogs is higher: 7ml/kg of undiluted antifreeze or 4.5 oz of 50% antifreeze
MOA of ethylene glycol
- Major toxic agents are metabolites produced by action of alcohol dehydrogenase
- glycolic acid
- glyoxylic acid
- oxalate/oxalic acid
What does glycolic acid cause?
acidosis
What does glyoxylic acid cause?
CNS signs
What does oxalate/oxalic acid cause?
Renal damage and hypocalcemia by binding to calcium to form calcium oxalate
Stage 1 clinical signs of ethylene glycol
- 30 mins to 3 hours
- “drunkenness”, ataxia, CNS depression
- nausea, vomiting
- PU/PD (dogs)
- usually missed with unobserved ingestions
Stage 2 clinical signs of ethylene glycol
- 12-24 hour
- Tachypnea, tachycardia (or bradycardia)
- often not severe and not recognized by owner
- cats typically remain depressed
Stage 3 clinical signs of ethylene glycol
- 12-72 hours
- Most animals present at this stage
- Polyuria progressing to oliguria and anuria
- Lethargy, anorexia, vomiting, seizures
- Oral ulcers, abdominal pain, dehydration, and enlarged kidneys
best method to diagnose ethylene glycol toxicity
- Measuring EG concentration in blood
- serum conc. peak in 1-6 hours
- non-detectable in serum and urine by 24 hours
- cats can be poisoned by levels below detection of many kits
other ways to diagnose ethylene glycol toxicity
- Azotemia
- Elevated BUN and creatinine in Stage 3
- UA: low USG (1.008-1.012) crystalluria (w/in 6 hours)
- Calcium oxalate crystals in kidney via ultrasound exam
- Serum biochem profile: hyperglycemia, hypocalcemia
- Anion and osmolal gap
how to measure anion gap
- (Na+K) - (HCO3 + Cl)
- anion gap >30 abnormal
- osmolal gap >20 abnormal
tx of ethylene glycol toxicity
- Prevent formation of toxic metabolites
- Achieved through admin of competitive inhibitors of alcohol dehydrogenase
- 20% ethanol and NaHCO3 (traditional tx)
- Fomepizole (4-MP) or Antizol
-
No benefit of giving ethanol or 4-MP if EG has already been metabolized
- contraindicated in animals with renal failure
why is sodium bicarbonate given with ethanol?
fix the metabolic acidosis
why is decontamination with charcoal not a treatment for EG toxicity?
EG does not bind to charcoal
prognosis of cats with EG poisoning
- Peak plasma concentrations occur about 1 hour after ingestion
- Survival highly dependent on treatment within 1st 3-4 hours
- mortality rate at least 90%
prognosis of dogs with EG poisoning
- Peak plasma concentration occurs at 2-3 hours
- Survival most likely if treatment is started within 6-8 hours of ingestion
- Azotemia on admission offers slim survival chance
- Renal failure indicates poor prognosis
duration of therapy for animals with EG toxicity
- Therapy often required up to 72 hours
- Recovery can take 3-5 days if treated aggressively
cholecalciferol/Vitamin D3 toxicity
- Overdosage of vitamin supplements or exposure to rodenticide
- Toxic at > 0.5 mg/kg, lethal around 10-15 mg/kg
- Dogs and cats most affected
- Less toxic than Warfarin
MOA of cholecalciferol
- Metabolized to 1,25-dihydroxycholecalciferol
- Causes massive increase in serum calcium by:
- increasing GI absorption
- decreasing renal excretion
- increasing synthesis of calcium binding protein
- mobilizing bone calcium
clinical signs of cholecalciferol toxicity
- typically appear 36-48 hours
- Anorexia, weakness, depression (non-descript signs)
- Thirst and polyuria (PU/PD)
- Calciuria
- diarrhea, dark feces due to intestinal bleeding, vomiting
- Hypertension, bradycardia, ventricular arrhythmia
- Mineralization of tissues when Ca*P > 70 mg/L
diagnosis of cholecalciferol toxicity
- Diagnosis based on history of ingestion, clinical signs, and hypercalcemia
- Most common finding is rapid increase in plasma P (>8 mg/dL) followed by increase in plasma Ca levels (>13 mg/dL)
- Low PTH (stimulates release of Ca from bone)
- Increased BUN and creatinine
- Low USG with calciuria
- High hydroxycholecalciferol level in bile and kidney
differential diagnosis to cholecalciferol toxicity
- Histological findings include mineralization in multiple organs (heart, pancreas, kidney, lung, stomach)
-
Ethylene Glycol
- elevated kidney Ca 2000-3000pppm, EG >8000 ppm
- Ca:P ratio in kidney 0.4:0.7, EG >2.5
- Differentiate from paraneoplastic syndrome, juvenile hypercalcemia, and hyperparathyroidism
treatment of cholecalciferol
- Reduce dietary Ca and P
- GI decontamination within 6-8 hours (usually too late)
- Monitor serum Ca from admission and every 1-2 days
-
Normal saline and furosemide
- promotes Ca excretion
-
Prednisolone (2-6 mg/kg)
- reduce bone resorption, intestinal Ca absorption, and kidney Ca resorption
-
Calcitonin
- side effects of anorexia, anaphylaxis, and emesis, inhibits bone resorption
- Pamidronate can replace calcitonin but $$
- Sucralfate or milk of magnesia for ulceration (also reduce P)
grape and raisin toxicity
grapes, grape skin, and raisins can cause acute renal failure in some dogs
MOA of grape toxicity
- Unknown
- Lack of dose response seen
- No relationship between dose ingested in dogs that died and those that survived
clinical signs of grape toxicity
- Initial signs is usually vomiting followed by signs of acute renal failure:
- hypercalcemia
- hyperphosphatemia
- increased Ca x PO4
- elevated BUN and serum creatinine
diagnosis of grape toxicity
based on clinical signs of acute renal failure and known ingestion
treatment of grape toxicity
- Recommend to treat following any ingestion of grapes at all
-
Emesis, lavage, activated charcoal for recent ingestion
- one method not recommended over another
- Fluid therapy for a min of 72 hours
-
Supportive therapy including:
- furosemide
- dopamine, mannitol, hemodialysis, or peritoneal dialysis
how does dopamine help treat grape toxicity?
facilitates kidney function and renal blood flow
main goal of treating a grape toxicity?
keep the kidney working!
general liver toxicosis
- The liver has a remarkable ability to regenerate itself because it is the first line of defense
- Intrinsic injury may lead to steatosis, necrosis, cholestasis
- occurs as dose-dependent reaction to a toxicant
- often caused by a reactive product of xenobiotic metabolism
acetaminophin toxicity
- One of the most common causes of poisoning in both humans and animals
- Metabolized in the liver by glucuronidation, sulphonation and oxidation pathways
- oxidation pathway results in the highly reactive metabolite NAPQI (N-acetyl-p-benzoquinone imine)
- Cats are extremely sensitive due to lack of glucouronidation (as low as 10 mg/kg)
MOA of acetaminophen
- Toxic effects due to formation of the metabolite NAPQI
- when glutathione stores are depleted, NAPQI binds to macromolecules and proteins and causes:
- liver tissue necrosis
- increased methemoglobin
- when glutathione stores are depleted, NAPQI binds to macromolecules and proteins and causes:
-
Erythrocyte injury is predominant problem in cats
- methemoglobin and Heinz body production (present with anemia)
- Hepatic effects dominate in dogs, mice, rats
clinical signs of acetaminophen toxicity
- characterized by methemoglobinemia and hepatotoxicity
- usually accompanied by tachycardia, hyperpnea, weakness, and lethargy
- Cats primarily develop methemogloninemia within a few hours, followed by Heinz body formation
-
Liver necrosis (dogs)
- liver damage 24-36 hours after ingestion
- centrilobar hepatocyte degeneration and necrosis
diagnosis of acetaminophen toxicity in cats
- Cyanosis, methemoglobinemia, dyspnea, weakness and depression, edema of paws and face
- anemia present in 75% of cats
diagnosis of acetaminophen toxicity in dogs
- Signs associated with acute centrilobar hepatic necrosis
- nausea, vomiting, anorexia, abdominal pain, shock, tachypnea, tachycardia
other possible clinical signs of acetaminophen toxicity that could be diagnostic
- Hemolysis
- Heinz body in cats and dogs stained with NMB
- elevated liver enzymes
treatment of acetaminophen toxicity
- Replace glutathione stores, increase productivity of the other 2 pathways, and manage the hematological signs
- Early decontamination only if very recent
- Give glutathione precursor N-acetylcysteine (NAC)
- loading dose is 140 mg/kg via slow IV
- follow w/ 70 mg/kg IV q 6 hrs for 24-48 hrs
- use methionine if NAC not immediately available
- Reduce methemoglobin levels with ascorbic acid
- Can consider administering cimetidine in cats (efficacy much less than NAC)
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Supportive care
- fluids and blood transfusions given as needed
- oxygen therapy for methemoglobinemia
