6-Renal Toxicity

Question 1

Renal toxicants

Answer 1

• Ethylene glycol
• Cholecalciferol/Vitamin D3
• Grape and raisin tox

Question 2

Hepatic toxicity

Answer 2

Acetaminophen

Question 3

Kidney is common site of toxicity

Answer 3

• High blood flow (22-25% cardiac output)
• Concentration of compounds
  
  • tubular concentration can be 600X that of plasma
  • Can lead to crystallization
    
    • oxalic acid
• Most imp organ for excretion of zenobiotics
  
  • dep on water solubility of toxican
  • high lipid solubility of xenobiotics
    
    • resorbed across tubular cells into bloodstream again

Question 4

Proximal Convoluted Tubule

Answer 4

• most common site of toxin induced injury
  
  • cytochrome P450 and cysteine conjugate Beta-lysase localized here
    
    • phase one detox enzymes
    • bioactivation => damage
  • Loose epithelium allows compounds to enter cells
  • Inc transport => ischemic injury to epithelial cells
    
    • anions
    • cations
    • heavy metals

Question 5

Acute Renal Failure

Answer 5

• Decreased GFR and renal azotemia
• Caused by transient damage to tubule, glomerulus or vasculature
• Signs
  
  • vomiting
  • GI bleeding
  • PUPD => anuria
  • diarrhea
  • tremors

Question 6

Chronic Renal Failure

Answer 6

• Mostly related to secondary pathological changes triggered by initial injury
• Secondary changes are compensatory mechanisms
• Signs
  
  • edema
  • hypocalcemiaparathyroid activity
    
    • inc Ca in blood
    • Calcitonin puts Ca back into bone
  • reduced RBC count

Question 7

Ethylene Glycol

Answer 7

• Major ingredient in normal antifreeze
• 2nd most common cause of fatal poisonings in animals
• Most frequently used for malicious poisoning
• Exposure common in Spring and Fall when people change antifreeze
• Very high rate of lethality (80%)
  
  • delay of clinincal symptoms and presentation
• Tastes sweet
• 1 tbspn can kill a cat
• 7 mL can kill a dog

Question 8

Ethylene glycol

MOA

Answer 8

• Metabolites caused by action of alcohol dehydrogenase are toxic
  
  • glycolic acid
    
    • acidosis
    • possibly CNS signs
  • oxalate/oxalic acid
    
    • causes renal damage and hypocalcemia
      
      • binds to calcium to form calcium oxalate

Question 9

Stages of ethylene glycol poisoning

Answer 9

• Stage 1: 30 minutes-3 hours
  
  • drunkenness, ataxia, CNS depression
  • nausea, vomiting
  • PU/PD (dogs)
  • Usually missed with unobserved ingestions
• Stage 2: 12-24 hours
  
  • tachypnea, tachycardia (rarely bradycardia)
  • cats typically remain depressed
  • signs often not recognized by owner
• Stage 3: 12-72 hours
  
  • most animals present in this stage
  • polyuria => oliguria => anuria
  • Lethargy, anorexia, vomiting, seizures
  • Oral ulcers, abdominal pain, dehydration, enlarged kidneys

Question 10

Ethylene glycol tox

Diagnosis

Answer 10

• measuring EG conc in blood
  
  • serum conc peak at 1-6 hours
  • no detection in serum and urine by 24 hours
  • cats can be poisoned by levels below detection of many kits
• Azotemia
• Elevated BUN and creatinine in Stage III
• Urinalysis
  
  • low USG (1.008-1.012 in dogs w/in 3 hours)
  • crystalluria (w/in 6 hours)
• Calcium oxalate crystals in kidney via ultrasound exam
• Shine a UV lamp

Question 11

Ethylene glycol toxicity

Serum biochem

Anion/osmol gap

Answer 11

• Serum biochem profile
  
  • hyperglycemia
  • hypocalcemia
• Anion and osmol gap
  
  • metabolites inc unmeasured anions resulting in anion gap
  • anion gap > 30 (normal is 10-25)
  • Osmol gap > 20 (normal is 10)
  • serum osmolality can reach 450 mosm (nor al is ~300)
• Ddx
  
  • rhubarb
  • pigweed
  • defebechia…?

Question 12

Ethylene glycol tox

Treatment

Answer 12

• prevent formation of toxic metabolites
• Achieved through administration of competitive inhibitors of alcohol dehydrogenase
  
  • 20% Ethanol and sodium bicarb (acidosis)
    
    • monitor CNS depression and ethanol administration
    • antagonized by fomepizole (bad!)
  • Fomepizole (4-methypyrazole, 4-MP) or Antizol
• No benefit of ethanol or 4-MP if ethylene glycol has already been metabolised
  
  • contraindicated in animals with renal failure
• no activated charcoal or emesis if 72 hours later (stage 3)

Question 13

Ethylene Glycol Toxicity

Prognosis

Answer 13

• Cats
  
  • peak plasma conc about 1 hour after ingestion
  • survival highly dependant on tx w/in first 3-4 hours
  • mortality rate at least 90%
• Dogs
  
  • peak plasma concentration occurs at 2-3 hours
  • survival most likely tx if started w/in 6-8 hours of ingestion
  • azotemia on admission => slim chance
• Renal failure => poor prognosis
• Survivors
  
  • therapy often required for up to 72 hours
  • recovery can take 3-5 days if treated aggressively

Question 14

Cholecalciferol / Vitamin D3

Answer 14

• Overdose of vitamin supplements
• exposure to rodenticide
• toxic at > 0.5 mg/kg
• lethal 10-15 mg/kg
• Dogs and cats most affected

Question 15

Cholecalciferol / Vitamin D3

MOA toxicity

Answer 15

• Cholecalciferol metabolized to 1,25-dihydroxycholecalciferol
• causes massive inc in serum calcium
  
  • inc GI absorption
  • dec renal excretion
  • inc synthesis of Ca binding protein
  • mobilizing bone Ca

Question 16

Cholecalciferol / Vitamin D3

Clinical Signs

Answer 16

• typically appear 36-48 hours after exposure
• anorexia, weakness, depression
• thirst, polyuria
• Calciuria
• Diarrhea, dark feces from intestinal bleeding, vomiting
• Hypertension, bradycardia, ventricular arrhythmia
• mineralization of tissues when Ca X P > 70 mg/L

Question 17

Cholecalciferol / vitamin D3 tox

Diagnosis

Answer 17

• hx of ingestion, clinical signs, hypercalcemia
• most common finding is rapid inc in plasma phosphorous
  
  • followed by inc in plasma calcium
• Low parathyroid hormone (PTH)
• Inc BUN and creatinine
• Low urine specific gravity w/ calciuria
• high hydroxycholecalciferol levels in bile and kidney

Question 18

Cholecalciferol / vitamin D3 tox

Answer 18

• histologic findings incl mineralization in multiple organs
  
  • heart, pancreas, kidney, lung, stomach
• Ethylene glycol
  
  • elevated kidney Ca usually higher (>8,000 ppm)
  • Ca:P ratio in kidney > 2.5 with EG
    
    • normal is 0.1
    • Cholecalciferol: 0.4-0.7
• Differentiate from
  
  • paraneoplastic syndrome
  • juvenile hypercalcemia
  • hyperparathyroidism

Question 19

Cholecalciferol / vitamin D3 tox

TX

Answer 19

• reduced dietary Ca and P
• GI decon w/in 6-8 hours (usually too late)
• monitor serum Ca from admission and every 24-48 hours
• encourage Ca secretion
  
  • normal saline
  • furosemide
• Prednisolone
  
  • reduces bone resorption, intestinal Ca absorption, and kidney Ca resorption
• Calcitonin
  
  • inhibits bone resporption
  • side effects
    
    • anorexia, anaphylaxis and emesis
  • Pamidronate can replace calcitonin
    
    • very expensive
• Sucralfate or milk of magnesia
  
  • for ulceration
  • helps reduce P

Question 20

Grape and raisin Toxicity

Answer 20

• renal failure
  
  • also sultanas and currants
• MOA unknown
• Lack of dose response seen

Question 21

Grape and Raisin toxicity

Clinical signs and diagnosis

Answer 21

• Clinical signs
  
  • vomiting usually initial sign
  • acute renal failure
• Pathologic findings (due to kidney failure)
  
  • hypercalcemia
  • hyperphosphatemia
  • inc Ca X PO₄
  • Elevated BUN and serum creatinine

Question 22

Grape and Raisin Toxicity

TX

Answer 22

• Emesis, lavage, activated charcoal for recent ingestion
• Fluid therapy for min 72 hours
• Supportive therapy
  
  • furosemide
  • dopamine, mannitol, hemodialysis, peritoneal dialysis

Question 23

Liver Toxicosis

Answer 23

• capable of significant regeneration and repair
• Intrinsic injury may lead to
  
  • steatosis
  • necrosis
  • cholestatis
• Injury occurs at dose-dependant reaction to a toxicant
• Often caused by reactive products of zenobiotic metabolism

Question 24

Acetaminophen toxicity

Answer 24

• very common poisoning in humans and animals
• metabolized in liver by glucuronidation, sulphonation and oxidation pathways
  
  • oxidation => reactive metabolite NAPQI
• Cats extremely sensitive
  
  • can show signs with doses as low as 10 mg/kg
  • lack of glucuronidation

Question 25

Acetaminophen toxicity MOA

Answer 25

* Toxic effects due to metabolite NAPQI * when glutathione stores depleted NAPQI bines to macromolecules and proteins * liver necrosis * increased methemoglobinemia * Erythrocyte injury is predominant problem in cats * methemoglobin * heinz body production * Hepatic effects dominate in dogs, mice, rats

Question 26

Acetaminophen toxicity Clinical Signs

Answer 26

* Methemoblobinemia and hepatotoxicity * usually with tachycardia, hyperpnea, weakness, and lethargy * Cats primarily develop methemoglobinemia w/in a few hours, then heinz body formation * Liver necrosis is clinical sign in dogs * liver damage in dogs after 24-36 hours * Centrilobular hepatocyte degeneration and necrosis

Question 27

Acetaminophen toxicity Diagnosis Cats Dogs Other clinical signs

Answer 27

* Cats * cyanosis * methemoglobinemia * dyspnea * weakness and depression * edema of paws/face * anemia in 75% of cats * Dogs * signs associated with **acute centrilobular hepatic necrosis** * nausea and vomiting * anorexia * abdominal pain * shock * tachypnea * tachycardia * Other CS * hemolysis * heinz bodies in cats and dogs in NMB stain * elevated liver enzymes

Question 28

Acetaminophen toxicity TX

Answer 28

* **Replace glutathione stores**, inc productivity of other two pathways, manage hematological signs * glutathione precursor N-acetylcysteine (NAC) * use methionine if NAC not immediately available * Early GI decon * Ascorbic acid * reduces methemoglobin levels * Cimetidine * less effective than NAC * Supportive care * Fluids and blood transfusions as needed * Oxygen therapy for methemoglobinemia