L5: Renal & Hepatic Toxicity (Martyniuk) Flashcards
2nd leading cause of fatalities in small animals
ethylene glycol
3 types of active compounds in rodenticides**
anticoags
cholecalciferol/Vit. D3
neurotoxicants
Why is kidney a common site of toxicity?
- very high blood flow (22-25% of cardiac output)
- compounds concentrate
- phase I/II enzymes present, allowing for bioactivation
- most important organ for excretion of xenobiotics:
- depends on water solubility of the toxicant
- high lipid solubility xenobiotics are reabsorbed across the tubular cells into the bloodstream again
What happens at Bowman’s capsule?
where glomerular filtration occurs. 100% filtrate produced.
What happens at Proximal convoluted tubule?
- Active and passive absorption
- 80% filtrate reabsorbed
- where most toxicosis occurs**
- increased transport of anions, cations, heavy metals, accumulation and ischemic injury to epithelial cells
- where Cytochrome P450 and cysteine conjugate b-lyase localize and bioactivate
What happens at loop of Henle?
- H2O and salt conservation
- 6% filtrate reabsorbed
What happens at Distal Tubule?
- where ADH acts
- 9% filtrate reabsorbed
- variable reabsorption, active secretion
What happens at Collecting tubule?
- Variable salt and H2O reabsorption
- 4% filtrate reabsorbed
Chars. of ACUTE renal failure
- char. by dec. GFR and subsequent renal azotemia
- damage to tubule, glomerulus or vasculature (usually reversible)
- symptoms: v, GI bleed, PU/PD –> anuria, lethargy, anorexia, depression, d, tremors
Chars. of CHRONIC renal failure
- related to 2ary pathological changes triggered by initial injury
- compensatory mechanisms that dec. glomerular fx & tubular and interstitial changes
- Symptoms: edema, hypocalcemia, parathyroid activity, reduced RBCs, bloody urine, eventual death
Markers of kidney injury
- changes in urine volume/osmolality/pH
- glucosuria
- BUN, creatinine (sensitive to hydration state)
- Proteinuria
- Presence of cellular enzymes in urine (alk phos, lactate dehydrogenase)
- Inulin clearance
Ethylene Glycol overview
- 2nd most common cause of fatal poisonings in animals
- most frequently used for malicious poisoning**
- very high rate of lethality (80+%) due to delays in presentation
- antidote = ethanol IV
T/F: very rare that poultry and cattle experience ethylene glycol toxicity?
T
ethylene glycol MOA
- acts like ethanol to produce early signs of “drunkenness”
- glyoxal causes CNS signs
- metabolized to glycolic acid, which causes acidosis
- metabolism to oxalic acid combines with Ca to form insoluble crystals in renal tubules and causes injury
conversion of ethylene glycol to calcium oxalate crystals
alcohol dehydrogenase converts ethylene glycol to glycoaldehyde, which eventually –> oxalic acid –> calcium oxalate
how does ethanol work as antidote to ethylene glycol toxicity?
binds alcohol dehydrogenase, so ethylene glycol can’t be converted to glycoaldehyde and other toxic metabolites
Stage 1 symptoms of ethylene glycol toxicity
30mins-3hrs
- “drunkenness”, ataxia, CNS depression
- nausea, vomiting
- PU/PD
- usually missed
Stage 2 symptoms of ethylene glycol toxicity
12-24hrs
- tachypnea, tachycardia (or brady)
- not severe
- cats depressed
Stage 3 symptoms of ethylene glycol toxicity
12-72hrs
- when most animals present**
- PU –> oliguria, anuria
- lethargy, anorexia, v, seizures
- oral ulcers, abd. pain, dehydration, enlarged kidneys
Dx of EG toxicity
- measure EG conc. in blood
- azotemia
- elevated BUN/creat.
- low urine SG
- crystalluria
- Ca oxalate crystals in kidney via ultrasound
- Hyperglycemia, Hypocalcemia
- inc. anion and osmolal gaps
Tx of EG toxicity
- emesis or lavage soon after ingesiton
- NO act. charc. (doesn’t bind)
- 20% ethanol and bicarb
- Fomepizole and Antizol (ADH inhibitors that replace ethanol)
- late stage tx: fluids, mannitol diuresis
Cholecalciferol/Vit. D3 source
overdose of vitamin supplements or exposure to rodenticide
-affects dogs/cats most
Cholecalciferol MOA
metabolized to 1,25-dihydroxycholecalciferol (which is also toxic)
-causes massive increases in serum calcium by inc. GI absorption, dec. renal excretion, inc. synthesis of Ca binding protein, and mobilizing bone C
Symptoms of cholecalciferol toxicity
- 36-48hrs later
- anorexia, weakness, depression
- PU/PD, low urine SG due to effects of Ca on vasopressin activity
- Caciuria
- d/v, hypertension, bradycardia, ventricular arrythmia
- mineralization of tissues
Dx of cholecalciferol toxicity
- based on Hx, CS, hypercalcemia
- rapid inc. in plasma phosphorus followed by inc. in plasma Ca lvls
- low PTH
- inc. BUN/creatinine
- low spec grav with calciuria
- high hydroxycholecalciferol lvls in bile/kidney
Differential dx of cholecalciferol toxicity
- mineralization in multiple organs (heart, pancreas, kid, lung, stomach)**
- ethylene glycol
- differentiate from paraneoplastic syndrome, juvenile hypercalcemia, and hyperparathyroidism
Tx of cholecalciferol toxicity
- reduced dietary Ca and phosphorus
- GI decon if early
- normal saline and furosemide**
- pred (reduces Ca reabsorption)
- Calcitonin (pushes Ca back into bones)
- Aredia (a calcitonin replacer)
- sucralfate for ulceration and to reduce P
Grape/raisin toxicity overview (everything - tx)
- can cause renal failure in some dogs
- symptoms: v, crystal formation?, signs of acute renal failure
- unknown MOA
- clin path: hypercalcemia, hyperphosphatemia, elevated BUN/creat
- poor prognosis
Tx of grape toxicity
- emesis, lavage, act. charc. if recent
- fluids
- supportive tx: furosemide, DA (increases filtration rates in the kidney), mannitol, hemodialysis, peritoneal dialysis
3 main roles of liver
detoxification
metabolism
reproduction (produces vitellogenin to make eggs)
intrinsic injury of liver –>
steatosis (retention of lipids), necrosis, cholestasis
- occurs as dose-dependent rxn to a toxicant
- often caused by reactive products of xenobiotic metabolism
Acetaminophen overview
- metabolized by liver
- cats extremely sensitive due to lack of glucuronidation
Acetaminophen MOA
- interferes with endoperoxidase
- toxic effects due to form. of metabolite NAPQI
- erythrocyte injury is predominant problem in cats (MetHb/Heinz bodies formed)
- hepatic effects dominate in dogs, mice, rats (centrilobular hepatocyte degeneration/necrosis)
Symptoms of acetaminophen
- MetHb and hepatotoxicity accompanied by tachycardia, hyperpnea, weakness, lethargy
- cats primarily develop metHb and Heinz bodies
- centrilobular necrosis in dogs
Dx of acetaminophen
Methb
Hemolysis
Heinz bodies
anemia in 75% of cats
-elevated alanine transferase and aspartate aminotransferase
-elevation of prothrombin time if liver damage severe
-progressive decrease in serum cholesterol and serum albumin
Tx of acetaminophen
- early decon
- N-acetylcysteine (NAC)
- cimetidine (Histamine receptor antagonist)
- Ascorbic acid to reduce MetHb
- supportive care (fluids, blood transfusion, O2)
cimetidine MOA
histamine receptor antagonist; makes stomach less acidic to protect it from ulcers/other adverse effects
NAC MOA
converts NAPQI to non-toxic compound using glutathione (phase II metabolic rxn)
