JPC SYSTEMIC PATHOLOGY
URINARY SYSTEM
December 2023
U-M19
Signalment (JPC Accession #1802815): 18-month-old female German shepherd Dog
HISTORY: This dog was bitten on the nose by a Mojave Desert rattlesnake. After 4 days of treatment, the dog became anorexic and began vomiting. Treatment was discontinued and the dog was euthanized.
HISTOPATHOLOGIC DESCRIPTION: Kidney: Diffusely within glomerular tufts, capillaries are variably dilated and often displace and replace the remaining glomerular tuft and efface glomerular architecture (capillary ballooning). Within these capillaries, there are aggregates of abundant brightly eosinophilic fibrillary, beaded, hyalinized and polymerized fibrin admixed with neutrophils and erythrocytes (organizing fibrin thrombi). Multifocally there is loss of mesangium (mesangiolysis) with replacement by a scant to small amount of cellular and nuclear debris (necrosis) and hemorrhage. Multifocally, within Bowman’s space there is hemorrhage admixed with fibrin, neutrophils, lymphocytes, plasma cells, and macrophages. Tubules have one or more of the following changes: 1) ectatic and lined by attenuated epithelium, 2) lined by degenerate epithelium with pale, swollen and vacuolated cytoplasm (tubular degeneration), 3) contain individual cells that are shrunken and hypereosinophilic with a pyknotic nucleus (necrosis), or 4) lined by epithelial cells with a basophilic cytoplasm that are 2-3 cells layers thick with disorganized arrangement and occasional mitotic figures (regeneration). Multifocally, tubules are ectatic and/or contain abundant eosinophilic homogenous proteinaceous material (tubular proteinosis) admixed with moderate amounts of hemorrhage and fibrin, occasional sloughed epithelial cells, cellular debris, few foamy macrophages that often contain phagocytized erythrocytes, and neutrophils (cellular casts).
MORPHOLOGIC DIAGNOSIS: Kidney: Glomerular mesangiolysis, diffuse, severe, with fibrin thrombi, hemorrhage and tubular degeneration, necrosis, and proteinosis, German shepherd dog, canine.
ETIOLOGIC DIAGNOSIS: Toxic glomerular vasculopathy
ETIOLOGY: Snake (pit viper) venom
GENERAL DISCUSSION:
- In the United States, the majority of envenomations are observed in dogs, horses, and (to a lesser extent) cats. Major snakes involved are typically rattlesnakes, copperheads, and water moccasins.
- Bites typically noted on the face and extremities.
- Factors that influence the seriousness of a venomous snakebite:
- Victim size, age and health
- Venom volume and potency
- Location of the injury (and depth of envenomation)
- Recent strikes (decreased venom available to inject) and/or ‘dry bites’
- Broad classification of poisonous snakes and major/predominant venom effects:
- Viperidae - Vipers or adders: (e.g. rattlesnakes and lanceheads) – cytotoxic effects (some neurotoxic effects)
- Elapidae - Cobras and related species (e.g. mambas, coral snakes) – mostly neurotoxic effects
- Colubridae (e.g. boomslang snake, vine snake) – hemotoxic effects
PATHOGENESIS:
- Snake venom is highly modified saliva that immobilizes prey and aids digestion by means of the actions of protein-degrading enzymes; about 25 different enzymes have been isolated and characterized; individual snake venoms are typically mix of these (~10 or more on average) and cross classes of effects noted in previous section
Venom Constituents Snake Type Major Mechanism of action
Cholinesterase |
Most dangerous species (particularly Elapidae) |
Blocks neuromuscular transmission by splitting acetylcholine to choline and acetic acid |
Phospolipases (PLA2) |
Virtually all venomous snakes, esp. elapids |
PLA2 cleave platelet membrane AA forming thromboxane A2; induce platelet aggregation; many effects in other tissues due to degradation of cellular membranes |
L-Amino acid oxidase (LAAO) |
Vipers |
Digests tissues |
Hyaluronidase |
All venomous snakes |
Dissolves intercellular matrix |
Proteinase |
Vipers |
Accelerates protein breakdown in prey |
Adenosine triphosphatase |
Most snakes, esp. vipers |
Lowers blood pressure through enzyme catabolism of ATP into toxic substances |
Phosphodiesterase |
Virtually all venomous snakes |
Induces negative cardiovascular effects |
Metalloproteinases |
Vipers (high quantities) |
Degrade extracellular matrix, esp. type IV collagen; induce vascular endothelial lesions |
- Snake venoms initially classified in 3 categories:
- Cytotoxic (tissue dissolving and blood cell lysing)
- Neurotoxic (nerve damaging)
- Coagulopathic (inducing bleeding)
- However, many venoms possess a combination of these actions
- Neurotoxic components: Block neurotransmission (i.e. acetylcholine cleavage) either pre- and/or post-synaptically
- Cardiotoxic components: Increase cellular membrane permeability to ions; alter fiber excitability
- Hemorrhagic toxins: Damage vascular endothelium in capillary walls (e.g. hemolysins, endotheliotoxic hemorrhagins)
- Thrombins (procoagulants): Induce coagulation and disrupt normal hemostatic balance and induce intravascular coagulation (e.g. esterases)
- Cytolysins: Lyse tissue cells and leukocytes
- Venom causes alterations in RBCs, WBCs and platelets; cause fluid and electrolyte shifts as well as direct cell damage
- Snake venoms are primarily removed by the kidney and can cause severe vasculitis leading to acute renal failure:
- Nephrotoxic effects of myoglobinuria and hemoglobinuria
- DIC
- Toxic nephropathy
- Hypovolemic shock with renal ischemia
TYPICAL CLINICAL FINDINGS:
- Bite site: Markedly swollen tissue, serous exudate; edema and later necrosis may obscure fang marks
- Rapid, weak heart rate, cardiac arrest, shock, depression, impaired vision, nausea, edema, and cyanosis
- Neurotoxic: Restless, irritability, trembling, paralysis, disorientation, muscle fasciculations, dysphagia with hypersalivation, ptosis, facial & ocular paresis, strabismus, dyspnea due to respiratory paralysis, unconsciousness, cardiac arrest, and rarely convulsions
Clinical Pathology:
- RBCs:
- Echinocytes: Spiculated erythrocytes with many evenly spaced, uniform projections
- Intravascular hemolytic anemia (cat, horse, dog)
- Leukocyte abnormalities:
- Leukocytosis, neutrophilia with a left shift
- Platelet abnormalities:
- Venom-induced thrombocytopenia due to vasculitis, sequestration of platelets in inflamed tissue, and consumption of platelets
- Puff adder venom contains an irreversible platelet aggregation-inducting component; other species venom can contain platelet inhibitory peptides or enzymes that degrade VWF and/or platelet receptors
- Hemostatic changes: Different venoms contain a wide variety of hemostatically active components that may exert procoagulant and anticoagulant properties; standard DIC treatment is often unsuccessful
- Venom-induced consumptive coagulopathy (VICC) in dogs: Prolonged aPTT, PT, elevated FDP’s, and fibrinogen depletion
- Thrombotic microangiopathy (TMA) may occur concurrently; etiology is unclear- possibly due to specific venom toxin
- Russell Viper venom directly activates Factor X, by-passing the intrinsic and extrinsic pathways; other venom can have components that activate Factor 5 and thrombin directly
TYPICAL GROSS FINDINGS:
- One or two puncture wounds on extremities, head and/or neck surrounded by hemorrhage
- Marked passive congestion of organs and hemorrhage at bite site
- Edema of facial or cervical tissue
- Hyperemic airways from respiratory distress
- After several hours: thrombosis and peripheral hemorrhages with tissue necrosis at envenomation site
- Kidney: Gross changes are typically not apparent – may include swollen and pale renal parenchyma and reddish discoloration
TYPICAL LIGHT MICROSCOPIC FINDINGS:
• Dilated and ruptured capillaries within glomeruli (described as mesangiolysis, capillary ballooning, and glomerular microaneurysm) with hyaline casts
• Tubular degeneration and necrosis within the proximal convoluted tubules and collecting ducts with hemorrhage and proteinosis
- Glomerular lipidosis (foam cells in glomerular tufts) reported with experimental intravenous injection of snake venom
- Blood smear: Ghost cells, spherocytes, and/or echinocytes may be seen
DIFFERENTIAL DIAGNOSIS:
- For glomerular aneurysms: Observed with certain types of glomerulonephritis, diabetes mellitus, immune reactions, ischemia, and the toxic effects of various chemicals
- Cutaneous and renal vasculopathy of greyhounds: Necrosis of glomerular afferent arterioles and coagulation necrosis in glomerular tufts; likely associated with primary endothelial cell injury (thrombotic microangiopathy)
- Cutaneous: Other envenomation (e.g. spider – ‘necrotic arachnidism’)
- Snakes are relatively resistant to their own venom due to neutralizing antibodies; also seen in some nonvenomous snakes that hunt other snakes (e.g. king snakes)
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