JPC SYSTEMIC PATHOLOGY
URINARY SYSTEM
January 2024
U-T09 (NP)
Signalment (JPC # 1947461): A neutered male Morgan horse
HISTORY: Tissue from a Morgan horse that was castrated. Hemorrhage from the surgical site was excessive, so the animal was treated with a single dose of vitamin K3.
HISTOPATHOLOGIC DESCRIPTION: Kidney: Multifocally 70% of the renal tubules within the cortex and medulla are mildly ectatic and lined by either attenuated, degenerate (hypertrophied with vacuolated cytoplasm), or necrotic (hypereosinophilic, angular cytoplasm with pyknotic nuclei) epithelial cells. There is rare tubular epithelial regeneration characterized by tubules which are lined by hypertrophied epithelial cells which pile up, have more basophilic cytoplasm, vesiculate nuclei with prominent nucleoli, and rare mitotic figures. Multifocally, tubules contain one or more of the following: red blood cells, fibrin, sloughed epithelial cells, granular eosinophilic material and rare oxalate-like crystals (birefringent, 40-70 µm). Focal glomerular changes include: mild dilatation of the uriniferous spaces, small amounts of granular to smooth eosinophilic material within uriniferous spaces, and hypertrophied parietal epithelial cells. There is mild, multifocal interstitial infiltration/expansion by congested vessels, small amounts of edema, and scattered small aggregates of lymphocytes, plasma cells, macrophages, and rare neutrophils.
MORPHOLOGIC DIAGNOSIS: Kidney, tubules: Degeneration and necrosis, multifocal, moderate, with mild lymphoplasmacytic interstitial nephritis, rare tubular regeneration, Morgan, equine.
ETIOLOGIC DIAGNOSIS: Renal menadione (Vit K3) toxicosis
GENERAL DISCUSSION:
- Vitamin K3 (menadione) is nephrotoxic in domestic animals
- Historically, common in the horse; reports are increasingly rare because the product has been removed from U.S. markets
- Vitamin K, a fat-soluble vitamin, is required for carboxylation of glutamic acid residues on the preformed hepatic coagulation factors II, VII, IX, and X, and proteins C and S
- Carboxyglutamate residues can bind calcium, essential for adherence of these proteins to phospholipid-rich surface (critical for coagulation)
- In the absence of Vitamin K or in the face of Vitamin K antagonism, non-functional proteins with fewer than normal number of carboxyl groups are produced
- These proteins are referred to by the acronym PIVKA (Proteins Induced by Vitamin K Absence/Antagonists)
- There are three main forms of vitamin K
- Vitamin K1 (phytonadione or phylloquinone) - in green, leafy, plants
- Vitamin K2 (menaquinone) - synthesized by microorganisms in the GI tract
- Vitamin K3 (menadione) - synthetic form
- In horses, Vitamin K3 has been used to treat the following conditions:
- Anticoagulant rodenticide toxicosis (coumarin, warfarin, indanediones, brodifacoum)
- Sweet clover (dicumarol) toxicosis
- Exercise-induced pulmonary hemorrhage
- When used at the manufacturer's recommended dose, toxic effects associated with administration of vitamin K3 have been observed in horses; the product has been removed from US markets
PATHOGENESIS:
- The mechanism for renal toxicity of vitamin K3 may relate to oxidative damage
TYPICAL CLINICAL FINDINGS:
- Within 6 to 48 hours of administration of vitamin K3 - depression, anorexia, weakness, stranguria, hematuria, muscle stiffness, laminitis, renal colic
- Acute or chronic renal failure
- Urinalysis - proteinuria, hematuria, low specific gravity
- Elevated BUN and creatinine
- Hyponatremia, hypochloremia, and hyperkalemia (consistent with renal tubular disease)
- History, clinical signs, lesions, serum chemistry and urinalysis help to make the diagnosis
- Heinz body formation; hemolytic anemia secondary to oxidative injury (dogs)
TYPICAL GROSS FINDINGS:
- Acute - Kidneys are enlarged, pale, and bulge from cut surfaces
- Chronic - Kidneys are small, with adherent capsules and pale streaks (fibrosis) in the cortices
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Acute nephrotoxic tubular necrosis (multifocal to diffuse) in proximal and distal tubular segments, tubular dilatation, protein casts
- The tubular basement membrane is generally preserved
- Chronicity may result in glomerulosclerosis, marked interstitial fibrosis, mononuclear inflammatory cells, and tubular casts (mineral, cellular)
DIFFERENTIAL DIAGNOSIS:
Common nephrotoxins in domestic animals:
- Heavy metals – mercury, cadmium, arsenic, thallium, and lead
- Nephrotoxic antibiotics – aminoglycosides (gentamicin), amphotericin B, tetracyclines
- Growth promoting agents – monensin
- Non-steroidal anti-inflammatory drugs –phenylbutazone, flunixin meglumine
- Plants – pigweed, oaks, Isotropis sp., lillies
- Food and food contaminants – melamine, cyanuric acid, grapes/raisins
- Bacterial and fungal toxins – C.perfringens type D epsilon toxin, Ochratoxin A, Citrinin
- Oxalates – ethylene glycol, plant-based (rhubarb, sorrel)
- Vitamin D
- Chemotherapeutic agents - cisplatin
REFERENCES:
1. Boudreaux MK, Spangler EA, Welles EG. Hemostasis. In: Latimer KS, ed. Duncan & Prasse’s Veterinary Laboratory Medicine Clinical Pathology. 5th ed. Ames, IA: John Wiley & Sons, Inc; 2011: 124-125
2. Cianciolo RE, Mohr CF. Urinary System. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals, Volume 2. 6th ed. St. Louis, MO: Elsevier; 2016: 424.
3. Stockham SL, Scott MA. Fundamentals of Veterinary Clinical Pathology. 2nd ed. Hoboken, NJ: Wiley; 2013.
4. Sula MM, Lane LV. The Urinary System. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:734.
5. Talcott P. Toxicologic problems. In: Reed SM, Bayly WM, Sellon DC, eds. Equine Internal Medicine. 4th ed. St Louis, MO: Elsevier; 2018: 1507.
6. Zablotsky SM, Walker DB. Peripheral Blood Smears. In: Valenciano AC, Cowell RL, eds. Diagnostic Cytology and Hematology of the Dog and Cat. 5th ed. St. Louis, MO: Elsevier Mosby; 2014:449.
