Read-Only Case Details Reviewed: Feb 2009

JPC SYSTEMIC PATHOLOGY

URINARY SYSTEM

January 2024

U-T05

Signalment (JPC #1896466): York/Landrace pig

HISTORY: Tissue from a 9-month-old York/Landrace female pig from a confinement operation in Illinois. Several other sows had died following a 2-5 day illness. This animal was presented alive and alert but with posterior paresis and rectal prolapse. At necropsy the kidneys were pale, yellow to tan, with scattered petechiae. The animal appeared dehydrated. Urinalysis revealed the following:

Color ‑ yellow
Ketones ‑ negative
Character - clear
Glucose ‑ trace
Specific gravity ‑ 1.011
Blood ‑ moderate
1. Protein ‑ 30.0 mg/dl
2. pH ‑ 5.0
3. Urine sediment: 2-3 erythrocytes/hpf with rare leukocytes
4. Crystals: None observed

HISTOPATHOLOGIC DESCRIPTION: Kidney: Diffusely, there is complete disruption of cortical tubular architecture. Cortical tubules are surrounded by increased clear space (edema), or tubular epithelium is lost. Multifocally, medullary tubules contain eosinophilic proteinaceous fluid (proteinosis) or granular sloughed cellular and nuclear debris (granular casts). Diffusely, the medullary tubules are separated by an increased amount of loose, fibrillar, finely beaded eosinophilic material (fibrin) and edema. Multifocally, there are mild interstitial lymphoplasmacytic infiltrates. Multifocally, cortical and occasionally medullary tubules are ectatic, dilated up to 4 times normal, and contain abundant translucent, pale yellow, anisotropic crystals arranged in sheaves, prisms, and rosettes (calcium oxalate) which are often in contact with the tubule basement membrane. Remaining cortical tubular epithelium is either markedly swollen with abundant clear to vacuolated cytoplasm (degeneration) or hypereosinophilic, angular and shrunken with pyknotic nuclei (necrosis). Multifocally, Bowman’s space is dilated, with rarely hypertrophied parietal epithelium.

MORPHOLOGIC DIAGNOSIS: Kidney, cortical and medullary tubules: Degeneration, necrosis, and loss, acute, diffuse, severe, with calcium oxalate crystals, tubular proteinosis, and rare lymphoplasmacytic interstitial nephritis, York/Landrace, porcine.

ETIOLOGIC DIAGNOSIS: Oxalate nephrosis

CAUSE: Ethylene glycol (EG) toxicosis

GENERAL DISCUSSION:

Dogs and cats are commonly poisoned by ingestion of ethylene glycol (antifreeze), uncommonly cattle, pigs, and horses; seasonal (spring and fall)
Sweet taste and consumed in largest quantity by young dogs; cats are more susceptible but less commonly affected

Glycolaldehyde and glycolate are the primary nephrotoxic metabolites

PATHOGENESIS:

Most ethylene glycol is excreted unchanged in the urine
Ethylene glycol (low toxicity) absorbed from GI tract > oxidized by alcohol dehydrogenase in the liver to glycolaldehyde > oxidized > glycolic acid, glyoxylate > oxalate
Glycolaldehyde and glycolate > ATP depletion and damage to membrane phospholipids and enzymes
Blood calcium oxalate > precipitates in the ultrafiltrate of renal tubules > calcium oxalate > crystals found in tubular lumens, tubular cells, and the interstitium
Additional end products: Lactic acid, hippuric acid, and carbon dioxide

TYPICAL CLINICAL FINDINGS:

Initial hours post ingestion: Depression, ataxia, and osmotic diuresis
Next 12 hours: Pulmonary edema, tachypnea, tachycardia
1-3 days: Acute renal failure from nephrotoxicity, renal edema; calcium oxalate crystals are an important cause of renal failure
Nervous signs: Result of aldehydes and severe metabolic acidosis from accumulation of lactic acid, glycolate, and glyoxylate
Large numbers of crystals in urinalysis is highly suggestive of poisoning; few crystals are normally seen
Hypercalciuria: Products of ethylene glycol metabolism bind calcium in renal tubular fluid > hypercalciuria and high plasma oxalate concentration
Hypocalcemia (mild) due to formation of crystals; acute nephrosis may decrease tubular resorption of calcium
Intravascular oxalate bind calcium to form intravascular calcium oxalate crystals

TYPICAL GROSS FINDINGS:

Kidneys are pale and slightly swollen with bulging on cut section; however, they may appear normal

TYPICAL LIGHT MICROSCOPIC FINDINGS:

Calcium oxalate crystals: Light yellow, arranged in sheaves, rosettes, or prisms, and are birefringent with polarized light
1. Large numbers of crystals in tubules are virtually pathognomonic of ethylene glycol poisoning; scattered oxalate crystals can be seen in many types of chronic kidney disease
2. Over time crystals are removed; few may remain
Acute tubular necrosis
1. Lesions are most severe in proximal tubules; range from acute cellular swelling to necrosis to regeneration
Animals that survive the toxicosis may have tubulointerstitial scarring

ADDITIONAL DIAGNOSTIC TESTS:

Diagnosis is confirmed by:
1. Detection of ethylene glycol in stomach contents
2. Gas chromatography early in toxicosis
3. Detection of glycolic acid in urine, serum, or ocular fluid by mass spectrometry later in toxicosis
Renal calcium to phosphorus ratio: >2.5 in dogs (normal is <0.1)
Cytologic findings: Calcium oxalate monohydrate crystalluria is pathological; early feature of ethylene glycol intoxication
1. Crystalluria is seen within 3 hours of ingestion in cats and within 6 hours of injection in dogs; persists for up to 18 hours
2. Crystals are colorless, variably sized, birefringent with polarized light, and pleomorphic with two morphologies commonly observed (picket fence or spindle/dumbbell-shaped)

DIFFERENTIAL DIAGNOSIS:

Small numbers of calcium oxalate crystals may be present in some species unassociated with disease, or secondary to nonspecific renal injury
Primary oxalate nephrosis: Oxalates are produced endogenously as a metabolic by-product of amino acid (hydroxyproline, glycine, serine) and vitamin C catabolism
Secondary/acquired oxalate nephrosis: Due either to severe liver disease or pyridoxine deficiency resulting in compromised oxalate metabolism, or increased absorption of oxalates via ingestion of oxalate (or their precursor) containing plants, ethylene glycol (as discussed above) or other glycols, xylitol, ascorbic acid, and collagen or feathers, methoxyflurane, rust-removing chemicals, Aspergillus niger (present on foodstuffs) or increased oxalate absorption secondary to an altered intestinal microbiome, excessive bile, low intestinal calcium content, enterocolitis, and intestinal surgical resection
1. Ingestion of oxalate-containing plants (especially pigs and cattle): Halogeton, Sarcobatus (greasewood), Rheum (rhubarb leaves), Rumex (sorrel and dock)
Melamine-cyanuric acid nephrotoxicity (U-T18): Outbreaks of acute renal failure and deaths in cats and dogs were attributed to contamination of commercial pet food with melamine and cyanuric acid (2004 and 2007); clinically and pathologically, this can be difficult to differentiate from oxalate nephrosis

	Oxalate nephrosis	Melamine-cyanuric acid
H&E appearance	Pale yellow; arranged in wheat sheaves, rosettes or prisms; may be difficult to see	Gold to brown; large round crystals with radiating striations; easily seen
Location in nephron	Proximal tubules	Distal nephron
Birefringent	Yes	Yes
Stains with	Von Kossa	Oil Red O
Clinical Path difference	Usually prominent hypocalcemia	Usually normal serum calcium

COMPARATIVE PATHOLOGY:

Captive cougars, jaguars, leopards, and cheetahs: Reports of oxalate nephrosis since the mid-1970’s; animals found dead or with severe azotemia, and poly- to anuria; characteristic birefringent crystals forming rosettes are present in renal tubules
1. Ethylene glycol is suspected, but cases have occurred in areas of the world that do not use antifreeze
2. Cheetahs are most susceptible; approximately 10% of the North American and South African captive cheetah population have histologically evident oxalate crystals at death; widespread toxicosis is unlikely and some case occur in young cheetahs; inherent predisposition likely, but pathogenesis is unknown
Galliformes and Columbiformes: Nephrosis and uric acid deposition in many organs (visceral gout); curious animals that may ingest toxic compounds from the environment
1. Ethylene glycol toxicosis is not reported in pet birds
Wild canids: Renal nephrosis with large numbers of birefringent crystals; crystal deposition can also occur in cerebral vessels or in the Virchow-Robbins space

REFERENCES:

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