JPC SYSTEMIC PATHOLOGY

URINARY SYSTEM

January 2024

U-T06

 

Signalment (JPC # 1947999): Hampshire ewe.

 

HISTORY: This tissue is from a 4-year-old Hampshire ewe that became ill 36 hours after initial access to a new field. Clinical signs included salivation, mydriasis, tremors, ataxia, and paresis.  

 

HISTOPATHOLOGIC DESCRIPTION: Kidney: Multifocally and predominantly within the cortex, tubules are ectatic, expanded up to 4 times normal, and lined by epithelium that is either attenuated, degenerative (characterized by pale, vacuolated cytoplasm), necrotic (characterized by fragmented, hypereosinophilic cytoplasm and pyknotic nucleus), or regenerative (characterized by increased mitotic activity and large pale basophilic nuclei with a high nuclear to cytoplasmic ratio and piling up of epithelium). Tubular lumina contain one or more of the following: intraluminal yellow, translucent, variably shaped, angular, prismatic, anisotropic crystals; rare small amounts of eosinophilic amorphous material (protein); rare sloughed epithelial cells (cellular casts); intensely basophilic acellular, fragmented material (mineral). Multifocally, the interstitium and perivascular connective tissue are mildly expanded by increased clear space (edema), eosinophilic beaded to fibrillar material (fibrin) and mild hemorrhage admixed with low numbers of neutrophils, lymphocytes and plasma cells.  

 

MORPHOLOGIC DIAGNOSIS: Kidney, cortical and medullary tubules: Degeneration and necrosis, acute, diffuse, moderate with marked tubular ectasia and numerous intratubular oxalate crystals, breed unspecified, ovine.  

 

ETIOLOGIC DIAGNOSIS: Oxalate nephrosis  

 

GENERAL DISCUSSION:  

• Oxalate toxicosis in ruminants occurs primarily from ingestion of plants that contain toxic amounts of soluble oxalate salts
• Oxalate content is highest in the leaves, with lesser amounts in the seeds, and the lowest concentrations in the stems; concentration varies with season and is highest in the autumn (Northern Hemisphere); adaptation to oxalate with chronic exposure to low doses occurs   
• Small numbers of oxalate crystals are found occasionally in the renal tubules of many species and are usually an insignificant finding as oxalates are also produced endogenously in the normal degradation of glycine, an important constituent amino acid of collagen and elastin  
• Common plants that contain large amounts of soluble oxalates:

Halogeton glomeratus (halogeton); Sarcobatus vermiculatus (greasewood); Rheum rhaponticum (rhubarb); Oxalis spp. (sorrel, soursop); Rumex spp. (sorrel, dock); Amaranthus sp. (pigweed) 

• Plants of lesser importance that contain soluble oxalates:

Beta spp. (beet, marigold); Brassica spp. (cauliflower, broccoli, kale, rape); Chenopodium album (lamb’s quarters); Portulaca oleracea (purslane); Salsola kali (Russian thistle); Setaria spp. (tropical grass)

 

PATHOGENESIS:  

• In ruminants, three events may occur following oxalate ingestion:

1. Degradation and detoxification of oxalate by rumen microorganisms into carbonate and bicarbonate (adaptation occurs over 3-5 days as the microorganisms proliferate)
2. Oxalate binds to free calcium in the rumen with excretion in feces
3. Absorption of oxalate into the blood; binds to circulating calcium and forms insoluble calcium oxalate; may lead to: Hypocalcemia, tetany, decreased milk production

• Reabsorption of water in renal tubules à calcium oxalate crystallization       à tubular obstruction à acute renal failure 
• Calcium oxalate crystal precipitation occasionally observed in vessel lumina or walls causing necrosis and hemorrhage
• Aspergillus genera of fungi may produce abundant oxalates on feedstuffs
• Primary hyperoxaluria: Inherited condition that may occur in cats, dogs (Tibetan spaniel, Shih Tzu) and beefmaster cattle
• Pyridoxine (vitamin B6) deficiency and methoxyflurane anesthesia ma also cause renal accumulation of oxalates

 

TYPICAL CLINICAL FINDINGS:

• May occur as early as 2-4 hours after ingestion
• Depression, anorexia, mild colic, slight to moderate bloating, weakness, restlessness, frequent attempts to urinate, hypocalcemic seizures, coma, and death  

 

TYPICAL GROSS FINDINGS:  

• Thin renal medulla with dilated renal calyces that contain numerous small, hard, pale yellow, granular to jagged calculi 

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Distension of cortical and medullary tubules with numerous small to large, clear, angular, prismatic, birefringent crystalline deposits or casts; crystals also occasionally in tubular epithelial cells
• Multifocal tubular degeneration and regeneration; occasional lymphoplasmacytic interstitial nephritis and interstitial fibrosis
• Minimal glomerular lesions
• Crystals occasionally present around cerebral, heart, and lung vasculature
• May see prominent oxalosis in the kidneys of aborted bovine fetuses secondary to maternal intake (plants or moldy feed)
• Few oxalate crystals are often seen in degenerate tubule in any species and are generally considered insignificant

 

ADDITIONAL DIAGNOSTIC TESTS:

• Serum chemistry: Hypocalcemia, hyperphosphatemia, hyponatremia, and hyperkalemia; elevations in BUN, creatinine, ALT, AST, LDH; and metabolic acidosis
• Urinalysis: Calcium oxalate crystalluria; proteinuria
  1. Two types of calcium oxalate crystals: calcium oxalate dihydrate and calcium oxalate monohydrate crystals
     • Calcium oxalate dihydrate (more common): Nonspecific finding; can be found in normal animals; colorless-variably sized, with intersecting lines that resemble a small envelope or Maltese cross.
     • Calcium oxalate monohydrate: Pathogenic; early feature of ethylene glycol toxicosis; flat, picket fence board-like morphology
       

 

DIFFERENTIAL DIAGNOSIS:

• Causes of tubular nephrosis in ruminants:
  1. Hemoglobinuric or myoglobinuric nephrosis (U-T10): Tubular lumina with orange-red, granular, refractile material; brown cortex with red-brown streaks in medulla
• Acute toxic nephrosis:
  1. Heavy metals: Arsenic, lead (U-T02), cadmium, natural gas condensate
  2. Pharmaceutic agents: Aminoglycosides (U-T07)
  3. Plants: Amaranthus retroflexus (pigweed) (U-T13), Quercus sp. (oak tree) (U-T14)
• Vitamin D nephropathy (U-T03): Prolonged ingestion of plants with vitamin D-like biologic activity (Cestrum diurnum, Solanum malacoxylon, Trisetum flavescens and Meticago sativa); chronic process; calcification of tubular basement membranes, tubular dilation and atrophy; interstitial fibrosis; chalky calcific deposits in cortex

 

COMPARATIVE PATHOLOGY

• Horses: Resistant to oxalate nephrosis; succumb to acute gastroenteritis if large amounts of oxalate is ingested
• Dogs, cats, humans, and poultry: Commonly poisoned by ingesting ethylene glycol (U-T05)
• Outbreaks of melamine (U-T18) associated renal failure also reported in dogs and cats due to contamination of commercial pet food; melamine alone is not toxic but forms insoluble crystals when combined with cyanuric acid which may be mistaken for oxalate crystals
• Captive cheetahs: Should be considered as a potential cause of acute renal failure in young captive cheetahs, predisposition is suggestive, although pathogenesis is unknown
• Captive jaguars, leopards, cougars: Sometimes found dead; ARF with poly-to anuria and severe azotemia; crystals in urine
• Koalas: Mild oxalate nephrosis most commonly an incidental finding. More severe cases result in significant nephrosis and renal failure 
• Reported in Gilbert’s potoroo, scaly tailed possum, swamp wallaby
• Amphibians: Renal oxalosis occurs in tadpoles and recently metamorphosed captive ranid frogs fed oxalate-rich plants, such as spinach. Also reported in waxy monkey frogs that consumed crickets fed an oxalate-containing plant and in tadpoles of wild anurans.
• Recent report of renal oxalosis as part of systemic oxalosis in a free-ranging green turtle (Chelonia mydas)(Nobrega, J Comp Pathol 2023) 

 

REFERENCES: 

1. Cianciolo RE, Mohr FC. The urinary system. In: Maxie MG, ed. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. Philadelphia, PA: Saunders; 2016:425, 456-457.
2. Higgins D, Rose K, Spratt D. Monotremes and Marsupials. In: Terio KA, McAloose, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. Oxford, UK: Elsevier, 2018: 458.
3. Nobrega DF, Marutani VHB, Alcala MM, et al. Systemic oxalosis in a free-ranging green turtle (Chelonia mydas). J Comp Pathol. 2023;201:13-15.
4. Pessier AP. Amphibia. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:922. 
5. Sula MM, Lane LV. The Urinary System. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:736-737.
6. Snyder L, Seelig D. Urinary System. In: Raskin RE, Meyer DJ, Boes KM, eds. Canine and Feline Cytopathology: A Color Atlas and Interpretation Guide. 4th ed. St. Louis, MO: Elsevier; 2023:399-401. 
7. Terio KA, McAloose D, Mitchell E. Felidae. In: Terio KA, McAloose, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. Oxford, UK: Elsevier, 2018: 268-269.
8. Wamsley HL. Examination of the Urine Sediment. In: Valenciano AC, Cowell RL, eds. Diagnostic Cytology and Hematology of the Dog and Cat. 5th ed. St. Louis, MO: Elsevier Mosby; 2014:396-398. 

 

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