JPC SYSTEMIC PATHOLOGY

URINARY SYSTEM

January 2023

U-P01

 

Signalment (AFIP Accession #1886196): English bulldog

 

HISTORY: Tissue from an eight‑week‑old English bulldog. 

 

HISTOPATHOLOGIC DESCRIPTION (U-P01A): Kidney: Affecting approximately 90% of the section (including cortex, medulla and renal pelvis), renal architecture is diffusely expanded and replaced by variable numbers of plasma cells, histiocytes, lymphocytes, rare neutrophils, mild fibrosis and small foci of hemorrhage that markedly separate and surround renal tubules. Tubular lumina contain a mixture of flocculent eosinophilic material, sloughed tubular epithelial cells, few neutrophils and histiocytes. Tubular epithelial cells exhibit one or more of the following changes: shrunken, hypereosinophilic with pyknotic and/or karyorrhectic nuclei (necrosis); swollen with vacuolated cytoplasm and indistinct cell borders (degeneration); and increased cytoplasmic basophilia and hypertrophied or vesiculate nuclei with rare mitoses (regeneration). Rare cells (tubular epithelial or endothelial cells) contain numerous cytoplasmic, 1-2 µm oval, basophilic spores. Multifocally, endothelial cells are mildly hypertrophic with enlarged nuclei that protrude into the lumen and the tunica media/adventitia and perivascular connective tissue is mildly edematous.  

 

Urinary bladder: Few small and medium caliber arterioles have expansion of the tunica media and adventitia by viable and necrotic neutrophils, cellular debris, and hypereosinophilic polymerized fibrin (fibrinoid vasculitis). The lamina propria multifocally contains low numbers of neutrophils, lymphocytes and plasma cells and a focal area of mild hemorrhage. 

 

(U-P01B) Brown and Brenn (B&B): Multifocally, within renal tubular lumina, capillary lumina, tubule epithelial cells and macrophages, there are numerous dark purple, oval, gram-positive, 1x2 µm spores.

 

MORPHOLOGIC DIAGNOSIS: 1. Kidney: Nephritis, tubulointerstitial, necrotizing, histiocytic and lymphoplasmacytic, chronic, diffuse, marked, with tubular degeneration, necrosis, and regeneration, and many intracellular, gram-positive spores, English bulldog, canine.

2. Bladder: Cystitis, lymphoplasmacytic and neutrophilic, diffuse, mild, with fibrinoid vasculitis.

 

ETIOLOGIC DIAGNOSIS: Renal encephalitozoonosis

 

CAUSE: Encephalitozoon cuniculi 

 

GENERAL DISCUSSION:  

• Note – see N-F05 for a discussion of the neurologic manifestation of E. cuniculi
• Gram-positive, obligate intracellular eukaryotic microsporidian; closely related to fungi; zoonotic 
• Can infect a wide range of mammals, including humans, and clinical disease occurs most often in puppies, fox pups, and rabbits
• Organism develops in many tissues but most easily found in brain and kidney in acute active infection; difficult to find organisms in chronic infections
• Causes diffuse nonsuppurative to granulomatous interstitial nephritis and granulomatous encephalitis in immature dogs and rabbits; also a potential cause of immune mediated glomerulonephritis in domestic animals

 

PATHOGENESIS:  

• Infection is acquired through ingestion (of infected prey), inhalation, or transplacentally; organism excreted in urine and feces 
• Penetration of the host cell may be associated with an extruded polar filament injecting infective sporoplasm into host cell or active migratory process à merogony or schizogony within a parasitophorous vacuole à mature spores à cell ruptures à cycle repeats
• Organisms are spread hematogenously via macrophages and selectively parasitize vascular endothelium (especially in brain and kidney) and renal tubular epithelium; may localize in the liver, lungs, adrenal glands, spleen, eye or other vascular organs  

 

TYPICAL CLINICAL FINDINGS:

• Weak, stunted puppies with renal failure, central nervous signs, and death; may be a cause of the “fading puppy syndrome”
• Abortion 
• Neurologic and ocular (uveitis, cataract, lens rupture) in rabbits

 

TYPICAL GROSS FINDINGS: 

• Frequently no apparent lesions, but may see cortical petechiae or pitted gray areas in the kidney 
• Eye: Phacoclastic uveitis; cataract (Dwarf rabbits)

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

•   Kidney: Severe nonsuppurative to granulomatous interstitial nephritis that is plasma cell-rich; parasitophorus vacuoles full of spores present in the tubular epithelium cells, tubular lumens, endothelial cells and vessel walls
•   CNS: Widespread nonsuppurative meningoencephalomyelitis
•   Segmental vasculitis with organisms in endothelial cells in many other tissues (liver, heart, lung, spleen, eye) 
• Organisms are small (1.5-2.0 x 2.5 µm), oval and can be difficult to identify on H&E and in chronic infections; in acute active infections, organisms can be found free in a focus of inflammation; contained within a parasitophorous vacuole in endothelial cells, epithelial cells, macrophages; intracellularly with no associated inflammatory response (pseudocyst), or spores may be found free extracellular

 

ULTRASTRUCTURAL FEATURES:

• Organism is often within a parasitophorous vacuole
• Thick outer coat enclosing a coiled polar filament (polar tube) and one or two nuclei

 

ADDITIONAL DIAGNOSTIC TESTS:

• Gram stain (gram positive) 
• Giemsa 
• Acid-fast positive 

 

DIFFERENTIAL DIAGNOSIS:

•   Primary differential is Toxoplasma gondii  
•   Clinicopathologic and microscopic differences between T. gondii and E. cuniculi:

 

TOXOPLASMA	ENCEPHALITOZOON
Cysts are small (60um)	Intracellular parasitophorus vacuole or “pseudocysts” (60-120um)
Spores not birefringent or acid fast	Spores are birefringent and acid fast
No Gram staining or Gram negative	Gram positive
Giemsa:  Cytoplasm is granulated	Giemsa:  Cytoplasm is light blue
Stains well with H&E	Stains poorly with H&E
No staining with iron hematoxylin	Stains black with iron hematoxylin
Fatal in mice	Not fatal in mice
Larger organism (2-6um)	Smaller organisms (1.5-2.5um)

 

                                       

COMPARATIVE PATHOLOGY:  

• E. cuniculi has been documented in rabbits, mice, rats, muskrats, guinea pigs, hamsters, ground shrews, goats, sheep, pigs, horses, domestic dogs, wild and captive foxes, domestic cats, meerkats, a variety of carnivores, birds and nonhuman primates (specifically, New World primates)
•   Rabbits: Dwarf rabbits are especially susceptible; three main forms: neurologic, ocular, and renal; disseminated infection uncommon; rabbits may present with a variety of neurological signs: head tilt, ataxia, vestibular signs; ocular disease may develop with penetration of lens and lens rupture, phacoclastic uveitis, and/or cataract formation possibly following transplacental infection
• Rodents: Infections in laboratory rodents are generally subclinical
• Birds: 

• E. cunniculi can infect birds, but does not cause disease
• E. bieneusi genotype D causes raised yellow nodules in the spleen, kidneys, and liver of falcons and transmural necrotizing enterocolitis; cross reactive with E. cuniculi
• E hellem is reported in a variety of passerines and young captive psittacines and involves the eye and/or kidneys, liver, and intestines; in the kidney, causes lymphoplasmacytic interstitial nephritis; often co-infected with circovirus, polyomavirus, cryptosporidia, giardia, Chlamydia, or Macrorhabdus ornithogaster

• Bearded dragons: E. pogonae causes granulomatous arteritis of the large arteries of the heart, as well as in paratesticular granulomas, with numerous intrahistiocytic microsporidia

 

References:

 

1. Barthol SW, Griffey SM, Percy DH.  Pathology of Laboratory Rodents and Rabbits. 4th ed. Oxford, UK: John Wiley & Sons, Inc; 2016:293-295. 
2. Cantile C, Youssef S.  Nervous system. In: Maxie MG, ed. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier; 2016:385-386.
3. Church ME, Terio TA, Keel MK. Procyonidae, Viverridae, Hyenidae, Herpestidae, Eupleridae, and Prionodontidae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:314. 
4. Cianciolo RE, Mohr FC.  Urinary system. In: Maxie MG, ed. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. St. Louis, MO: Elsevier; 2016: 410, 431.  
5. Delaney MA, Treuting PM, Rothenburger JL. Lagomorpha. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:495. 
6. Reavill DR, Dorrestein G. Psittacines, Coliifomes, Musophagiformes, Cuculiformes. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:787. 
7. Schmidt R, Reavill DR, Phalen DN. Pathology of Pet and Aviary Birds. 2nd ed. Ames, IA: John Wiley & Sons, Inc.; 2015:111. 
8. Simmons J, Gibson S. Bacterial and Mycotic Diseases of Nonhuman Primates. In: Abee CR, Mansfield K, Tardif S, Morris T, eds. Nonhuman Primates in Biomedical Research: Volume 2: Diseases. 2^nd ed. San Diego, CA: Elsevier; 2012:148-150. 
9. Trupkiewicz J, Garner MM, Juan-Salles C. Passeriformes, Caprimulgiformes, Coraciiformes, Piciformes, Bucerotiformes, and Apodiformes. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:807. 
10. Wunschmann A, Armien AG, Childress AL et al. Intrapericardial Encephalitozoon pogonae-associated arteritis with fatal hemopericardium in two juvenile central bearded dragons. J Vet Diagn Invest. 2019; 31(3)
11. Wunschmann A, Armien AG, Hofle U, et al. Birds of Prey. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:731.

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