JPC SYSTEMIC PATHOLOGY

URINARY SYSTEM

January 2024

U-V08

 

Signalment (JPC # 1851279): 10-day-old budgerigars

 

HISTORY: Flock had high mortality in birds less than 15 days of age. Grossly, nesting down feathers were nearly absent.

 

HISTOPATHOLOGIC DESCRIPTION: Kidney: Multifocally, Glomerular tufts are often swollen with a decreased uriniferous space or have synechia. Mesangial cells are swollen with vacuolated cytoplasm (degeneration) and nuclei are often expanded up to three times normal size (karyomegaly) by 10 to 20µm diameter amphophilic, glassy intranuclear inclusions that peripheralize chromatin. Tubular epithelial cells often exhibit similar swelling and intranuclear inclusions as those in mesangial cells or are shrunken with bright eosinophilic cytoplasm and a pyknotic nucleus (necrosis), and tubular lumina are often filled with cellular debris and sloughed epithelial cells with few previously described intranuclear inclusions. There is multifocal interstitial hemorrhage. 

 

MORPHOLOGICAL DIAGNOSIS: Kidney: Mesangial and tubular degeneration and necrosis, multifocal, moderate, with karyomegaly and intranuclear inclusion bodies, budgerigar (Melopsittacus undulatus), avian.

 

ETIOLOGIC DIAGNOSIS: Polyomaviral nephritis

 

CAUSE: Budgerigar fledgling disease virus (BFDV-1) – avian polyomavirus 

 

CONDITION: Budgerigar fledgling disease (BFD)

 

GENERAL DISCUSSION:  

• Avian polyomavirus causes disease primarily in psittacines (especially budgerigars, lovebirds, macaws, conures, caiques, eclectus parrots, and ring-necked parrots); histologic lesions vary by species; budgerigar and non-budgerigar parrots may express the disease differently
• Most consistent lesions include hepatic necrosis and membranous glomerulonephritis
• Avian polyomavirus generally causes acute, fatal disease in fledgling animals (30-80% mortality); affected budgerigars are typically 10 to 20d old; conures, 2 to 4 wks; macaws, 4 to 8 wks; eclectus parrots, 4 to 14 wks 
• Disease in adult parrots is rare (immunosuppressed); feather abnormalities
• Polyomaviruses are small, double-stranded, unenveloped, circular DNA viruses; the viral genome is functionally divided into early, late and regulatory regions; the early region encodes DNA regulatory proteins known as large or small T (tumor) antigens
  • Large T: Binds pRb gene, which leads to the inactivation of the p53 tumor suppressor gene
  • Small T: Stimulates expression of increased cyclin D1 (cell cycle initiator) 
• Polyomaviruses are potentially oncogenic (mammals) and can cause tumors in multiple tissues; avian polyomavirus has not been demonstrated to be oncogenic
• There are several different but closely related strains of avian polyomaviruses, each with a distinct tropism for various avian species; infections reported in several bird species include conures, Amazon and other parrots, macaws, cockatoos, cockatiels, lorries, lovebirds, parakeets, finches, geese, aracaris, falcons, buzzards, and chickens  

 

PATHOGENESIS:  

• Feather dander, regurgitated food fed to nestlings, respiratory secretions, and/or urinary excretions all serve as a source of infection; there is speculation that vertical transmission through the egg is possible  
• Virus replicates at the site of entry > released into the blood stream (viremia) > infects and replicates in a variety of different target cells 
• The development of immunocompetence is critical to surviving infection;  nestlings unprotected by passive antibody are susceptible and experience high mortality  
• Protected and older immunocompetent birds may survive mild disease but can become persistently infected carriers  
• Coinfection with psittacine circovirus can worsen disease due to immune suppression from PsCV
• Glomerulopathy secondary to immune complex deposition (type III hypersensitivity) 

 

TYPICAL CLINICAL FINDINGS: 

• The majority of polyomavirus infections are asymptomatic
• Often, affected birds die suddenly without clinical signs
• May briefly show weakness, have pallor, subcutaneous hemorrhage, anorexia, dehydration, inappetence, and crop stasis

 

TYPICAL GROSS FINDINGS:  

• Budgerigars:
  • GI tract: Full crop, distended abdomen (ascites) 
  • Liver: Hepatomegaly, yellow-white foci (necrosis)
  • Skin: Subcutaneous hemorrhage, feather dystrophy (lack of downy feather development in birds that survive up to 28 days of age; incomplete development of tail and contour feathers in older birds)
  • Heart: Hydropericardium, cardiomegaly and myocardial hemorrhage
  • Kidney: Swelling and serosal hemorrhages
• Nonbudgerigar parrots:
  • Typically well grown, well-muscled and have substantial body fat
  • Splenomegaly and hepatomegaly with variable mottling (necrosis)
  • Subcutaneous and subserosal hemorrhage
  • Enlarged bursa of Fabricius with serosal hemorrhages

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:  

• Budgerigars:
  • Karyomegaly with marginated chromatin and large clear to amphophilic intranuclear inclusion bodies; differentiate from adenovirus inclusions based on tinctorial properties (confirm with additional diagnostic)
    • Most often in kidney (mesangial and less in tubular epithelium); present in brain, spleen (PALS), liver (hepatocytes), myocardium, pancreas, intestine, lung, skeletal muscle and bone marrow  
    • Karyomegalic cells numerous in feather follicles; focal to confluent ballooning degeneration in the follicular epithelium, barb ridges and cells in the pulp
    • There is often necrosis, but generally little inflammation associated with the karyomegalic, inclusion-bearing cells
  • Mesangial cell necrosis is common
  • Swollen glomeruli due to capillary endothelial cell swelling
  • Up to 70% of affected birds develop secondary glomerulopathy 
    • Due to immune complex deposition 
    • Immune complex Y, with smaller amounts of immune complex M) 
    • Deposits appear as PAS positive aggregates in capillary lumina and mesangium, with or without subendothelial deposits
• Non-budgerigar parrots:
  • Midzonal to massive hepatic necrosis (severity varies by species)
  • Inclusion bodies may be seen in Kupffer cells
  • Splenic and renal lesions are common
  • Karyomegalic cells may also be present in kidney (mesangial cells); mesangial cell necrosis is common; glomerular capillary endothelial cells are often swollen and capillary walls may be thickened by dense immune complex deposition (type III hypersensitivity; membranous glomerulonephritis)
• Finch: 
  • Renal tubular epithelial and mesangial karyomegaly with INIBs
  • Urate accretions in kidneys
  • Chronic renal disease and glomerulosclerosis in surviving birds

            

ULTRASTRUCTURAL FINDINGS:  

• Intranuclear virions, 40 to 48 nm, nonenveloped, icosahedral paracrystalline array

 

ADDITIONAL DIAGNOSTIC TESTS:  

• Serology is especially useful for carriers; viral antibodies remain elevated for lifetime in a persistently infected carrier bird
• PCR (liver, kidney, +/- spleen) is effective and can detect presence of virus in tissues without histological lesions (Gibson et al., JVDI, 2019)
• IHC, ISH, TEM

 

DIFFERENTIAL DIAGNOSIS:

• Intranuclear inclusions in avian kidneys:
  • Lead toxicity:  Intranuclear acid-fast inclusions in tubular epithelium 
  • Pacheco’s disease (Psittacid herpesvirus 1): Intranuclear eosinophilic inclusions (Cowdry A) in psittacine tubular epithelium, hepatocytes, splenic reticuloendothelial cells and bile duct epithelium; coagulative necrosis of hepatocytes
  • Adenovirus: Psittacine birds; kidney may or may not be only organ affected; histologic lesions may be minimal including interstitial inflammation and tubular changes including karyomegalic nuclei with large darkly eosinophilic or basophilic intranuclear inclusion bodies; differentiate from adenovirus inclusions based on tinctorial properties

• Older birds with feather lesions: 
  • French moult (unknown etiology): Breakage and loss of flight and tail feathers; bilateral and symmetrical  
  • Psittacine beak and feather disease (Circovirus): Psittacines only; usually in young birds during first feather formation; causes symmetric feather dystrophy and loss, beak deformities, with globular, basophilic, botryoid intracytoplasmic inclusion bodies in macrophages and basophilic intranuclear inclusions in epithelial cells; may be concurrent with BFD

 

COMPARATIVE PATHOLOGY: 

• Goose: Goose hemorrhagic polyomavirus causes hemorrhagic nephritis and enteritis; this is the only known polyomavirus that does not produce viral inclusion bodies
• Other birds: Finch, canary, crow, and butcherbird polyomaviruses cause similar disease to that seen in psittacines
• Hamster: Transmissible lymphoma and trichoepitheliomas in hamsters are caused by hamster polyomavirus (HaPV), no inclusions
• Raccoons: Olfactory neuroglial brain tumors associated with polyomavirus
• Mouse: Important polyomaviruses of mice include mouse polyomavirus (parotid tumor agent/salivary gland tumor virus) and K virus. Also genetically engineered MMTV-PyMT (mouse mammary tumor-polyomavirus middle T antigen) mouse used as mammary cancer model (Shanker et al. J Comp Pathol 2023)
• Rat: Polyomavirus (serologically distinct from mouse polyoma and K viruses)
• Cottontail rabbit: Subclinical infection with rabbit kidney vacuolating virus; intranuclear inclusions in renal tubular epithelium an incidental finding in domestic rabbits
• Nonhuman primate: SV40 virus (polyomavirus); latent infection in rhesus monkeys is common, usually with no clinical signs; in immunocompromised (SIV infected) macaques, SV40 may cause interstitial pneumonia, renal tubular necrosis, encephalitis and demyelination similar to Progressive Multifocal Leukoencephalopathy (PML) in humans; large basophilic intranuclear inclusions are present in lung, oligodendroglia and renal tubular epithelium

 

References: 

1. Abdul-Aziz T, Fletcher OJ, Barnes HJ. Avian Histopathology. The American Association of Avian Pathologists. 4th ed. 2016:426,454.
2. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: Blackwell Publishing Professional; 2016:19-21; 122; 176-178; 197.
3. Church ME, Terio KA, 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; 2018:309.
4. Delaney MA, Treuting PM, Rothenburger JL. Rodentia. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:506-507
5. Fahey MA, Westmoreland SV. Nervous system disorders of nonhuman primates and research models. In: Abee CR, Mansfield K, Tardif S, Morris T, eds. Nonhuman Primates in Biomedical Research: Diseases. Vol 2. 2nd ed. San Diego, CA: Academic Press; 2012:739-741.
6. Gibson DJ, Nemeth NM, Beaufrère H, et al. Development and use of a triplex real-time PCR assay for detection of three DNA viruses in psittacine birds. J Vet Diagn Invest. 2019;31(5):719-725.
7. Ito S, Chambers JK, Mori C, et al. Comparative In Vitro and In Vivo Studies on Feline, Canine, and Human Merkel Cell Carcinoma. Vet Pathol. 2021;58(2):276-287.
8. Ito S, Chambers JK, Son NV, et al. Hamster polyomavirus-associated T-cell lymphomas in Syrian hamsters (Mesocricetus auratus). Vet Pathol. 2023;60(2):267-275.
9. Reavill DR, Dorrestein G. Chapter 32: Psittacines, Coliiformes, Musophagiformes, Cuculiformes. In: Terio KA, McAloose D, St. Leger J, ed. Pathology of Wildlife and Zoo Animals, Cambridge, MA Academic Press; 2018: 786-787.
10. Schmidt RE, Reavill DR, Phalen DN, eds. Pathology of Pet and Aviary Birds. Ames, IA: Iowa State Press; 2016:130-132.
11. Shanker EM, Beck AP. If you give a mouse a mutation: comparing the therapeutic utility of renowned mouse models of human cancers. J Comp Pathol. 2023;203:26-30.
12. Trupkiewicz J, Garner MM, Juan-Sallés C. Chapter 33: Passeriformes, Caprimulgiformes, Coraciiformes, Piciformes, Bucerotiformes, and Apodiformes. In: Terio KA, McAloose D, St. Leger J, ed. Pathology of Wildlife and Zoo Animals, Cambridge, MA Academic Press; 2018:807.
13. Wachtman L, Mansfield K. Viral diseases of nonhuman primates. In: Abee CR, Mansfield K, Tardif S, Morris T, eds. Nonhuman Primates in Biomedical Research: Diseases. Vol 2. 2nd ed. San Diego, CA: Academic Press; 2012:30-33.

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