JPC SYSTEMIC PATHOLOGY
URINARY SYSTEM
February 2018
U-V06

Signalment (JPC # 1917806):  Cat, age, breed and sex unspecified

HISTORY:  This cat was weak, depressed, anorexic, and had severe halitosis upon presentation to the veterinary hospital.  Radiographs demonstrated enlarged kidneys.

HISTOPATHOLOGIC DESCRIPTION:  Kidney:  Diffusely affecting small and medium caliber venules, there is loss of the endothelium within the tunica intima and expansion and effacement of the tunica media and expansion of the tunica adventitia with many viable and degenerate neutrophils; fewer lymphocytes, histiocytes and plasma cells; necrotic cellular debris; fibrin and edema (phlebitis). This cellular infiltrate also expands the capsule up to 2 mm; separates, surrounds, and replaces glomeruli and tubules; and is admixed with plump fibroblasts, fibrous connective tissue, and abundant fibrin, hemorrhage, and edema. Rare venules within affected areas are occluded by an eosinophilic hyalinized fibrin with entrapped erythrocytes and leukocytes (fibrin thrombi). Multifocally within the cortex and medulla there are many ectatic tubules, lined by attenuated epithelium, which contain variable amounts of eosinophilic proteinaceous material, sloughed epithelial cells, necrotic debris, granular basophilic material (mineral), and variably sized anisotropic crystals (oxalate).   

MORPHOLOGIC DIAGNOSIS:  Kidney:  Phlebitis and interstitial nephritis, pyogranulomatous, multifocal, moderate with fibrin thrombi, tubular and glomerular loss, fibrinosuppurative capsulitis, and tubular oxalate crystals breed not specified, feline.

ETIOLOGIC DIAGNOSIS:  Coronaviral nephritis

CAUSE:  Mutated feline enteric coronavirus (feline infectious peritonitis virus)

GENERAL DISCUSSION:

• Family Coronaviridae, genus Coronavirus - enveloped, single stranded, positive sense RNA viruses
• Feline infectious peritonitis (FIP) is a worldwide, invariably fatal, sporadic, low prevalence viral disease of domestic and wild felids caused by feline coronavirus (FCoV)
• Purebred domestic cats and certain species of large cats (e.g. cheetahs) may be genetically predisposed to developing FIP
• FECV infects and replicates only in enterocytes, causing diarrhea or asymptomatic infection; FIPV infects and replicates primarily in macrophages, resulting in macrophage activation and systemic infection

PATHOGENESIS:

• Fecal-oral transmission and possibly inhalation of FCoV > replication in enterocytes / lymphoid system > mutation (FIPV), virus able to replicate in macrophages > secondary macrophage associated viremia and macrophage activation > dissemination to multiple organs and vessels (systemic infection) > host immune response
• The progression of disease depends on the cat’s immune response:
  • Strong cell-mediated immune response: Results in activation of macrophages, FIP virus replication is terminated, and cleared 
  • Weak or ineffective cell-mediated response: Delayed (Type IV) hypersensitivity response;  noneffusive (dry form) syndrome ensues, with a less florid macrophage response in tissue and reduced virus production; this form has a more prolonged clinical course (1-6 months)
  • No/ineffective cell-mediated immunity: Antibody is produced, but there is a failure to generate a cell-mediated response and cats develop effusive disease (wet form); vasculitis results from both Type III hypersensitivity response [primary immune complex] and activation of macrophages; this syndrome has a rapid clinical course, progressing to death in 1-12 weeks
• Granulomatous inflammation and granulomatous phlebitis (due to enhanced adhesion of virally infected monocytes/macrophages to endothelial cells)
• Antibody-mediated lysis of infected macrophages in or around vessels (predominantly veins) may enhance the inflammatory reaction
• Release of substance from infected cells causes apoptosis of bystander lymphocytes

TYPICAL CLINICAL FINDINGS:

Effusive (wet form):  Weight loss, dyspnea, tachypnea, mild pyrexia, icterus, scrotal enlargement, palpable abdominal masses (from adhesions)

• Clinicopathological features:
• Plasma proteins typically elevated because of hypergammaglobulinemia (may be polyclonal or monoclonal) due to chronic inflammation and antibody production
• Effusion is a high protein exudate or modified transudate
• Albumin:globulin ratio less than 8 and typically 0.45 or less (albumin level remains normal or falls slightly and globulin levels increase, possibly through stimulation of B cells by IL-6)
• Elevated Alpha1-acid glycoprotein (AGP) >1500 ug/mL
• Neutrophillia with left shift

Noneffusive (dry form): Typically granulomatous inflammation, localized in the lymph nodes, kidneys, uvea, meninges, ependyma, and choroid plexus of the brain and spinal cord with vague signs of dullness, weight loss and anorexia and CNS signs (ataxia, nystagmus, seizures) in 12.5% of cases

• Clinicopathological features:
• Neutrophilia with left shift
• Lymphopenia
• Nonregenerative anemia (HCT <30%; anemia of chronic disease)
• Cerebral spinal fluid elevated protein levels (56-348 mg/dL with normal <25 mg/dL) and pleocytosis (100-10,000 nucleated cells/mL)

TYPICAL GROSS FINDINGS:  

Effusive form – Pleural effusion (40%) and effusive peritonitis (60‑70%)

• The surfaces of abdominal and/or thoracic contents covered with small (1-2 mm) white plaques of fibrin with a granular appearance; large amounts of fibrin can result in adhesions on visceral and peritoneal surfaces
• Orchitis and periorchitis (reported, but uncommon) - scrotal swelling and enlarged testicles

Noneffusive form – Granulomatous lesions in various organs (on surface and throughout)

• Colon: Thickened with a gross appearance similar to alimentary lymphosarcoma
• Abdominal and thoracic lymph nodes: Lymphadenopathy
• Kidneys: Enlarged with vasculocentric pyogranulomas
• Brain: Hydrocephalus with gelatinous foci resembling cryptococcosis possible in cats with neurologic involvement
• Eye: Keratic precipitates in anterior chamber, hypopyon, hyphema, corneal edema

TYPICAL LIGHT MICROSCOPIC FINDINGS: 

• Phlebitis (vessels typically surrounded by a zone of necrosis and a mixed inflammatory cell infiltrate)
• Pyogranulomas, large or small, consolidated or numerous; focal tissue necrosis
• Lymphoid tissue: T-cell (CD4+ lymphocytes) and B-cell lymphocyte depletion due to apoptosis
• Eye: gliosis can be present in affected retinas; breakdown of the blood-ocular barrier may allow FCoV-bearing macrophages access to the eye

ULTRASTRUCTURAL FINDINGS:

• Coronaviruses are 80-160 nm in diameter and have a distinctive fringe of petal-shaped peplomers or spikes that resemble a crown or corona; peplomers are approximately 20 nm long and 7 nm wide at the tip
• Virions may form paracrystalline arrays

ADDITIONAL DIAGNOSTIC TESTS:

• Clinical signs, gross and histologic findings are critical diagnostically
• There is a lack of specificity of serologic tests for the FIP virus due to cross reaction with other antigenically related coronaviruses
• Detection of intracellular FCoV antigen by immunoflourescence or immunohistochemistry (CCV2-2 more sensitive than FIPV3-70)
• Virus detection tests include:
• RT-PCR (reverse transcriptase polymerase chain reaction) – can perform on abdominal or thoracic effusions
• Direct FA – monoclonal antibodies against FIP N protein
• Immunohistochemistry
• Electron microscopy

DIFFERENTIAL DIAGNOSIS:

• Effusive form: Chylothorax, pyothorax, cancers associated with effusion, heart failure or cirrhosis of the liver with abdominal transudate, chronic bacterial peritonitis
• Non-effusive form: Lymphosarcoma, steatitis, mycotic infections, toxoplasmosis
• For ocular lesions: Toxoplasmosis, lymphosarcoma and mycotic infections

COMPARATIVE PATHOLOGY:

• Avian:

• Chickens: Avian infectious bronchitis virus - tracheobronchitis, nephritis
• Turkeys: Bluecomb virus - enteritis

• Bovine: Bovine coronavirus - gastroenteritis (winter dysentery); bovine respiratory coronavirus
• Canine: Canine coronavirus - enteritis
• Guinea pigs: Coronavirus-like infection - enteritis, wasting syndrome
• Mice: Mouse hepatitis virus - hepatitis, enteritis, encephalomyelitis
• Mink: Mink enteric coronavirus
• Ferret:
  • Ferret enteric coronavirus - enteritis
  • Ferret systemic coronavirus infection - similar to dry form of FIP but no effusion, icterus, or increased bilirubin
• Rabbits:
  • Rabbit coronavirus - enteritis
  • Rabbit pleuritis virus - pleural effusion disease and cardiomyopathy
• Rats: Sialodacryoadenitis virus
• Swine:

• Transmissible gastroenteritis virus (TGEV)
• Porcine epidemic diarrhea virus - gastroenteritis
• Hemagglutinating encephalomyelitis virus - vomiting, wasting, encephalomyelitis
• Porcine respiratory coronavirus - mutation from TGEV

REFERENCES

1. Addie DD. Feline coronavirus infections. In: Greene CE, ed. Infectious Diseases of the Dog and Cat. 4th ed. Philadelphia, PA: Saunders Elsevier; 2012:92-108.
2. Fujii Y, Tochitani T, Kouchi M, et al. Glomerulonephritis in a ferret with feline coronavirus infection. J Vet Diagn Invest. 2015;27(5):637-640.
3. Garner MM, Ramsell K, Morera N, et al. Clinicopathologic features of a systemic coronavirus-associated disease resembling feline infectious peritonitis in the domestic ferret (Mustela putorius). Vet Pathol. 2008;45:236-246.
4. Graham E, Lamm C, Denk D, Stidworthy MF, Carrasco DC, Kubiak M. Systemic coronavirus-associated disease resembling feline infectious peritonitis in ferrets in the UK. Vet Rec. 2012;171(8):200-201.
5. Hartmann K. Coronavirus infections (canine and feline), including feline infectious peritonitis. In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine. Vol 1. 8th ed. Philadelphia, PA: Elsevier Saunders; 2017:984-991.
6. Kipar A, Kohler K, Leukert W, Reinacher M. Comparison of lymphatic tissues from cats with spontaneous feline infectious peritonitis (FIP), cats with FIP virus infection but no FIP, and cats with no infection. J Comp Pathol. 2001:125:182-191.
7. Kipar A, May H, Menger S, Weber M, Leukert W, Reinacher M. Morphologic features and development of granulomatous vasculitis in feline infectious peritonitis. Vet Pathol. 2005;42:321-330.
8. Kipar A, Meli ML. Feline Infectious Peritonitis: Still an Enigma? Vet Pathol. 2014;(51):505-526.
9. Labelle P. The eye. In: Zachary JF, McGavin MD, eds. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2016:1317-1318.
10. MacLachlan NJ, Dubovi EJ. Coronaviridae. In: MacLachlan NJ, Dubovi EJ, eds. Fenner’s Veterinary Virology. 4th ed. Oxford, UK: Elsevier Academic Press; 2011:402-404.
11. Mwase M, Shimada K, Mumba C, et al. Positive immunolabelling for feline infectious peritonitis in an African lion (Panthera leo) with bilateral panuveitis. J Comp Pathol. 2015;152(2-3):265-268.
12. Miller AD, Zachary JF. Nervous system. In: Zachary JF, McGavin MD, eds. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2016:896-897.
13. Oliveira LB, Susta L, Rech RR, et al. Vet med today: pathology in practice. 2014; 245(8):899-901.
14. Pesavento PA, Murphy BG. Reviews: Common and Emerging Infectious Diseases in the Animal Shelter. Vet Pathol. 2014;(51):478-491.
15. Poncelet L, Coppens A, Peeters D, Bianchi E, Grant CK, Kadhim H. Detection of antigenic heterogeneity in feline coronavirus nucleocapsid in feline pyogranulomatous meningoencephalitis.Vet Pathol. 2008;45:140-153.
16. Stranieri A, Paltrinieri S, Giordano A. Diagnosing feline infectious peritonitis using sysmex XT-2000iV based on frozen supernatants from cavitary effusions. J Vet Diagn Invest. 2017; 29(3):321-324.
17. Uzal FA, Plattner BL, Hostetter JM. Alimentary system. In: Maxie MG, ed. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. Philadelphia, PA: Elsevier Saunders; 2016:253-255.
18. Zachary JF. Mechanisms of microbial infections. In: Zachary JF, McGavin MD, eds. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2016:217-218.
19. Ziolkowska N, Pazdzior-Czapula K, Lewczuk B, et al. Feline infectious peritonitis: immunohistochemical features of ocular inflammation and the distribution of viral antigens in structures of the eye. Vet Pathol. 2017;54(6):933-944.

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