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Read-Only Case Details Reviewed: Jan 2009
AFIP SYSTEMIC PATHOLOGY

JPC SYSTEMIC PATHOLOGY

URINARY SYSTEM

January 2018

U-M15

 

Signalment (AFIP #1518769): New Zealand Black (NZB) mouse

 

HISTORY: None

 

HISTOPATHOLOGIC DESCRIPTION: M15a: Kidney: Glomerular tufts diffusely and globally exhibit the following changes: mild to moderate thickening of mesangial matrix and basement membranes by eosinophilic amorphous material (matrix), moderate hypercellularity, and hypertrophic visceral epithelial cells/podocytes. Focally, glomeruli exhibit one or more of the following changes: occasional karyorrhectic debris in place of mesangial and/or endothelial cells (lytic necrosis), multifocal adherence of tufts to Bowman’s capsule (synechia), mild thickening of Bowman’s capsule, hypertrophied parietal epithelial cells, and ectatic urinary spaces. Multifocally, tubules are ectatic and occasionally contain proteinaceous eosinophilic material (proteinosis), sloughed epithelial cells (cellular casts) and/or mineral. Tubular epithelial cells are often attenuated, and/or contain yellow-brown pigment, or many eosinophilic globules within the cytoplasm. Plasma cells and lymphocytes are present multifocally in scattered small aggregates within the interstitium frequently around vessels. The kidney surface is diffusely irregular and pitted.

 

M15b: Kidney (PAS): The mesangium and basement membranes of glomerular capillaries, Bowman’s capsules, and occasional tubules are mildly thickened by PAS-positive material.

 

MORPHOLOGIC DIAGNOSIS: Kidney: Glomerulonephritis, membranoproliferative, chronic, diffuse, global, moderate, with glomerulosclerosis, and lymphoplasmacytic interstitial nephritis, NZB mouse, rodent.

 

Signalment (AFIP #1771042): 8-year-old mixed breed terrier

 

HISTORY: Polyuria/polydipsia, lethargy and ascites. Significant clinical laboratory data include: BUN-145; creatinine-4.5; total protein-3.6; albumin-1.1; calcium-7.2; urinary protein 3+; urine specific gravity-1.018; no significant sediment in urine. No reference intervals are provided.

 

HISTOPATHOLOGIC DESCRIPTION: M15c: Kidney: Diffusely within the cortex, the glomeruli exhibit one or more of the following changes: diffusely and globally, the glomerular basement membrane (GBM) is thickened by a densely eosinophilic homogenous material (membranous change); glomerular tufts are occasionally enlarged with increased numbers of hypertrophic visceral epithelial cells; dilated uriniferous spaces; rare, small periglomerular interstitial aggregates of plasma cells and lymphocytes. Renal tubular epithelium exhibit one or more of the following changes: mild tubular degeneration (swollen and vacuolated cytoplasm); necrosis (hypereosinophilic cytoplasm with nuclear pyknosis, karyorrhexis, or karyolysis); rare regeneration (basophilic cytoplasm with vesiculate nuclei, mitotic figures, piling up of epithelium); intraluminal eosinophilic homogenous material (proteinaceous fluid) occasionally admixed with sloughed cellular and karyorrhectic debris (cellular casts); and tubular epithelial and luminal yellow-brown globular pigment (hemosiderin or lipofuscin)

 

M15d: Kidney (PAMS - silver): Glomerular basement changes, including spikes and holes, associated with membranous glomerulonephropathy and best visualized with silver stain are subtle and inconsistent in this section

 

M15e: Kidney (Masson): Diffusely there are regularly spaced red nodules along the abluminal surface of capillary walls (immune deposits)

 

MORPHOLOGIC DIAGNOSIS: Kidney: Glomerulonephritis, membranous, diffuse, global, moderate, with tubular degeneration and protein casts, terrier mix, canine.

 

ETIOLOGIC DIAGNOSIS: Immune-mediated glomerulonephritis (presumed, demonstration of immune complexes or complement required for definitive diagnosis)

 

CAUSE: Immune-mediated

 

GENERAL DISCUSSION:

·      Glomerulonephritis (GN) in domestic animals is classified based on histologic appearance as: Membranous, proliferative, membranoproliferative, mesangioproliferative or glomerulosclerosis

o  Membranous: basement membrane thickening predominates

o   Proliferative: cellular proliferation predominates in the absence of significant basement membrane alterations, +/- immune complexes

o   Membranoproliferative (mesangiocapillary): both membranous and proliferative changes predominate

o   Mesangioproliferative: there is increased cellularity with immune complexes in the mesangium

o   Glomerulosclerosis: there is an increase in mesangial matrix and obliteration of capillary lumina; this may progress to glomerular obsolescence, characterized by marked hyalinization resulting in a shrunken, eosinophilic, hypocellular mass

·      GN and glomerulopathy are often used interchangeably; however, glomerulonephritis has been more recently and concisely defined as a primary glomerular disease with secondary tubulointerstitial and vessel changes, while glomerulopathy is defined as glomerular disease without inflammatory cells and/or of unknown etiology/pathogenesis.

·      Cats: membranous GN may predominate but reports may have included tissues that were not thoroughly analyzed according to current recommendations

·      Horses: proliferative GN predominates buy also can see other types; horses may have atypical ICs that resemble a specific GN in people (immunotactoid GN)

·      Clinical, clinical pathologic, and histologic evidence are required for definitive diagnosis of GN; histologic changes can be present without clinical signs

 

PATHOGENESIS:

·      Most cases of GN are immune-mediated and may result from the deposition of circulating preformed immune complexes in glomeruli, from formation of antibodies against the glomerular basement membrane, or from activation of the alternative pathway of complement

o   Immune complex disease can be caused by any infection of low pathogenicity that produces persistent antigen

o   Type II hypersensitivity reactions result from circulating antibodies binding to intrinsic / self-antigens or binding to exogenous antigens bound to or located within the glomerulus

o   Type III hypersensitivity reactions result from circulating immune complex deposition; causative antigens may be exogenous or endogenous

·      Antigen-antibody complexes can result in complement fixation with resultant chemotaxis of neutrophils

o   complement components C3a, C5a and C567 can attract neutrophils

o   C5b-9, the membrane attack complex, can also injure glomeruli by releasing chemokines and oxidants that damage cellular constituents

o   complement fragments can also cause histamine release from mast cells, increasing capillary permeability à possible increased deposition of IC in capillary wall

·      Immune complexes can localize within different areas of the glomerulus

o   using TEM, complexes can be identified as subendothelial, subepithelial, intramembranous, or within the mesangium

·      Direct epithelial cell injury can occur leading to loss of foot processes, vacuolization, retraction and epithelial detachment

·      Immune complexes can be removed over time but glomerular changes persist (such as thickened basement membrane)

·      Mediators of glomerular injury include:

  • Complement activation and generation of chemotactic components and formation of membrane attack complex (MAC)
  • Antibody-dependent cell-mediated cytotoxicity (ADCC)
  • Leukocyte influx and release of oxygen-free radicals and lysosomal enzymes
  • Cytokine synthesis and generation of proinflammatory lipid mediators by leukocytes and resident glomerular cells (epithelial and mesangial cells)
  • Extra cellular matrix modification
  • Activation of coagulation cascade
  • Altered physical forces/non-immunologic changes (altered hemodynamics and physical charge)

·      Complement is also capable of solubilizing ICs to facilitate their removal; hereditary hypocomplementemia may lead to persistence of ICs and contribute to glomerular injury

 

TYPICAL CLINICAL FINDINGS:

·      Proteinuria – hallmark sign; urine protein to urine creatinine ratio is usually 5-15

·      Nephrotic syndrome – proteinuria, hypoalbuminemia; generalized edema; hypercholesterolemia

 

TYPICAL GROSS FINDINGS:

·      Bilateral distribution

·      Acute glomerulonephritis may not significantly alter gross appearance

·      Kidneys may be enlarged early (pale, edematous) and later shrunken with granular pitted surface

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

·      Glomerular endocapillary hypercellularity caused by polymorphonuclear leukocytes, or endothelial or mesangial cell hyperplasia

·      Periodic acid Schiff (PAS) and Jones methenamine silver may reveal remodeling of the glomerular basement membrane (GBM) with spike-like projections on the sub-epithelial surface OR remodeling of the GBM characterized by double contours of the GBM (See reference 4 below, Figure 1 and/or reference 6 table 7)

·      Masson’s trichrome stain may demonstrate red ‘dots’ suggestive of large immune complexes (most often noticeable subepithelially but may also be observed on the luminal side of the GBM as well)

·      In dogs there tends to be diffuse glomerular involvement

·      Capsular cells may form crescents

·      Synechia may obliterate the urinary space

 

ULTRASTRUCTUAL FINDINGS:

·      Local or diffuse mesangial proliferation

·      Thickening or splitting of the glomerular basement membrane due to deposition of variably electron-dense material (immune complexes) in four patterns:

·      Subendothelial

·      Intramembranous

·      Subepithelial

·      Within the mesangium

·      Fusion of visceral epithelial (podocyte) foot processes

·      Parietal epithelial proliferation (crescents)

·      Periglomerular fibrosis

·      Endothelial alterations

·      Minimal change disease is characterized by minimal to absent light microscopic changes and ultrastructural diffuse loss of epithelial cell foot processes

 

ADDITIONAL DIAGNOSTIC TESTS:

·      Immunofluorescence or immunohistochemistry demonstration of immunoglobulin or complement component in the glomerular tuft

·      PAS stains basement membranes bright pink

·      Masson’s trichrome may help highlight immune complexes (red dots)

·      Jones methenamine silver highlights the GBM and may reveals spikes or double

contours of the GBM

·      TEM to highlight electron-dense immune complexes

 

DIFFERENTIAL DIAGNOSIS:

·      Glomerular amyloidosis: smooth, eosinophilic, amorphous deposits in glomeruli; Congo red will stain amyloid (green birefringence under polarized light)

·      Glomerular changes with chronic nephropathy of B6C3F1 mice are not immune-mediated

·      Diabetic glomerulosclerosis: ultrastructurally, there is regular thickening of GBM and no electron dense deposits; termed diabetic nodular glomerulosclerosis (nodules are called Kimmelstiel-Wilson nodules in people)

 

COMPARATIVE PATHOLOGY:

·      Mice:

o   NZB hybrids’ (these mice and their crosses have naturally occurring immune disease) incidence approaches 100%

o   Relatively common in other strains: AKR, BALB/c, B6, CBA, and 129/SvTer mice

o   There is thickening of the GBM with deposition of PAS-positive material +/- proliferation of mesangial cells; focal to diffuse mononuclear cell infiltration and fibrosis may be present in the interstitium

·      Dogs: GN is usually membranoproliferative type, but all other types have been described; GN may be secondary to a variety of conditions including dirofilariasis, infectious canine hepatitis, pyometra, systemic lupus erythematosus, autoimmune hemolytic anemia, leishmaniasis, and neoplasia

o   Brittany spaniels: autosomal recessive C3 deficiency resulting in decreased IgG, increased IgM and recurrent sepsis and immune-complex membranoproliferative glomerulonephritis

·      Cats: GN is usually membranous and can be secondary to feline leukemia virus infection, feline infectious peritonitis, neoplasia, and other conditions

·      Cows: Proliferative GN is a common finding but usually no clinical signs; BM thickening is usually not evident; bovine viral diarrhea and trypanosomiasis have been associated with GN in cattle

·      Sheep: In hereditary membranoproliferative (mesangiocapillary) GN of Finnish Landrace sheep, a hereditary deficiency of C3 (hypocomplementemia) leads to impaired complement-mediated solubilization of immune complexes

·      Horses: GN associated with equine infectious anemia (lentivirus)

·      Swine: GN associated with chronic classical swine fever (porcine pestivirus) and African swine fever (asfarvirus)

·      Gottingen Minipigs: Spontaneous membranous or membranoproliferative glomerulonephritis; unknown cause

·      Yorkshire pigs: have an autosomal recessive hereditary factor H deficiency

·      Pig-tailed macaques: Crescentic glomerulonephritis with IgA immune complex deposition in the glomerular basement membrane and mesangium

·      Common marmosets: Spontaneous glomerular, tubular, and interstitial lesions: (glomeruli) increase in mesangial matrix with slight mesangial proliferation; IgA and IgM may be involved with the pathogenesis; (tubular) regeneration and hyperplasia; (interstitium) inflammation and fibrosis

·      Gerbils: Chronic glomerulopathy is seen in older gerbil and is characterized by glomerular hypercellularity, thickening of glomerular basement membranes, and tubular degeneration with dilation and cast formation in tubules

 

REFERENCES:

 

1.    Aresu L, Benali S, Ferro S. et al. Light and electron microscopic analysis of consecutive renal biopsy specimens from Leishmania-seropositive dogs. Vet Pathol. 2012; 50(5): 753-760.

2.    Barthold SW, Griffey SM, Percy DH. Mouse. In: Barthold SW, Griffey SM, Percy DH eds. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: John Wiley & Sons, Inc. 2016:102.

3.    Breshears MA, Confer AW. The urinary system. In: Zachry JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St Louis, MO: Elsevier; 2012017:644-650.

4.    Cianciolo RE, Brown CA, Morh FC et al. Consensus statement: Pathololgic evaluation of canine renal biopsies: methods for identifying features that differentiate immune-mediated glomerulonephritides from other categories of glomerular diseases. J Vet Intern Med. 2013; 27:S10-18.

5.    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; 2016:401-418

6.    Cianciolo RE, Mohr FC, Aresu L et al. World small animal veterinary renal pathology initiative: classification of glomerular disease in dogs. Vet Pathol. 2016; 53(1): 113-135.

7.    Isobe K, Adachi K, Hayashi S: Spontaneous Glomerular and Tubulointerstitial lesions in Common Marmosets (Callithrix jacchus). Vet Pathol. 2012; 49(5):839-845.

8.    Gonzales-Viera O, Ruoppolo V, Marigo J et al. Renal lesions in cetaceans from Brazil. J Comp Path. 2015; 152(4): 345-354.

9.    Vezzali E, Manno RA, Slaerno D. Spontaneous Glomerulonephritis in Gottingen Minipigs. Tox Pathol. 2011;39:700-705


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