JPC SYSTEMIC PATHOLOGY
Signalment (AFIP #81-978): Adult owl monkey (Aotus trivirgatus), gender unspecified
HISTORY: This owl monkey had been maintained in a research laboratory.
HISTOPATHOLOGIC DESCRIPTION: Kidney: Diffusely there are changes at all levels of the nephron. Glomeruli have one or more of the following changes: thickening of the mesangial matrix; thickening and hyalinization of Bowman’s capsule; hypercellularity; hypertrophy of the parietal and visceral epithelium; thickening of the glomerular basement membrane; glomerulosclerosis (obsolescence); synechiae between the glomerulus and Bowman’s capsule; homogeneous brightly eosinophilic proteinaceous fluid within the uriniferous space and periglomerular fibrosis. Multifocally, infiltrating the interstitium, surrounding, separating and replacing tubules and glomeruli are high numbers of lymphocytes, plasma cells and eosinophils. Multifocally, tubules within areas of inflammation have one or more of the following changes: shrunken with attenuated epithelium and thickened basement membranes up to two times normal (atrophy); ectasia; homogeneous brightly eosinophilic intraluminal protein casts (proteinosis) and variable amounts of intraluminal sloughed epithelial cells, necrotic and cellular debris. Multifocally, tubular epithelium is swollen with vacuolated cytoplasm (degeneration); has bright eosinophilic cytoplasm with a shrunken, pyknotic or absent nucleus (necrosis) or has amphophilic cytoplasm with a high nuclear to cytoplasmic ratio and piles up (regeneration). Rarely, tubular epithelial cells contain intracytoplasmic golden-brown, granular pigment (bile or hemosiderin). There is mild, diffuse interstitial medullary fibrosis. Multifocally, the subcapsular surface is irregular and occasionally indented.
Kidney: Periodic acid methenamine silver strain (PAMS stain): Multifocally, there is thickening and reduplication of glomerular basement membranes
MORPHOLOGIC DIAGNOSIS: Kidney: Glomerulonephritis, membranoproliferative, chronic, multifocal, moderate, with glomerular obsolescence, lymphoplasmacytic and eosinophilic interstitial nephritis, tubular degeneration, atrophy, and proteinosis, owl monkey (Aotus trivirgatus), nonhuman primate.
CONDITION: Glomerulonephritis (GN)
- Glomerulonephritis, interstitial nephritis and nephrotic syndrome are common causes of morbidity and mortality in captive owl monkeys; other causes include hemolytic anemia and myocardial disease
- Among primates, glomerulopathies most common in New World species [squirrel monkey (IgM), owl monkey, marmoset], also occurs in several prosimian species and to a lesser extent in macaques
- May be membranous, mesangioproliferative or sclerotic
- Glomerulonephritis (GN): usually of immune origin, is a common form of renal disease affecting all domestic animals; the underlying etiology is often not determined
- GN implies that secondary tubulointerstitial and vascular changes accompany a primary glomerular disease
- Glomerulitis: used when inflammation is restricted to glomeruli (e.g. acute septicemia)
- Glomerulonephropathy: refers to glomerular disease without inflammatory cells or with uncertain etiology or pathogenesis
- Membranous GN: glomerular basement membrane (GBM) remodeling secondary to immune complex deposition
- Membranoproliferative GN (mesangiocapillary): proliferation with remodeling of capillary loop from IC deposition, usually between endothelial cell and GBM
- Mesangioproliferative: there is increased cellularity with immune complexes in the mesangium
- Proliferative GN: increased cellularity (endothelial, epithelial, or mesangial cells) without significant alterations to GBM
- It should be noted that not all references agree in this distinction with some stating that proliferative GN is merely a variant of membranoproliferative GN
- Segmental glomerulosclerosis: segmental effacement of peripheral capillary loops
- Global glomerulosclerosis (glomerular obsolescence): tuft is shrunken, eosinophilic and hypocellular
- Lesions are consistent with an immune-mediated, membranoproliferative glomerulonephritis
- Exact mechanism for this species has not been elucidated
- Proposed causes include malarial infections, filarial parasites, genetic predisposition, and other infectious causes
- Could result from accumulate of circulating immune complex in the glomerulus or by in situ formation of glomerular basement antigen with subsequent accumulation of immune aggregates (anti-GBM disease)
- Any infection of low pathogenicity that is able to produce persistent antigenemia has to potential to cause IC disease
- Most cases of GN are immune-mediated (ICGN) and may be primary (idiopathic) or secondary to other diseases or conditions
- Immune complexes form when there is antigen-antibody equivalency or slight antigen excess à complexes selectively deposit in glomerular capillaries due to increased permeability of the glomeruli basement membranes à activated platelets stimulate complement fixation with formation of C3a, C5a and C567 à mesangial and endothelial cell proliferation à neutrophils release proteinases and oxidants (e.g. hydrogen peroxidase, oxygen-derived free radicals) and arachidonic acid metabolites which damage the basement membrane à leakage of protein into the glomerular filtrate
- Continue to damage basement membrane by the release of biologically active molecules from monocyte infiltration (in later stages of inflammation)
- Both the glomerular epithelial cells and mesangial cells produce damaging oxidants and proteases in response to the direct action of C5b-C9 on the glomerulus
- To confirm anti-GBM ICGN, Ig and/or complement (usually C3), must be demonstrated in glomeruli (via IHC, IF or EM)
- Factors determining extent of deposition of immune complexes:
- Persistence of immune complexes in circulation
- Glomerular permeability
- Size (small or intermediate-sized complexes are the most damaging; large complexes are readily removed from circulation by phagocytosis)
- Molecular charge of immune complexes (cationic immune complexes interact with anionic sites on endothelial cells and within the membrane proper)
- The strength of the bond between antigen and antibody (avidity)
TYPICAL CLINICAL FINDINGS:
- Nephrotic syndrome (proteinuria, hypoalbuminemia, hypercholesterolemia and edema)
TYPICAL GROSS FINDINGS:
- Subacute glomerulonephritis enlarged, pale and tan, smooth surface, non-adherent surface
- Chronic shrunken and contracted with generalized fine granularity of capsular surface
- Ascites and peripheral edema (part of nephrotic syndrome)
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Glomeruli: Cellular proliferation, increased mesangial matrix, glomerulosclerosis, synechiae, periglomerular fibrosis, thickened capillary loops
- Interstitial inflammation: Eosinophils, lymphocytes and plasma cells predominate
- Ectatic tubules containing protein casts
- Cortical interstitial fibrosis
- Immunofluorescent studies reveal granular deposits of immunoglobulins and complement within affected glomeruli and occasionally surrounding tubules
- Classification of ICGN
- Focal – involving <50% of glomeruli
- Diffuse – involving >50% of glomeruli
- Segmental – involving portion of glomerular tuft
- Global – involving all of glomerular tuft
- Mesangial – primarily affects mesangial area
- Deposits of electron dense granular material in the glomerular basement membrane and mesangial matrix
- Thickening of the lamina densa of the basement membrane; deposits extend into the subepithelial regions in more advanced lesions
- Thickening, fusion and distortion of epithelial/podocyte foot processes
ADDITIONAL DIAGNOSTIC TESTS:
- Diagnosis of ICGN can be made by IF or IHC demonstration of Ig and complement components, usually C3, in glomerular tufts
- IF: Granular staining along capillary loops with antibodies against IgG, lambda light chains, C3
- JMS and PAS used to visualize GBM contours
- Systemic trauma (muscle crushing injury) causing rhabdomyolysis, myoglobinemia, and subsequent renal failure; renal lesions consist of tubular degeneration and necrosis with myoglobin casts
- Bush babies, pig-tailed macaques and baboons: Membranous glomerulonephritis
- Cetacean: Membranous glomerulonephritis, membranoproliferative glomerulonephritis
- Dog: Glomerular lesions in Aotus NHPs are similar to those of membranoproliferative glomerulonephritis in dogs, associated with IgM or IgG; however, interstitial nephritis is not a component of canine disease; may result in renal failure
- Horse: Common and rarely associated with renal failure; proliferative or membranoproliferative; anti-glomerular basement membrane disease documented in the horse (only domestic animal)
- European captive cheetah: Glomerulonephritis in 91%, with predominance of membranous glomerulonephritis (77%)
- Mice: Membranoproliferative glomerulonephritis with deposition of immune complexes within basement membranes has been reported in some strains of mice (especially NZB x NZW hybrids)
- Owl monkeys: Malaria research may induce glomerulonephritis
- Sheep: Systemic infection by Erysipelothrix rhusiopathiae
- Diseases with immune complex mediated glomerulonephritis
- Cat: FeLV, FIP, FIV, neoplasia, GN (progressive membranous glomerulonephritis, nephrotic syndrome)
- Cattle: Bovine viral diarrhea, trypanosomiasis
- Dog: Infectious canine hepatitis, chronic hepatitis, chronic bacterial diseases, endometritis (pyometra), pyoderma, prostatitis, dirofilariasis, borreliosis, systemic lupus erythematous, polyarteritis, autoimmune hemolytic anemia, immune-mediated polyarthritis, hereditary c3 deficiency, neoplasia (mastocytoma)
- Horse: Equine infectious anemia (EIA), Streptococcus, herpesvirus infection
- Marmoset: Young animals; progressive glomerulonephropathy
- IgM deposition in GBM with or without basement membrane alteration; IgA and IgG also present in cases with basement membrane thickening (IgM presumed to be primary deposit early in disease process)
- Podocyte foot process effacement
- Pig: Hog cholera, African swine fever, PCV-2, spontaneous in Göttingen minipigs
- Red fox: Infectious canine hepatitis
- Sheep: Hereditary hypocomplementemia in Finnish Landrace lambs
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