JPC SYSTEMIC PATHOLOGY

URINARY SYSTEM

December 2023

U-M14

 

Signalment (JPC #81-978): Adult owl monkey (Aotus trivirgatus), gender unspecified

 

HISTORY: This owl monkey had been maintained in a research laboratory.

 

HISTOPATHOLOGIC DESCRIPTION:  

SLIDE A: Kidney: Diffusely there are changes at all levels of the nephron. Glomeruli often exhibit periglomerular fibrosis, Bowman’s capsule thickening and hyalinization, synechiae between the glomerular tuft and Bowman’s capsule; hypertrophy of the parietal and visceral epithelium; thickening of the glomerular basement membrane; mesangial matrix thickening and mesangial hypercellularity, homogeneous, brightly eosinophilic, proteinaceous fluid within the uriniferous space (proteinosis); and/or glomerulosclerosis (obsolescence). Multifocally infiltrating the renal interstitium, separating and surrounding tubules and glomeruli are abundant lymphocytes, plasma cells, and eosinophils with fewer fibroblasts. Multifocally within areas of inflammation, tubules are shrunken with attenuated epithelium and thickened basement membranes up to two times normal (atrophy) or are ectatic with homogeneous brightly eosinophilic intraluminal material (protein casts) or intraluminal sloughed epithelial cells and necrotic cellular debris (cellular and granular casts). Tubular epithelium has swollen borders with pale cytoplasm and a vesiculate nucleus (degeneration), are shrunken with hypereosinophilic cytoplasm and a pyknotic nucleus (necrosis), or have pluristratified cells with basophilic cytoplasm and a high nuclear to cytoplasmic ratio (regeneration).  Rarely, tubular epithelial cells contain intracytoplasmic golden-brown, granular pigment (bile or hemosiderin). Multifocally, the capsular surface is irregular and occasionally contracted. 

 

SLIDE B: Kidney: Periodic acid methenamine silver stain (PAMS stain): Multifocally, there is thickening and reduplication of glomerular basement membranes.

 

MORPHOLOGIC DIAGNOSIS: Kidney: Glomerulonephritis, membranoproliferative, chronic, diffuse, moderate, with lymphoplasmacytic and eosinophilic interstitial nephritis, interstitial fibrosis, tubular degeneration, atrophy, and regeneration, proteinosis, and glomerular obsolescence, owl monkey (Aotus trivirgatus), nonhuman primate. 

 

CONDITION: Glomerulonephritis (GN)

 

GENERAL DISCUSSION: 

• 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
• Terminology:  

• 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: Term 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 on abluminal surface. IC in GBM *subepithelial
• Membranoproliferative GN (mesangiocapillary): Proliferation with remodeling of capillary loop from IC deposition. IC in GBM *subendothelial (type I) or lamina densa (type II)

• 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; not all references agree in this distinction: some consider proliferative GN to be merely a variant of membranoproliferative GN
  • Segmental glomerulosclerosis: Segmental effacement of peripheral capillary loops
  • Global glomerulosclerosis (glomerular obsolescence): Tuft is shrunken, eosinophilic and hypocellular

• Descriptors of glomerular disease:
  • 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

 

PATHOGENESIS:

• Lesions are consistent with an immune-mediated, membranoproliferative glomerulonephritis
• Exact mechanism for Aotus NHP’s has not been elucidated
  • Proposed causes include malarial infections, filarial parasites, genetic predisposition, and other infectious causes 
  • Could result from accumulation 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 the potential to cause immune complex disease
  • Most cases of GN are immune-mediated (ICGN) and may be primary (idiopathic) or secondary to other diseases or conditions
• Immune complexes (IC) form when there is antigen-antibody equivalency or slight antigen excess à complexes selectively deposit in glomerular capillaries due to increased permeability of the glomerular basement membranes à activated platelets stimulate alternative pathway complement formation of C3a, C5a, and C567 à chemotactic for neutrophils à neutrophils release proteinases, oxidants, and arachidonic acid metabolites à basement membrane damage and membrane attack complex damage to glomerular cellsà Chemokines released from glomerular cells activates circulating leukocytes à leakage of protein into the glomerular filtrate; eventual monocyte infiltration in later stages of inflammation à continued damage to basement membrane by release of biologically active molecules à Complement paradoxically assists in IC removal
• Factors determining extent of deposition of immune complexes:
  • Persistence of immune complexes in circulation
  • Glomerular permeability
  • Size of immune complexes: 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)
• Proteinuria without urinary tract inflammation suggests glomerular damage
• Hypercoagulability due to increased acute phase proteins and loss of antithrombin III
• Increased urinary high molecular weight proteins; albumin and IgG
• GFR reduction to 30-50% of normal will progress to end-stage renal failure

 

TYPICAL GROSS FINDINGS:

• Acute glomerulonephritis: No gross changes
• Subacute glomerulonephritis: Kidneys are enlarged, pale tan cortex, normal colored medulla, smooth surface and non-adherent capsule
• Chronic glomerulonephritis: Kidneys are shrunken and contracted with fine granularity of capsular surface and streaky cut surface
• Ascites and peripheral edema (part of nephrotic syndrome)

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Differ markedly based on location of ICs, type of GN, and stage of disease
• Immunofluorescence (IF) studies reveal granular deposits of immunoglobulins and complement within affected glomeruli and occasionally surrounding tubules
• Acute phase: +/- Fibrin thrombi (esp. swine), variable tubular changes, hyaline, granular, or red blood cell casts. Proliferative and membranoproliferative GN; inflammatory influx. Membranous GN: No H&E glomerular changes
• Subacute phase: +/- Mesangial hypercellularity, GBM remodeling, segmental glomerulosclerosis, glomerular synechiae, tubulointerstitial scarring. Subendothelial (membranoproliferative) deposits: “double contour” of GBM. Subepithelial (membranous) deposits: “spike formation”
• Chronic phase: Glomerular obsolescence, interstitial fibrosis and lymphocytosis, tubular atrophy or dilation with epithelial hyperplasia

 

ULTRASTRUCTURAL FINDINGS:

• Deposits of electron-dense 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 anti-GBM ICGN requires IF, IHC, or EM demonstration of Ig in glomerular tufts

• The horse is the only domestic animal to have confirmed anti-GBM ICGN

• IF: Characteristic granular pattern along capillary loops with antibodies against IgG, lambda light chains, C3
• Histochemical stains: Jones Methenamine Silver (JMS) and PAS used to visualize GBM contours
• Unlikely to produce diagnostic cytology

 

DIFFERENTIAL DIAGNOSIS:

 

COMPARATIVE PATHOLOGY: Most cases of GN in animals are idiopathic

• Human: Anti-GBM glomerulonephritis; antibodies against intrinsic GBM antigens. Creates linear pattern of IF, humans only. Rat experimental model of this disease is called nephrotoxic nephritis
• Marmoset: Young animals; progressive glomerulonephropathy associated with 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), early podocyte foot process effacement (as part of marmoset wasting syndrome)
• Prosimians, pig-tailed macaques, and baboons: Membranous glomerulonephritis 
• Cetacean: Membranous glomerulonephritis, membranoproliferative glomerulonephritis
• Dog: Familial glomerulonephritides; Bernese autosomal recessive membranoproliferative GN with IgM and C3 deposits, Brittany spaniel C3 deficiency with membranoproliferative GN and immune deficiency
• Cat: Usually membranous GN
• Iberian lynx: Progressive membranous GN; IgM and IgG, suspect genetic
• Frogs: Membranous GN is common
• Horse: Membranoproliferative GN, rarely leads to renal failure; anti-GBM disease documented in one horse
• Swine: Sporadic, of minimal economic importance, porcine dermatitis and nephropathy syndrome is associated with porcine circovirus-2, hereditary factor H deficiency causes membranoproliferative GN type II in Norwegian Yorkshire pigs
• Sheep: Often get immunologic evidence of GN without clinical disease except Finnish Landrace sheep have recessive C3 deficiency and get membranoproliferative GN 
• Mice: Membranoproliferative GN with deposition of IC within GBM has been reported in some strains of mice (especially NZB x NZW hybrids), graft vs. host disease, aging change
• Diseases associated with immune complex mediated glomerulonephritis (2°)
  • Cat: FeLV, FIP, FIV, neoplasia
  • Cattle: Bovine viral diarrhea, trypanosomiasis
  • Dog: Canine adenovirus-1, chronic hepatitis, chronic bacterial diseases, endometritis (pyometra), pyoderma, prostatitis, dirofilariasis, borreliosis, leishmaniasis, systemic lupus erythematous (SLE), polyarteritis, autoimmune hemolytic anemia, immune-mediated polyarthritis, hereditary c3 deficiency, neoplasia (mastocytoma)
  • Horse: Equine infectious anemia (EIA), Streptococcus sp., herpesvirus infection
  • Pig: Classical swine fever, African swine fever, PCV-2 (PDNS), spontaneous in Göttingen minipigs
  • Psittacines: Avian polyomavirus IgY deposition in 70% of infected birds
  • Mink: Aleutian mink disease (parvovirus) get fatal glomerulonephritis
  • Red fox: Infectious canine hepatitis
  • NHPs: HIV crescentic glomerulonephritis, Squirrel monkeys: high incidence of GN, Owl monkeys: Malaria research may induce glomerulonephritis, GN also common in prosimians

 

References:

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