JPC SYSTEMIC PATHOLOGY
SIGNALMENT (Accession #: 1951287): 10-year-old Suffolk ram
HISTORY: A 10-year-old Suffolk ram died after a two-day illness. At necropsy, both kidneys were swollen and had roughened surfaces.
HISTOPATHOLOGIC DESCRIPTION: (Slide A) Kidney: Diffusely affecting 100% of this section there is extensive glomerular loss, with the remaining glomeruli exhibiting one or more of the following changes: expansion of the glomerulus up to three times normal by an increase in mesangium characterized by abundant eosinophilic homogenous to fibrillar material; increased mesangial cellularity; vacuolation of the mesangium; hypersegmented glomerular tufts; parietal and visceral epithelial hyperplasia and hypertrophy; adhesions between glomerular tufts and Bowman’s capsule (synechiae); sclerosis or obsolescence of the glomerulus; thickening of Bowman’s capsule; and periglomerular fibrosis. In the cortex and medulla, there is extensive tubule loss, and remaining tubules exhibit one or more of the following changes: ectasia with an attenuated epithelium lining, filling of lumina with proteinaceous or cellular casts and rarely small amounts of mineral; degeneration with swollen vacuolated epithelial cells; necrosis with shrunken hypereosinophilic epithelium which are often sloughed; and regeneration with increased cytoplasmic basophilia, piling up of cells, and rare mitotic figures. Multifocally infiltrating the cortical and medullary interstitium are numerous lymphocytes, plasma cells, and fewer macrophages, admixed with variably dense and abundant fibrous connective tissue that separates and surrounds remaining tubules and glomeruli. Diffusely the capsule is thickened up to 60 microns by fibrosis.
(Slide B) Kidney (Periodic Acid Methenamine Silver, PAMS): Basement membranes of Bowman’s capsule and tubules are diffusely thickened up to 2-3 times normal. Frequently, glomerular capillary basement membranes are also thickened and densely packed.
MORPHOLOGIC DIAGNOSIS: Kidney: Glomerulonephritis, membranoproliferative, diffuse, severe with synechiae, tubular degeneration, necrosis, regeneration, and loss, protein and cellular casts, and multifocal chronic lymphoplasmacytic interstitial nephritis, Suffolk, ovine.
ETIOLOGIC DIAGNOSIS: Idiopathic glomerulonephritis
CAUSE: Etiologies may include idiopathic, viral, bacterial, parasitic or neoplastic conditions
- Two large categories of glomerular disease:
- Immune complex-mediated glomerulonephritis (ICGN) which includes membranoproliferative, membranous, and +/- proliferative depending on text
- Non-ICGN: e.g. glomerular amyloidosis or focal segmental glomerulosclerosis
- 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 (mesangiocapillary) GN: proliferation with remodeling of capillary loop from IC deposition, usually between endothelial cell and GBM
- Mesangioproliferative: increased cellularity in mesangium only with evidence of immune complex deposition in 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
- In sheep and goats histologically glomerulonephritis may be generalized and well developed, but the changes appear to have little clinical significance with few exceptions
- Causes include: Campylobacter fetus; pregnancy toxemia; hypocomplementemia in Finnish Landrace lambs (complement can solubilize ICs to facilitate their removal therefore hypocomplement can cause IC deposition)
- There are 2 mechanisms of antibody-associated glomerular injury
- Antibodies react in situ with the glomerulus, either with intrinsic glomerular antigens or those planted within glomerular membranes (demonstrated only in experimental animals)
- Deposition or trapping of soluble circulating antigen-antibody complexes in the glomerulus (common form in domestic animal); antibodies with no immunological specificity for the glomerulus
- 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
- Soluble antigen-antibody (Ag-Ab) complexes are formed in the presence of antigen-antibody equivalency or slight antigen excess in plasma, remain in the blood by escaping the normal physiologic destruction by the monocyte-macrophage system, and are deposited in the glomerular capillaries; IgM and IgG are most common
- Fc fragment of Ag-Ab complex binds C1 > activation of classical complement pathway > generation of C3a and C5a (anaphylatoxins), and C5-7 (chemotactic for neutrophils)> stimulation of mesangial cell proliferation
- Activated neutrophils attempt to ingest complexes (frustrated phagocytosis)> leakage of lysosomal enzymes (proteases)> formation of oxygen-free radicals > GBM damage
- Simultaneous complement induced degranulation of mast cells> release of vasoactive amines> increased capillary permeability > deposition of more immune complexes
- Hageman factor (Factor XII) connects complement, coagulation, and kinin-forming pathways leading to coagulation, thrombosis, and fibrinolysis
- Complement fixation also incites activation of glomerular epithelial and mesangial cells, causing them to release proteases and oxidases, which further damage glomerular capillary walls resulting in protein leakage
- With fibrin exudation, monocytes infiltrate, parietal epithelial cells proliferate and crescents are formed
- Once GFR has decreased to 30-50% of normal, end-stage renal failure tends to be unavoidable
TYPICAL CLINICAL FINDINGS:
- A common indicator of glomerular damage and increased glomerular permeability is persistent proteinuria in the absence of lower urinary tract infection or inflammation
- Animals may appear emaciated and may have generalized edema (nephrotic syndrome)
- Antithrombin III lost with proteinuria or protein-losing enteropathy > hypercoagulable state > thrombosis
- Marked proteinuria may lead to the development of the nephrotic syndrome:
- Generalized edema
TYPICAL GROSS FINDINGS:
- Extrarenal lesions include oral and gastric ulcers, gastric and pleural mineralization, and loss of bone mass, parathyroid hyperplasia (renal secondary hyperparathyroidism)
- Kidneys may appear nearly normal, swollen in the subacute stage, or shrunken and firm with irregular pitted capsular surface in chronic stages
- On cut surface, glomeruli occur as red foci of punctate petechiae when evaluated during an acute process (normal in the horse), or appear as granular yellowish white foci (sclerosis) after progression of the condition
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Global diffuse endocapillary and mesangial hypercellularity, +/- double contours of GBM (best seen with JMS and PAS)
- Acute phase: Exudative inflammation; hyperemic, swollen glomerular tufts; filling of Bowman’s space with leukocytes, protein, and erythrocytes; hyalin droplets in tubular epithelium; cellular and protein casts; interstitial edema
- Subacute: Mesangial hyperplasia or glomerular crescent formation; tubular epithelial cells containing hyaline droplets, or fatty degeneration; tubule epithelial necrosis; tubular casts
- Chronic phase: Fibrous scarring and loss of glomeruli; synechia; increase in mesangial matrix; tubular loss; ectasia of remaining tubules with epithelial hypertrophy and hyperplasia; interstitial fibrosis and lymphocyte infiltration
- Deposited immune complexes may be subendothelial (Type 1), intramembranous (Type II), and subepithelial (Type III may include both subepithelial and subendothelial) and appear as electron dense bodies
- Fusion of visceral epithelial podocyte processes
- Ultrastructure can be used to differentiate circulating immune-complex disease from anti-glomerular basement membrane deposits; deposition of circulating complexes occurs in a granular or lumpy-bumpy pattern, while deposition of anti-glomerular basement membrane antibodies occurs in a smooth linear pattern
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
- Leading cause of renal failure; commonly membranoproliferative with IgG or IgM most common
- Causes include: Canine adenovirus-1 (Infectious canine hepatitis); Borrelia burgdorferi (Lyme nephritis, U-B01); pyometra; leishmaniasis; Dirofilaria immitis; neoplasms; autoimmune disease; and canine familial renal disease
- Canine familial glomerulonephritides in Bernese Mountain dogs
- Common in the cat; major cause of renal disease and nephrotic syndrome; predominantly membranous
- Causes include: FIP; feline progressive polyarthritis; autoimmune diseases
- FeLV with hematopoietic tumors has been associated with proliferative GN
- Common and rarely associated with renal failure; proliferative or membranoproliferative; anti-glomerular basement membrane disease documented in the horse (only domestic animal)
- Causes include: Equine Infectious Anemia (lentivirus); Streptococcus equi; herpes virus infections
- Occurrence is sporadic and of little economic importance
- Proliferative GN can be a result of immune-mediated systemic necrotizing vasculitis in Porcine Dermatitis and Nephropathy Syndrome from PCV-2
- Hereditary deficiency of factor H causes lethal dense deposit disease (MPGN Type II)
- Other causes of MPGN: Classical Swine Fever (pestivirus) and African swine fever
- Spontaneous glomerulonephritis reported in Göttingen minipigs (nonrodent species used in safety studies); lesions range from membranous or membranoproliferative at different stages
- Evidence of glomerulonephritis is common but clinical disease is not; BVDV antigens have been detected in GBM, but not yet proven to cause GN
- Mink: Aleutian mink disease
- Occurs sporadically in clinically normal animals and in various poultry disease conditions; proliferative form is considered more common
- Causes include: inclusion body hepatitis (adenovirus), infectious bursal disease, infectious bronchitis, retroviruses, Mycoplasma synoviae, urolithasis, sodium chloride toxicity
- Nonhuman primates
- Most frequently associated with infectious agents that cause chronic antigen-antibody formation
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- Cline JM, Brignolo L, Ford EW. Urogenital system. In: Abee CR, Mansfield K, Tardiff S, Morris T, eds. Nonhuman Primates in Biomedical Research: Disease. Vol. 2. London, UK: Academic Press, 2012:489-491.
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- Slauson DO, Cooper BJ. Mechanisms of Disease, 3rd ed. St. Louis, MO: Mosby, 2002:274-281.
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- Wilson FD, Wills RW, Senties-Cue CG, Maslin WR, Stayer PA, Magee DL. High incidence of glomerulonephritis associated with inclusion body hepatitis in broiler chickens: routine histopathology and histomorphometric studies. Avian Dis. 2010;54(3):975-80.