JPC SYSTEMIC PATHOLOGY
URINARY SYSTEM
December 2023
U-M16 (NP)
SIGNALMENT (JPC 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 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
GENERAL DISCUSSION:
- 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
- NOTE: Not all references agree in this distinction with some stating that proliferative GN is merely a variant of membranoproliferative GN
PATHOGENESIS:
- General pathogenesis for immune-mediated glomerulonephritis (ICGN):
- Most cases of GN are immune-mediated and may be primary (idiopathic) or secondary to other diseases or conditions
- Any infection of low pathogenicity that can produce persistent antigenemia has to potential to cause IC disease
- 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 in dogs
- 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
- Leads to increased glomerular permeability, and protein leakage and proteinuria develops, which may result in lead to the nephrotic syndrome
- With fibrin exudation, monocytes infiltrate, parietal epithelial cells proliferate, and crescents are formed
- May progress to renal failure with only 30-50% of normal GFR
- Most cases of GN are immune-mediated and may be primary (idiopathic) or secondary to other diseases or conditions
- Proliferative glomerulonephritis:
- Hypercellularity of glomerular tufts (see Light Microscopic Findings) can be due to infiltrate of inflammatory cells or hypertrophy or hyperplasia of native glomerular cells in situ (i.e., endothelial and mesangial cells); mesangial cells may also migrate out into the capillary loop
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:
- Proteinuria
- Hypoalbuminemia
- Generalized edema
- Hypercholesterolemia
TYPICAL GROSS FINDINGS:
- Kidneys may appear nearly normal, swollen, or shrunken and firm with irregular pitted capsular surface in chronic stages; the capsular surface may have a generalized fine granularity
- On cut surface, the cortex may be somewhat shrunken; glomeruli can appear as red foci of punctate petechiae (acute or normal in the horse) or as pinpoint pale grey foci (more chronic)
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Glomerular tuft hypercellularity: Global diffuse endocapillary and mesangial hypercellularity due to proliferation of endothelial, epithelial, and/or mesangial cells, +/- double contours of GBM (best seen with JMS and PAS)
- Mesangial cells in dog glomeruli usually occur singly or in pairs, thus >3 mesangial cells in proximity support mesangial cell hyperplasia; mesangial cell number in other species may vary
- Proliferation of endothelial versus mesangial cells may be difficult to distinguish on standard H&E sections
- Acute: Exudative inflammation; hyperemic, swollen glomerular tufts; filling of Bowman’s space with leukocytes, protein, and erythrocytes; hyaline 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: 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
ULTRASTRUCTURAL FINDINGS:
- Deposited immune complexes may be subendothelial, intramembranous, or subepithelial and appear as electron dense bodies (<25 nm)
- In horses with proliferative glomerulonephritis, there may be atypical immune complexes which can vary from fibrillar to crystalline and rhomboid
- Fusion of visceral epithelial podocyte processes and intramesangial hypercellularity
ADDITIONAL DIAGNOSTIC TESTS:
- Diagnosis of ICGN can be made by immunofluorescent (IF) or immunohistochemical (IHC) demonstration of Ig and complement components, usually C3, in glomerular tufts
- Hypercellularity that is limited to the mesangium can often be easily distinguished using PAS or trichrome stains on thin (3 μm) sections
- Blood work/urinalysis
- Blood smear may reveal poikilocytes (abornal erythrocyte shape) including acanthocytes, keratocytes, and schizocytes; Chemistry: See above (nephrotic syndrome)
- Urine Protein: Creatine ratio (UP:C): UP:C will be elevated, with large elevations (e.g., >5.0) suggestive of glomerular proteinuria
COMPARATIVE PATHOLOGY:
- Dogs
- ICGN occurs most commonly in dogs and cats and is the most common glomerular disease in dogs, accounting for 48% of glomerular diseases in one study; commonly membranoproliferative with IgG or IgM
- 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, bull terriers, Dalmatians, and Doberman pinschers; ICGN is much less common in other breeds
- Proliferative and sclerosing glomerulopathy has a genetic basis (the COL4A gene): English Cocker Spaniel (single nucleotide substitution COL4A4) and Samoyed (nonsense mutation in COL4A5)
- Cats
- 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
- Horse
- 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
- Pigs
- 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
- Ruminants
- Evidence of glomerulonephritis is common but clinical disease is not; BVDV antigens have been detected in GBM, but not yet proven to cause GN
- Avian: Immune-complex glomerulonephritis is not well documented in birds, but is reported (membranous as well as proliferative GN described)
- NHPs: GN most frequently associated with infectious agents that cause chronic antigen-antibody formation
- ZEW:
- Proliferative GN reported in a White-Faced Saki (Pithecia pithecia) (species of New World monkey) secondary to septicaemic listeriosis; other lesions included suppurative ventriculitis and periventricular encephalitis and meningitis as well as hepatitis (Struthers, J Comp Pathol. 2022)
- Proliferative GN reported in a red fox secondary to leptospirosis
REFERENCES:
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- 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.
- 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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- Schmidt R, Reavill DR, Phalen DN. Urinary System. In: Pathology of Pet and Aviary Birds. 2nd ed. Ames, IA: John Wiley & Sons, Inc.; 2015:127-144.
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- Struthers JD, Kucerova Z, et al K. Septicaemic Listeriosis in a White-Faced Saki (Pithecia pithecia). J Comp Pathol. 2022;194:7-13.
- Sula MM, Lane LV. The Urinary System. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:725-727.
- Terio KA, McAloose D, et al. Felidae. In: Terio KA, et at. Pathology of Wildlife and Zoo Animals. San Diego, CA: Elsevier; 2018: 266.
- Wong, A, Cianciolo RE. Comparison of immunohistochemistry and immunofluorescence techniques using anti-lambda light chain antibodies for identification of immune complex deposits in canine renal biopsies. J Vet Diag Invest. 2018; 30(5):721-727.