JPC SYSTEMIC PATHOLOGY

URINARY SYSTEM

December 2023

U-M06

 

Signalment (JPC #1741589): Dog of unknown age and gender.

 

HISTORY: This dog had proteinuria, hypoproteinemia, and had lost more than 2 grams of protein in the urine in a 24-hour period. 

 

HISTOPATHOLOGIC DESCRIPTION: Slide A (H&E): Kidney: Diffusely and globally, glomerular tufts are expanded by variable amounts of amorphous, extracellular, hyaline to finely fibrillar material (amyloid) that compresses capillaries and obscures glomerular architecture. Glomerular tufts are hypocellular with pyknosis and rare karyorrhectic debris (necrosis), and frequently fill Bowman’s space and adhere to Bowman’s capsule (synechia). Multifocally, tubular epithelium exhibits one or more of the following changes: swollen and vacuolated with vesiculate nuclei (degeneration); shrunken and hypereosinophilic with pyknotic nucleus (necrosis); increased basophilia, occasional mitoses, and irregularly spaced hyperchromatic nuclei (regeneration); or contain brown cytoplasmic globular pigment (hemosiderin/lipofuscin). Multifocally, tubules are ectatic, lined by attenuated epithelium, and contain abundant eosinophilic homogenous proteinaceous material (proteinosis) or tubular lumina contain necrotic cellular debris, deeply basophilic granular material (mineral), or round birefringent crystals with radiating lines (calcium carbonate). Multifocally within the interstitium, there are small amounts of amyloid, mild vascular congestion, minimal hemorrhage, and few lymphocytes and plasma cells.  

 

Slide B (Congo red): Diffusely, glomerular tufts are expanded by abundant congophilic material that displays bright green birefringence under polarized light (amyloid).

 

MORPHOLOGIC DIAGNOSIS: Kidney: Amyloidosis, glomerular, global, diffuse, severe with multifocal tubular epithelial degeneration, necrosis, and rare regeneration, breed unspecified, canine. 

 

CONDITION: Glomerular amyloidosis 

 

GENERAL DISCUSSION:  

• Diverse group of disorders with a common pathogenesis (protein misfolding) and morphologic appearance
• Characterized by the extracellular deposition of an insoluble fibrillar protein with a b-pleated sheet protein structure
• The kidney is the most commonly involved organ, with glomeruli the most common renal site of deposition
• Composed of 95% fibril proteins and 5% serum amyloid P & other glycoproteins
• Types of amyloidosis:

1. Immunoglobulin-derived amyloidosis (primary; AL) 

• Associated with a monoclonal B-cell proliferation (multiple myeloma, extramedullary plasmacytoma)
• Uncommon in animals; most common form in humans
• Can be either systemic or localized
• AL (amyloid light chain) 

• Composed of immunoglobulin light chains 
  1. Either λ (most common) or κ

1. Reactive systemic amyloidosis (secondary; AA)

• Most common form in domestic animals
• Related to chronic inflammation or infection
• AA (amyloid associated)

1. Derived from serum amyloid A (SAA) – an acute-phase lipoprotein produced in the liver in response to IL-1, IL-6 and TNF-α
2. SAA easily detectable in plasma during the acute phase of inflammation

1. Familial amyloidosis

• Can be systemic or localized (renal)
• AA amyloidosis in dogs & cats 

1. Apolipoprotein A-I (apoA-I) derived amyloidosis

• Affects the pulmonary vessels in old dogs

1. Islet amyloid polypeptide (IAPP) derived amyloidosis

• IAPP normally secreted by β cells of pancreas
• Deposition of amyloid in pancreas of cats, macaques, baboons, raccoons, and humans

1. Amyloid of aging

• Aβ amyloid - Derived from amyloid precursor protein (APP)
• Localized amyloidosis associated with some forms of canine neurodegenerative disease, senile plaques, and cerebral amyloid angiopathy (rare in animals)

1. Other causes of localized amyloidosis

• Amyloid-producing odontogenic tumor (APOT) of cat and dog

1. Amyloid of ameloblastic lineage (positive for ameloblastin, amelogenin, sheathlin, laminin)

• Some transmissible spongiform encephalopathies (e.g. chronic wasting disease) form amyloid plaques in brain in addition to intraneuronal vacuolation

 

PATHOGENESIS:

• Requires overproduction of a precursor protein along with either a defective degradation system or a protein that is resistant to degradation
• Systemic reactive (AA) amyloidosis:
  1. Chronic inflammation à macrophage activation à secrete IL-1 and IL-6 à stimulates hepatocytes to produce SAA à increased serum SAA concentrations à limited proteolysis à AA protein accumulation
• Immunoglobulin-derived amyloidosis:
  1. Unknown stimulus (possible carcinogen) à monoclonal B lymphocyte proliferation à plasma cells synthesize large amounts of immunoglobulin light chains that are resistant to complete degradation & prone to forming insoluble fibrils à limited proteolysis à AL protein accumulation
• Structural misfolding of precursor proteins into a cross-β-pleated sheets à deposition into tissues à disruption of normal function or pressure atrophy, degeneration, necrosis.  
• Glomerular amyloidosis: Long-standing glomerular amyloidosis > reduced renal vascular perfusion > ischemia and pressure atrophy of nephrons > tubular epithelial degeneration, necrosis and atrophy; interstitial fibrosis
• Medullary amyloidosis: amyloid deposition in medullary interstitium à compression of vessels à ischemia à papillary necrosis 
• Some studies indicating AA amyloidosis may be transmitted between animals and between species via seeding nucleation process (similar to prion diseases); studies involving cows, birds, cheetahs, mice, Japanese quail
• Linked to infection with Hepatozoon americanum and Ehrlichia canis in dogs and excess dietary vitamin A in cats
• Possible sequela of systemic amyloidosis: Chronic renal failure, nephrotic syndrome, thrombosis, hepatic failure, spontaneous hepatic hemorrhage & rupture, arthritis, diabetes mellitus

 

TYPICAL CLINICAL FINDINGS:

• Dependent on the magnitude of the deposits and organs affected 

• Kidney is the most common site of deposition in dogs and cats

• Vague clinical signs initially: Lethargy, anorexia, vomiting, weight loss, and polyuria/polydipsia
• Clinical pathology:

• Complete blood counts, serum biochemistry, and urinalysis suggestive of acute or chronic kidney disease 
• Nephrotic syndrome (proteinuria, hypoalbuminemia, generalized edema, and hypercholesterolemia); proteinuria may be severe and occur in the absence of nephrotic syndrome
• Dogs with amyloidosis usually have higher UP:UC ratios (>18) than with glomerulonephritis (5-15); [WNL<0.5)]
• Bence-Jones proteinuria with multiple myeloma

• Cattle: Chronic diarrhea, poor productivity, weight loss are common

 

TYPICAL GROSS FINDINGS: 

• Normal size to mildly enlarged, firm, diffusely pale, waxy kidney
• Capsule strips smoothly and cortex appears finely stippled
  • Numerous fine yellow spots (glomeruli) and gray translucent foci (dilated tubules)
• Cats:
  • Often are small, firm, with a pitted surface (similar to chronic interstitial nephritis)
  • Difference is due to amyloid deposition in the papilla & medulla instead of glomeruli
• Amyloid stains red-brown with iodine solution and turns purple when subsequently exposed to acetic acid/vinegar

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:  

• Amyloid is an acellular, finely fibrillar to waxy, pale eosinophilic (H&E), homogenous, extracellular material 
• Kidney:  

• H&E alone is unreliable due to similarity in microscopic appearance between amyloid and sclerotic collagen
• Deposits first occur in the mesangial area and in the subendothelial zone of glomerular capillaries and gradually cause glomerular enlargement
• Also can deposit in the tubular basement membrane, forming cuffs around tubules
• Other findings: Interstitial fibrosis and lymphoplasmacytic infiltration, tubular atrophy, tubular dilation, mineralization, intratubular oxalate crystals, glomerular atrophy, and glomerulosclerosis
• Amyloid is usually localized to glomeruli in dogs
  1. Medullary localization more common in Shar-pei dogs, cats, and sometimes cattle

• Amyloidosis secondary to chronic inflammation most commonly involves kidney, liver, spleen, lymph nodes, CNS, testicles, lungs, and adrenal and thyroid glands 

 

ULTRASTRUCTURAL FINDINGS:

• Characteristic non-branching 7-10 nm-diameter fibrils that form single to laterally aggregated bundles or interlocking mesh-like ribbons 
• Fibrils lack periodicity (collagen fibers have periodicity)

 

ADDITIONAL DIAGNOSTIC TESTS:  

• Congo red stain (8-10 µm thick sections): Amyloid stains peach or orange-red, with “apple green” birefringence in polarized light

1. Required for definitive diagnosis
2. Material may also be present in medullary interstitium or artery walls
3. Loss of congophilia after potassium permanganate treatment = AA amyloid
4. Retention of congophilia after potassium permanganate treatment = AL amyloid

• Thioflavin T (fluorescent stain): Brilliant yellow fluorescence

1. May be needed in cats as their amyloid may stain poorly with Congo red

• Masson’s Trichrome: Amyloid is pale blue to orange
• Jones Methenamine Silver (JMS):  Amyloid does not take up silver, but sclerotic collagen does 
• IHC
• Mass spectrometry was more sensitive than IHC and Congo red staining after potassium permanganate treatment for identification of AL amyloidosis (Kadota et al., Vet Pathol., 2020)

 

COMPARATIVE PATHOLOGY: 

Domestic Species:

• Dogs: 
  1. Common in older dogs; usually idiopathic
  2. Cyclic hematopoiesis of gray collies:
     • Systemic AA amyloidosis occurs due to cyclic increased acute phase protein production during periods of monocytosis
  3. Familial AA amyloidosis in Shar-pei dogs:
     • Autosomal recessive
     • Intermittent fever, swollen hock syndrome, and renal +/- hepatic amyloidosis
     • Medullary deposition predominates
• Cats:  
  1. Amyloid mainly in medulla & papilla with papillary necrosis; minimal glomerular involvement
  2. Grossly looks similar to chronic interstitial nephritis (shrunken, firm, pitted surface)
  3. Increased prevalence in cats on diets with excess vitamin A
  4. Islet amyloidosis
     • Beta cells produce islet amyloid polypeptide (IAPP) also referred to as amylin
     • IAPP-derived amyloid deposited within islets
     • Advanced stages lead to hypoinsulinemia
     • Familial AA Amyloidosis:
       • Abyssinians: Medullary & glomerular amyloid
       • Siamese & Oriental cats: Liver, kidney, other
         • Amyloid-producing odontogenic tumors have been reported in the facial skin in 3 cats

1. Localized AL amyloidosis in skin, upper respiratory system (nasal), conjunctiva
2. AA amyloid in eyes of horses with recurrent uveitis

• Cattle:  

1. Glomerular and medullary amyloidosis almost always secondary to chronic inflammation
   • Glomerular amyloidosis – can cause severe proteinuria
   • Medullary amyloidosis – common subclinical disease
   • ApoE is a signature protein of feline amyloidosis (Miyazaki, J Comp Pathol,  2020)
2. Cattle with mastitis, metritis, arthritis and pododermatitis have a high prevalence of systemic AA amyloidosis in response to inflammation

• Sheep and goats: Glomerular & medullary amyloidosis secondary to chronic inflammatory diseases
• Chickens, turkeys, and pigeons:  Common; mainly affects liver & spleen

1. Chickens - Amyloid arthropathy (associated with Enterococcus faecalis)

• Pigs: Rare

Wildlife and Zoo Animals:

• Birds: Common in waterfowl, secondary to conditions such as ulcerative pododermatitis (bumble foot) or mycobacteriosis; may be transmissible 
  1. Ducks, swans, geese (liver, spleen, kidney)
     1. Flamingos: Systemic AA (reactive) amyloidosis secondary to pododermatitis (or other chronic inflammatory conditions such as pneumonia and arthritis)
        • Common cause of death in captive birds
     2. Birds of prey: Systemic AA amyloidosis is a major cause of death in captive falcons in the Middle East
        • Gyrfalcons susceptible; saker falcons relatively resistant
  2. Amyloid can be found in most tissues except the brain

• Most common in kidneys, oral tissues, and spleen

• Black-footed cats: High prevalence of systemic AA amyloidosis 
  1. Renal medulla, glomeruli, spleen, and GI tract
  2. Develop amyloid-associated renal failure around 4 years of age 
  3. Not associated with chronic inflammation; may have genetic component
• Cheetahs: High prevalence of systemic AA amyloidosis 
  1. Renal medulla (as seen in domestic cats), less often in liver
  2. Associated with chronic inflammation, especially Helicobacter-associated gastritis
  3. β-amyloid deposits occasionally found in brain, with a subset having neurofibrillary tangles similar to those found in Alzheimer’s disease
• Captive hoofstock: Relatively common
  • Only systemic reactive (AA) amyloidosis has been reported in non-domestic bovids
• Northern Tree Shrews: AA-amyloidosis demonstrated in captive colony without predisposing factors identified. (Klein et al., Vet Pathol, 2022)
• Raccoons: Pancreatic islet amyloidosis is common in captive and free-ranging animals
• Grey Seal: Hepatic and renal amyloidosis is reported to be a possible sequela of chronic entanglement (Barnett 2022)
• Cetaceans: Amyloid expands vascular walls in multiple organs; corticomedullary area of kidneys; thyroid gland; palatal salivary gland
• California sea lions: Systemic AA amyloidosis  
  • Kidney (interstitium, glomeruli, and forms a band at the corticomedullary junction), thyroid gland, and vessels are most common sites

Laboratory Animals: Reported in most species

• Mice: 
  • Two types:

• Reactive systemic form (AA): Spleen, liver intestines, kidney
  1. CBA, B6, C3H/HE, BLAB/c, SWR
  2. A/J resistant
• Senile form: Apo AII
  1. A/J, SJL
     • IL-1 receptor antagonist knockout mice used as model to study AA amyloidogenesis
       • Amyloidosis associated with cardiac atrial thrombosis and left or right congestive heart failure

1. May be associated with Giardia spp. infection
2. Renal amyloidosis can lead to atrial thrombosis (secondary to AT III loss)

• Gerbil: Secondary to chronic renal disease; affects liver, spleen, lymph nodes
• Rabbit: Deposited in the renal interstitium
• NHP: Most common urogenital lesion reported to be amyloidosis (Kirejczyk et al., Vet Pathol, 2021)

1. Reactive secondary amyloidosis is prevalent in aged macaques, baboons, common marmosets

• Common sites include the spleen, lymph nodes, adrenal glands, kidney, liver, pancreatic islets and lamina propria or submucosa of the small intestine
• Often due to chronic enterocolitis (macaques) or other chronic inflammatory conditions including indwelling catheters & medical devices, TB, or retroperitoneal fibromatosis/SIV infection

1. Cerebral amyloid-β plaques described in macaques

 

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