JPC SYSTEMIC PATHOLOGY
SIGNALMENT (JPC #2182655): Tissue from a 35-day-old Finnish-Landrace cross lamb
HISTORY: Euthanized following a two-day episode of anorexia and depression
MICROSCOPIC DESCRIPTION: Kidney: Diffusely and globally, glomerular tufts are hypercellular and lobulated with increased mesangial cells and infiltration by variable numbers of neutrophils; glomerular capillary basement membranes are variably thickened by eosinophilic, homogenous material. Multifocally, glomeruli further exhibit one or more of the following changes: uriniferous spaces occasionally contain pale, eosinophilic, homogenous material (protein) and/or eosinophilic beaded fibrillar fibrin with cellular infiltration (crescent formation); and/or there is occasional hypertrophy and hyperplasia of the parietal and visceral layers of Bowman"s capsule. Multifocally, predominantly around glomeruli, the interstitium is expanded by small aggregates of many lymphocytes, fewer plasma cells, rare neutrophils, eosinophils, and variable amounts of fibrosis. Rarely, tubules are mildly ectatic and contain eosinophilic, homogenous material (proteinaceous fluid), hemorrhage, or sloughed cells and cellular and karyorrhectic debris (cellular casts). Multifocally, tubular epithelial cells exhibit one or more of the following changes: attenuation and flattening; hypereosinophilic epithelial cytoplasm with pyknotic nuclei (necrosis); microvacuolated epithelial cytoplasm with rare hyaline droplets (degeneration); slightly basophilic cytoplasm with vesiculate nuclei and occasional mitoses (regeneration). Multifocally, the perivascular interstitium is mildly expanded by increased clear space (edema).
MORPHOLOGIC DIAGNOSIS: Kidney: Glomerulonephritis, membranoproliferative (mesangiocapillary), neutrophilic, global, diffuse, moderate, with crescent formation and lymphoplasmacytic interstitial nephritis, Finnish-Landrace cross, ovine.
ETIOLOGIC DIAGNOSIS: Hereditary glomerulonephritis
- Recessive inherited deficiency of C3 that is lethal in Finnish Landrace and Finnish Landrace cross lambs less than 4 months of age; very low levels of C3
- Progressive disease that begins in utero with increasing subendothelial deposition of IgM, IgA, complement, and later IgG, leading to generalized immune complex disease
- Affected lambs absorb an as yet unknown colostral antigen > subendothelial deposition of immune complexes (IC) and complement in glomerular vessels > Type 1 membranoproliferative (mesangiocapillary) glomerulonephritis (MPGN)
- C3 deficiency may contribute to IC persistence through impaired solubilization of immune complexes, facilitating glomerular damage
- IC deposition stimulates endothelial cell swelling and proliferation and stimulates mesangial cell proliferation with release of IL-6 and TGF-beta
- IL-6 stimulates autocrine growth of mesangial cells
- TGF-beta stimulates production of the extracellular matrix
- Both mesangial and endothelial cell proliferation can lead to fibrosis
TYPICAL CLINICAL FINDINGS:
- Many lambs are apparently normal at birth and later found dead of renal failure
- Clinical signs develop any time from within hours of birth to 3 months of age
- Dullness, ataxia, fine tremors, colic, convulsions, tachycardia, conjunctival edema, nystagmus, circling are all reported in affected lambs
TYPICAL GROSS FINDINGS:
- Enlarged, pale kidneys with multiple, pinpoint, yellow and red foci (glomeruli) in the cortex
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Finnish Landrace lambs
- Mesangial proliferation, capillary wall thickening, crescent formation
- Severe vascular lesions of choroid plexuses and lateral ventricles in the brain due to IC deposition; leads to encephalopathy
- MPGN in general:
- Glomerular tufts are hypercellular (endocapillary and mesangial proliferation) with thickening of the glomerular basement membrane
- Neutrophilic infiltration and margination within glomerular capillaries
- +/- synechiae of Bowman’s capsule, glomerular basement membrane hyalinosis, afferent and efferent arteriolar hyalinosis, parietal cell proliferation, splitting of Bowman’s capsule, periglomerular fibrosis, deposition of fibrinogen and fibrinous thrombi in glomerular capillaries
- In severe cases, proliferation of parietal epithelium, an influx of monocytes, and deposition of fibrin can occur within Bowman’s capsule, resulting in the formation of a semicircular, hypercellular, intraglomerular lesion known as a glomerular crescent
- Subendothelial and mesangial electron-dense deposits of C3, IgM, IgA, and IgG
- Numerous neutrophils in the glomerular tuft
- Hypercellularity of mesangium
ADDITIONAL DIAGNOSTIC TESTS:
- Serum C3 is 5% of normal levels
- Serum biochemistry and urinalysis: uremia, proteinuria, hypoalbuminemia, hyperphosphatemia, hypocalcemia
- Lesions characteristic; clinical differential is renal amyloidosis
- Leading cause of renal failure; commonly membranoproliferative
- Causes include: Canine adenovirus-1 (Infectious canine hepatitis); Borrelia burgdorferi (Lyme nephritis); pyometra; leishmaniasis; Dirofilaria immitis; neoplasms; autoimmune disease; and canine familial renal disease
- Inherited deficiency of C3 in Brittany spaniels leads to development of MPGN
- Common in the cat; major cause of renal disease and nephrotic syndrome; predominantly membranous but MPGN also occurs; may be mistaken for primary segmental glomerulosclerosis so findings should be interpreted with caution in the absence of TEM and IF
- Causes include: FLV; FIP; feline progressive polyarthritis; autoimmune diseases; hematopoietic tumors
- 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) (MPGN); Streptococcus equi (and purpura hemorrhagica); herpes virus infections
- ICs may appear atypical (fibrillar to crystalline) on TEM, similar to immunotactoid glomerulonephritis in humans
- Occurrence is sporadic and has little economic or clinical significance; lesions are membranoproliferative
- Causes include: PDNS (PCV-2) (proliferative with crescent formation), Classical Swine Fever (pestivirus) and African swine fever
- Reported hereditary factor H deficiency caused lethal Type II MPGN (dense deposit disease) in Norwegian Yorkshire pigs
- Evidence of glomerulonephritis is common but clinical disease is not
- Nephrotic syndrome in cattle is usually caused by amyloidosis
- Glomerular immune complexes most commonly derive from organisms involved in purulent metritis, from BVDV infection or infections with Trypanosoma congolense or Fasciola hepatica
- 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
- Mice: Membranoproliferative glomerulonephritis with deposition of immune complexes within basement membranes has been reported in some strains of mice (especially NZB x NZW hybrids)
- Angus KW. Nephropathy in young lambs. Vet Rec. 1990;126(21):525-528.
- Angus KW, Gardiner AC. Mesangiocapillary glomerulonephritis in Dorset-Finnish landrace cross lambs. Vet Rec. 1979;105(20):471.
- Angus KW, Gardiner AC, Mitchell B, Thomson D. Mesangiocapillary glomerulonephritis in lambs: the ultrastructure and immunopathology of diffuse glomerulonephritis in newly born Finnish landrace lambs. J Pathol. 1980;131(1):65-74.
- Breshears MA, Confer AW. Urinary system. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:644-653.
- Cianciolo RE, Mohr FC. Urinary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol. 2. 6th ed. Philadelphia, PA: Elsevier; 2016:401-417.
- Cianciolo RE, Mohr FC, Aresu L, et al. World Small Animal Veterinary Association renal pathology initiative: Classification of glomerular diseases in dogs. Vet Pathol. 2016 Jan;53(1):113-135.
- Constable PD, Hinchcliff KW, Done SH, Gruenberg W. Diseases of the Kidney. In: Veterinary Medicine, A Textbook of the Diseases of Cattle, Horses, Sheep, Pigs, and Goats. 11th ed. New York, NY: Elsevier; 2017: 1110-1111.
- Gonzales-Viera O, Ruoppolo V, Marigo J, et al. Renal lesions in cetaceans from Brazil. J Comp Pathol. 2015 May;152(4):345-354.
- Tizard IR. Veterinary Immunology: An Introduction. 8th ed. Philadelphia, PA: Elsevier; 2009:361-364.
- Trang NT, Hirai T, Nabeta R, et al. Membranoproliferative glomerulonephritis in a calf with nephrotic syndrome. J Comp Pathol. 2014 Aug-Oct;151(2-3):162-165.